Lin, Wei-Yu, Fo rd h a m, S a r a h E., S u n t er, Nicola, Els tob, Clai r e , R a h m a n, Tha hi r a, Willmor e, Elaine, S h e p h e r d, Colin, S t r a t h d e e , Gor don, M ainou-Fowler, Tryfonia, Piddock, R ac h el, M e a r n s, H a n n a h, Ba r row, Timot hy, H o uls ton, Rich a r d S., M a rr, H ele n, Wallis, Jona t h a n P, S u m m e rfield, Geoffr ey, M a r s h all, Sco t t , Pe t ti t t , Andr ew, Pep p er, Ch ris top h er, Fe g a n, Ch ris top h er, Forco ni, F r a nc es co, Dyer, M a r tin J. S., Jayn e, S a n d rin e , S ello r s, April, Sc h u h, Anna, Rob b e, Pa uline, Oscier, David, Bailey, Jam es, R ais, Sye d, Be n tley, Alison, Ca wkw ell, Lynn, Eva ns, Pa ul, Hillm e n, Pe t er, P r a t t , Guy, Allsup, David J. a n d Allan, Ja m e s M. (20 21) Geno m e-wid e a s socia tion s t u dy ide n tifies r i sk loci for p ro g r e s sive c h ro nic lym p hocytic leuk e mia. N a t u r e Co m m u nica tions, 1 2 (1). p . 6 6 5. ISS N 2 0 4 1-1 7 2 3

Downloa d e d fro m: h t t p://su r e . s u n d e rl a n d. ac.uk/id/e p rin t /13 1 1 1/

U s a g e g u i d e l i n e s

Ple a s e r ef e r to t h e u s a g e g uid elines a t h t t p://su r e . s u n d e rl a n d. ac.uk/policies.h t ml o r al t e r n a tively con t ac t s u r e@s u n d e rl a n d. ac.uk.

Genome-wide association study identifies risk locifor progressive chronic lymphocytic leukemia

Wei-Yu Lin1, Sarah E. Fordham1, Nicola Sunter1, Claire Elstob1, Thahira Rahman1, ElaineWillmore1, Colin Shepherd1, Gordon Strathdee1, Tryfonia Mainou-Fowler1, Rachel Piddock1, Hannah

Mearns1, Timothy Barrow2, Richard S. Houlston3, Helen Marr4, Jonathan Wallis4, GeoffreySummerfield5, Scott Marshall6, Andrew Pettitt7, Christopher Pepper8, Christopher Fegan9, FrancescoForconi10, Martin J. S. Dyer11, Sandrine Jayne11, April Sellors11, Anna Schuh12, Pauline Robbe12,

David Oscier13, James Bailey14, Syed Rais14, Alison Bentley15, Lynn Cawkwell16, Paul Evans17, PeterHillmen18, Guy Pratt19, David J. Allsup14,15,*,+, James M. Allan1,*,+

1Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of MedicalSciences, Newcastle University, Newcastle upon Tyne, UK.

2Faculty of Health Sciences & Wellbeing, University of Sunderland, Sunderland, UK.3Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

4Department of Haematology, Freeman Hospital, Newcastle upon Tyne, UK.5Queen Elizabeth Hospital, Gateshead, UK.

6City Hospitals Sunderland NHS Trust, Sunderland, UK.7University of Liverpool, Liverpool UK.

8Brighton and Sussex Medical School, University of Sussex, Brighton, UK.9Institute of Cancer and Genetics, School of Medicine, Cardiff, UK.

10Cancer Sciences Unit, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Universityof Southampton, Southampton, United Kingdom.

11The Ernest and Helen Scott Haematological Research Institute, Leicester Cancer Research Centre,University of Leicester, Leicester, UK.12University of Oxford, Oxford, UK.

13Royal Bournemouth Hospital, Bournemouth, UK.14Hull University Teaching Hospital NHS Trust, Hull, UK.

15Hull York Medical School, Hull, UK.16University of Hull, Hull, UK.

17Haematological Malignancy Diagnostic Service Laboratory, St James’s Institute of Oncology, Leeds, UK.18Section of Experimental Haematology, Leeds Institute of Medical Research at St James’s, University of

Leeds, Leeds, UK.19University of Birmingham, Birmingham, UK.

*Joint contribution.+Corresponding author: James M. Allan. Email: james.allan@newcastle.ac.uk. Telephone: +44 (0) 191

208 4435, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UnitedKingdom, NE2 4HH; David Allsup. Email hycda1@hyms.ac.uk. Telephone +44(0) 1482 461294, Hull York

Medical School, University of Hull, Hull United Kingdom, HU6 7RX.

List of Figures

1 Kaplan-Meier plot of time to first treatment for CLL patients stratified by Binet stageof disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2 Kaplan-Meier plot of time to first treatment for CLL patients stratified by IGHV status 23 Kaplan-Meier plot of time to first treatment for CLL patients stratified by CD38 status 34 Kaplan-Meier plot of time to first treatment for CLL patients stratified by β2 Mi-

croglobulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Kaplan-Meier plot of time to first treatment for CLL patients stratified by TP53 status 56 GWAS QC and analysis flowchart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Principal component analysis plot of ethnicity structure in CLL GWAS and 1000

genomes population panels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Sanger validation genotyping for rs736456 and rs3778076 . . . . . . . . . . . . . . . . 89 Quantile-Quantile plot of fixed-effect meta-analysis for time to first treatment . . . . 910 Regional association plots for association analysis conditioning on the top variant . . 1011 Associations between post-treatment survival and risk variants for progressive CLL . 1112 Time to first treatment for CLL patients stratified by Binet stage of disease and SNP

genotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213 Time to first treatment for CLL patients stratified by IGHV status and SNP genotypes 1314 Time to first treatment for CLL patients stratified by CD38 status and SNP genotypes 1415 Time to first treatment for CLL patients stratified by β2 Microglobulin and SNP

genotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1516 Time to first treatment for CLL patients stratified by TP53 status and SNP genotypes 1617 Survival curves in low-risk CLLs by rs736456 (a) rs3778076 (b) and risk allele groups

of rs736456 and rs3778076 (c) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818 Regional association plot of TTFT for known CLL etiological risk variant rs34676223 1919 Regional association plot of TTFT for known CLL etiological risk variant rs41271473 2020 Regional association plot of TTFT for known CLL etiological risk variant rs3770745 . 2121 Regional association plot of TTFT for known CLL etiological risk variant rs13401811 2222 Regional association plot of TTFT for known CLL etiological risk variant rs17483466 2323 Regional association plot of TTFT for known CLL etiological risk variant rs9308731 . 2424 Regional association plot of TTFT for known CLL etiological risk variant rs3769825 . 2525 Regional association plot of TTFT for known CLL etiological risk variant rs13397985 2626 Regional association plot of TTFT for known CLL etiological risk variant rs757978 . . 2727 Regional association plot of TTFT for known CLL etiological risk variant rs9880772 . 2828 Regional association plot of TTFT for known CLL etiological risk variant rs1274963 . 2929 Regional association plot of TTFT for known CLL etiological risk variant rs10936599 3030 Regional association plot of TTFT for known CLL etiological risk variant rs10028805 3131 Regional association plot of TTFT for known CLL etiological risk variant rs898518 . . 3232 Regional association plot of TTFT for known CLL etiological risk variant rs57214277 3333 Regional association plot of TTFT for known CLL etiological risk variant rs31490 . . 3434 Regional association plot of TTFT for known CLL etiological risk variant rs872071 . . 3535 Regional association plot of TTFT for known CLL etiological risk variant rs73718779 3636 Regional association plot of TTFT for known CLL etiological risk variant rs674313 . . 3737 Regional association plot of TTFT for known CLL etiological risk variant rs210142 . . 3838 Regional association plot of TTFT for known CLL etiological risk variant rs3800461 . 3939 Regional association plot of TTFT for known CLL etiological risk variant rs2236256 . 4040 Regional association plot of TTFT for known CLL etiological risk variant rs17246404 4141 Regional association plot of TTFT for known CLL etiological risk variant rs2456449 . 4242 Regional association plot of TTFT for known CLL etiological risk variant rs1679013 . 4343 Regional association plot of TTFT for known CLL etiological risk variant rs4406737 . 4444 Regional association plot of TTFT for known CLL etiological risk variant rs61904987 45

I

45 Regional association plot of TTFT for known CLL etiological risk variant rs735665 . . 4646 Regional association plot of TTFT for known CLL etiological risk variant rs10735079 4747 Regional association plot of TTFT for known CLL etiological risk variant rs8024033 . 4848 Regional association plot of TTFT for known CLL etiological risk variant rs7169431 . 4949 Regional association plot of TTFT for known CLL etiological risk variant rs7176508 . 5050 Regional association plot of TTFT for known CLL etiological risk variant rs783540 . . 5151 Regional association plot of TTFT for known CLL etiological risk variant rs391525 . . 5252 Regional association plot of TTFT for known CLL etiological risk variant rs305065 . . 5353 Regional association plot of TTFT for known CLL etiological risk variant rs305061 . . 5454 Regional association plot of TTFT for known CLL etiological risk variant rs1036935 . 5555 Regional association plot of TTFT for known CLL etiological risk variant rs4368253 . 5656 Regional association plot of TTFT for known CLL etiological risk variant rs4987855 . 5757 Regional association plot of TTFT for known CLL etiological risk variant rs7254272 . 5858 Regional association plot of TTFT for known CLL etiological risk variant rs11083846 5959 Regional association plot of TTFT for known CLL etiological risk variant rs140522 . . 6060 Regional and forest plots of rs4752676 . . . . . . . . . . . . . . . . . . . . . . . . . . . 6161 Regional and forest plots of rs736457 . . . . . . . . . . . . . . . . . . . . . . . . . . . 6262 Regional and forest plots of rs11757517 . . . . . . . . . . . . . . . . . . . . . . . . . . 63

List of Tables

1 Demographic and clinical characteristics of chronic lymphocytic leukemia (CLL) cases 642 eQTL results for rs736456 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653 eQTL results for rs3778076 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664 eQTL results for rs3800461 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

II

Supplementary Figures

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++ ++++++ +++++

+++ + ++ ++ +

+++

+++

++

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y+ + +Binet A Binet B Binet C

664 175 28 5 078 5 1 0 077 2 1 0 0---0 10 20 30 40

Time in years

Number of patients at risk

Supplementary Figure 1: Kaplan-Meier plot showing time to first treatment (TTFT) forCLL patients stratified by Binet stage of disease. TTFT is defined as the time from diagnosisof CLL to treatment or last follow-up without treatment. Patients censored at last follow-up areindicated by a cross. The number of patients in each group at each timepoint are indicated in thetable.

1

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++ ++ ++++++ +++

++++++++++++++

++++++++++++++++++++

+ + ++0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

+ +Mutated Unmutated

382 132 23 5 0

175 10 2 0 0--0 10 20 30 40

Time in years

Number of patients at risk

Supplementary Figure 2: Kaplan-Meier plot showing time to first treatment (TTFT) forCLL patients stratified by IGHV status. TTFT is defined as the time from diagnosis of CLLto treatment or last follow-up without treatment. Patients censored at last follow-up are indicated bya cross. The number of patients in each group at each timepoint are indicated in the table.

2

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++ ++++++ ++

++++++

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++

+0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

+ +CD38 negative CD38 positive

480 132 27 4 0

234 23 2 0 0--0 10 20 30 40

Time in years

Number of patients at risk

Supplementary Figure 3: Kaplan-Meier plot showing time to first treatment (TTFT) forCLL patients stratified by CD38 status. TTFT is defined as the time from diagnosis of CLL totreatment or last follow-up without treatment. Patients censored at last follow-up are indicated by across. The number of patients in each group at each timepoint are indicated in the table.

3

+++++ + ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++++++++++++++++ +

++++ +++ ++

+

+ ++++++++++++++++++

++++ + ++++++ + + ++

+

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20Time in years

Surv

ival p

roba

bilit

y

+ +≤ 3.5mg/L >3.5mg/L

198 109 42 9 2

91 34 10 3 1--0 5 10 15 20

Time in years

Number of patients at risk

Supplementary Figure 4: Kaplan-Meier plot showing time to first treatment (TTFT) forCLL patients stratified by β2 Microglobulin. TTFT is defined as the time from diagnosisof CLL to treatment or last follow-up without treatment. Patients censored at last follow-up areindicated by a cross. The number of patients in each group at each timepoint are indicated in thetable. High serum β2 microglobulin is defined as > 3.5 mg/L.

4

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++ ++ ++++++ ++

++

++

++ +

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

+ +Normal Abnormal

390 77 21 4 0

40 2 0 0 0--0 10 20 30 40

Time in years

Number of patients at risk

Supplementary Figure 5: Kaplan-Meier plot showing time to first treatment (TTFT) forCLL patients stratified by TP53 status. TTFT is defined as the time from diagnosis of CLL totreatment or last follow-up without treatment. Patients censored at last follow-up are indicated by across. The number of patients in each group at each timepoint are indicated in the table. Abnormalis defined as a 17p deletion by FISH or a TP53 mutation by Sanger sequencing. It should be notedthat TP53 status is not routinely determined in patients with early stage CLL. As such, the cohorttested for TP53 has an over-representation of patients with progressive CLL.

5

922269

InfiniumOmniExpressExome(8v1-3; N=958497)

HumanOmniExpressExome(8v1-2; N=964193)

HumanOmniExpressExome

(8v1; N=951117)

GWAS 3N=160

GWAS 2N=132

GWAS 1N=216

GWAS 4N=139

GWAS 5N=67

GWAS 6N=170

Genotypingarrays

HWE(P ≤ 10−3)

SNP call rate(CR ≤ 95%)

Batch effect(P ≤ 10−3)

Study Level

Population StratificationPCA (1000 genome)

Heterozygosity(mean±3 × SD)

Call Rate(CR ≤ 95%)

RelatednessIBD (π̂ ≥ 0.1875)

Sample QC

No. samples excludedGWAS 1: 62GWAS 2: 6GWAS 3: 8GWAS 4: 10GWAS 5: 10GWAS 6: 14

MAF(≤ 1%)

Call Rate(CR ≤ 95%)

HWE(P ≤ 10−5)

Marker QC

ImputationHaplotype Reference Consortium

(SHAPEIT & IMPUTE2 )

No.SNPsremained :

504370

Cox proportional hazard models (by study)

GWAS 3N=152

GWAS 2N=126

GWAS 1N=154

GWAS 4N=129

GWAS 5N=57

GWAS 6N=156

Survival analysis Imputation info scores> 0.9MAF> 2.5%

Meta-analysis (fixed and random effects models)GWAS hits

(fixed effect P ≤ 5 × 10−8)

Study 7 (N=87)pooled analysis

Sanger Sequencing

rs736456 rs3778076

1

Supplementary Figure 6: Details of quality control filters applied to each CLL GWAS and dataanalysis workflow. SNPs with a call rate < 95%, significant heterogeneity between studies (batch effectP ≤ 10−3) or showing significant deviation from Hardy-Weinberg equilibrium (P ≤ 10−3) were excluded. Sampleswere excluded due to low call rate (< 95%), ancestry (principle components analysis), relatedness (π ≥ 0.1875)or heterozygosity (mean ±3× SD). Imputed SNPs with information score < 0.9 and MAF < 0.025 were excluded.For each study, allelic dosage was estimated for the minor allele at each variant position and included in acox proportional hazard model to estimate hazard ratio (HR) and 95% confidence interval (CI). Study-specificsingle nucleotide polymorphism (SNP) effects were combined using an inverse-variance-weighted method (fixedeffects model) and the DerSimonian-Laird approach (random effects model). SNPs with fixed-effect P values of≤ 5 × 10−8 were deemed significant at genome-wide level.

6

−0.01 0.00 0.01 0.02 0.03

−0.

04−

0.03

−0.

02−

0.01

0.00

0.01

PC 1

PC

2

●

●

●

GWAS 1GWAS 2GWAS 3GWAS 4GWAS 5GWAS 6EUREASAFR

CLL cases of European ancestry (N=871) & 1000G EUR

●

●

●

●

●

GBRFINIBSCEUTSI

Supplementary Figure 7: Principal component analysis (PCA) plot of ethnicity structurein CLL GWAS and 1000 genomes population panels. The first two principal components ofthe analysis are plotted for CLL cases recruited to this study (crosses). 1000 genomes European(EUR), East Asian (EAS) and African (AFR) individuals (open circles) are plotted in brown, pinkand gray, respectively. CLL cases of European ancestry included in subsequent analysis (top-leftcorner) are shown in the inset together with 1000G EUR sub-populations (closed circles) comprisingCEU (Utah Residents (CEPH) with Northern and Western European Ancestry; pink), GBR (Britishin England and Scotland; dark green), FIN (Finnish in Finland; orange), IBS (Iberian Population inSpain; blue), and TSI (Toscani in Italia; light green). PC1, principal component 1; PC2, principalcomponent 2.

7

a

rs Identifier Primer sequences PCR conditions

rs736456F 5’ CTGTTTGAGGCAGGCTTCTC 3’ 25 µL reactions included: 9 µL H2O, 12.5 µL Dream-

Taq Green PCR Master Mix (2X), 1.25 µL of eachforward and reverse primers (10 µM) and 50 ng DNA(1 µL).Cycling conditions: 2 minutes at 95 ◦C followed by35 cycles (25 seconds at 95 ◦C, 35 seconds at 60 ◦Cand 45 seconds at 72 ◦C). Final step of 5 minutes at72 ◦C with 4 ◦C hold.

R 5’ GAGCCCTTCCCTGAAAACCTC 3’

rs3778076F 5’ CTACTTTCCCCGATGCCTGG 3’

R 5’ ATGTCCTGGGGTTTCAGTGC 3’

1

b

A.

rs

IdentifierPrimer sequences PCR conditions

rs736456

F 5’ CTGTTTGAGGCAGGCTTCTC 3’

R 5’ GAGCCCTTCCCTGAAAACCTC 3’

25 μL reactions included: 9μL H2O, 12.5 μL DreamTaq

Green PCR Master Mix (2X), 1.25 μL of each forward

and reverse primers (10μM) and 5 DNA.

Cycling conditions: 2 minutes at 95˚C followed by 35

cycles (25 seconds at 95˚C, 35 seconds at 60˚C and 45

seconds at 72˚C). Final step of 5 minutes at 72˚C with

4˚C hold.

rs3778076

F 5’ CTACTTTCCCCGATGCCTGG 3’

R 5’ ATGTCCTGGGGTTTCAGTGC 3’

B.

C.

c

rs Identifier Region Successful reads Concordance

rs736456 10q26.13 89/100 89/89 (100%)rs3778076 6p 96/100 96/96 (100%)

2

Supplementary Figure 8: Sanger validation genotyping for rs736456 and rs3778076. Primersequences and PCR conditions for validation of rs736456 and rs3778076 (a). Representative genotyperesults for rs736456 and rs3778076 (b). Concordance between GWAS genotyping and Sanger validationgenotyping for rs736456 and rs3778076 (c).

8

Supplementary Figure 9: Quantile-Quantile plot of fixed-effect meta-analysis for time tofirst treatment (TTFT). For each study, allelic dosage was estimated for the minor allele at eachvariant position and included in a cox proportional hazard model to estimate hazard ratio (HR) and95% confidence interval (CI). Variants were included in the meta-analysis if they had results from allsix studies. Study-specific single nucleotide polymorphism (SNP) effects were combined in a fixedeffect model using an inverse-variance-weighted method. Expected (under the null hypothesis ofno association) and observed distributions of -log10(P ) values are shown on the x-axis and y-axis,respectively. The red line corresponds to y = x. Inflation lambda (λGC= 1.027) is the observedmedian χ2 test statistic divided by the median expected χ2 test statistic under the null hypothesis.

9

aTTFT_DX_RX_Status results conditional on rs736456

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rs144931779

0.2

0.4

0.6

0.8

r2

TACC2 BTBD16 PLEKHA1

MIR3941

ARMS2

HTRA1

123.8 123.9 124 124.1 124.2Position on chr10 (Mb)

bTTFT_DX_RX_Status results conditional on rs3778076

0

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P)

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rs3889226

0.2

0.4

0.6

0.8

r2

NUDT3

RPS10−NUDT3

RPS10 PACSIN1

SPDEF

C6orf106

LOC101929243

SNRPC

UHRF1BP1

34.3 34.4 34.5 34.6 34.7Position on chr6 (Mb)

Supplementary Figure 10: Regional association and linkage disequilibrium plots for associationanalysis conditioning on the top variant at each susceptibility locus for progressive CLL.Regional association plots of time to first time treatment (TTFT) survival associations for the chromosome10 (a) and chromosome 6 (b) loci conditioning on rs736456 and rs3778076, respectively. For each study,Cox proportional hazard models were used to estimate the conditional results for each variant at the regionby including the top variant. The resulting effect sizes were combined using an inverse-variance-weightedapproach. All statistical tests were two-sided. SNP coordinates based on genomic build b37/hg19 areshown on the x-axis and -log10 (P values) on the y-axis. Genotyped and imputed SNPs are represented bydiamonds and circles, respectively. SNPs are coloured according to their linkage disequilibrium (pairwiser2) with the lead SNP (annotated) based on the 1000 Genomes European panel. Reference genes in theregion are shown in the lower panel, with arrows indicating transcript direction, dense blocks representingexons and horizontal lines representing introns.

10

a

Fixed−effect (P=8.01×10−1)

0.5 1 2 3

rs736456,10:124012547 (Phet=0.589; I 2=0%)

GWAS 6

GWAS 5

GWAS 4

GWAS 3

GWAS 2

GWAS 1

105/46

28/24

68/27

89/57

34/20

66/57

G/A

G/A

G/A

G/A

G/A

G/A

0.12

0.25

0.15

0.19

0.16

0.14

17.25% 1.06 [0.56, 2.01]

13.03% 0.81 [0.39, 1.70]

8.61% 0.58 [0.24, 1.44]

29.74% 1.19 [0.73, 1.94]

6.79% 0.69 [0.25, 1.91]

24.57% 1.33 [0.78, 2.27]

100.00% 1.03 [0.79, 1.35]1.03 [0.79, 1.35]Random−effect (P=8.01×10−1)

Study No/events Eff/Ref EAF Weight(%) HR [95% CI]

b

Fixed−effect (P=9.77×10−1)

0.5 1 2 3

rs3778076,6:34513266 (Phet=0.584; I 2=0%)

GWAS 6

GWAS 5

GWAS 4

GWAS 3

GWAS 2

GWAS 1

105/46

28/24

68/27

89/57

34/20

66/57

A/C

A/C

A/C

A/C

A/C

A/C

0.081

0.107

0.103

0.085

0.088

0.098

19.03% 0.82 [0.37, 1.86]

11.01% 0.99 [0.34, 2.89]

8.40% 0.64 [0.19, 2.19]

27.26% 1.72 [0.87, 3.40]

7.31% 0.89 [0.24, 3.31]

27.00% 0.77 [0.39, 1.53]

100.00% 0.99 [0.70, 1.42]0.99 [0.70, 1.42]Random−effect (P=9.77×10−1)

Study No/events Eff/Ref EAF Weight(%) HR [95% CI]

Supplementary Figure 11: Forest plots showing associations between post-treatment sur-vival and risk variants for progressive CLL. Forest plots for rs736456 (a) and rs3778076 (b)and their age-adjusted association with post-treatment survival stratified by GWAS. Post-treatmentsurvival is defined as the time from first treatment for CLL-related symptoms to death or lastfollow-up. No/events: Number of CLL patients/Number of patients receiving treatment; Eff/Ref:effect/reference allele; EAF: effect allele frequency; HR: hazard ratio; CI: confidence interval; Squaresdenote the per-allele HR, with size proportional to the weight of the study. Pooled HRs derived fromboth the fixed and random-effects models are indicated by diamonds with their corresponding metaP values shown in the left parentheses. X-axis label formats include reference sequence (rs) identifierand chromosome:position (b37). P values for Cochran’s Q test (Phet) and I2 for heterogeneity areshown in parentheses. All statistical tests were two-sided.

11

a

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++ ++++ + +

+++++++++++++++++++++++++++++++++++++++++++++++++ ++++ ++ + ++ + + + +

+++++

++ +++ + +++ +++ +

+

P = 3.81 × 10−5P = 0.12

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

Binet A, rs736456 A/ABinet A, rs736456 G/A or G/G

Binet B or C, rs736456 A/ABinet B or C, rs736456 G/A or G/G

523 150 22 2 0133 24 6 3 0106 6 1 0 047 1 1 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

b

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++ ++++ + ++ +

++

++++ +++++

+++++

++ ++ + +

++++

+++++ +++ + +++ + ++

P = 1.93 × 10−9P = 0.69

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

Binet A, rs3778076 C/CBinet A, rs3778076 C/A or A/A

Binet B or C, rs3778076 C/CBinet B or C, rs3778076 C/A or A/A

593 162 26 5 071 13 2 0 0131 5 2 0 024 2 0 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

Supplementary Figure 12: Kaplan-Meier plot showing time to first treatment (TTFT) forCLL patients stratified by Binet stage of disease and SNP genotype for rs736456 (a)and rs3778076 (b). P values are obtained from pairwise log-rank tests for survival curves, withfalse discovery rate (FDR) corrections for multiple testing. For simplicity, p values are only shown forthe comparisions of SNP genotypes within the same prognostic factor stratum. TTFT is defined asthe time from diagnosis of CLL to treatment or last follow-up without treatment. Patients censoredat last follow-up are indicated by a cross. The number of patients in each group at each timepointare indicated in the table. All statistical tests were two-sided.

12

a

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++ +++ ++ ++++ + +

++++ +

+++++++++++ ++ ++

++++ ++ ++ + + + +

++++++++++++ +++

++++++++++++++

+ + +

++

+ + ++

P = 5.79 × 10−4P = 0.21

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

Mutated, rs736456 A/AMutated, rs736456 G/A or G/G

Unmutated, rs736456 A/AUnmutated, rs736456 G/A or G/G

306 114 18 2 072 17 5 3 0125 7 1 0 048 3 1 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

b

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++ ++++ ++ ++++ + ++ +

+++ +

++

++

++ ++ + +

+++++++++++++++++++++++++++++ +++++ + +++

P = 6.45 × 10−4P = 0.04

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

Mutated, rs3778076 C/CMutated, rs3778076 C/A or A/A

Unmutated, rs3778076 C/CUnmutated, rs3778076 C/A or A/A

343 120 21 5 039 12 2 0 0146 9 2 0 029 1 0 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

Supplementary Figure 13: Kaplan-Meier plot showing time to first treatment (TTFT)for CLL patients stratified by IGHV status and SNP genotype for rs736456 (a) andrs3778076 (b). P values are obtained from pairwise log-rank tests for survival curves, with falsediscovery rate (FDR) corrections for multiple testing. For simplicity, p values are only shown for thecomparisions of SNP genotypes within the same prognostic factor stratum. TTFT is defined as thetime from diagnosis of CLL to treatment or last follow-up without treatment. Patients censored atlast follow-up are indicated by a cross. The number of patients in each group at each timepoint areindicated in the table. All statistical tests were two-sided.

13

a

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++++++ ++ ++++ + +

++++++++++++++++++++++++++++++++++ ++ + ++++ + +

++++++

++++++++++++++++++++++++++++++++++++++++ ++++++ + ++++

++

+++++

+

+ ++ + + + +

P = 1.43 × 10−4P = 0.1

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

CD38 negative, rs736456 A/ACD38 negative, rs736456 G/A or G/G

CD38 positive, rs736456 A/ACD38 positive, rs736456 G/A or G/G

382 116 22 2 092 15 5 2 0164 16 1 0 066 7 1 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

b

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++++++++ ++ ++++ + + +

+++

+++

++

++

++ + +

++++++++++++++++++++++++++++++++++++++++++++++++++ ++++ ++++ + +++++

+

+

++ +

+ + +

P = 2.74 × 10−8P = 0.09

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

CD38 negative, rs3778076 C/CCD38 negative, rs3778076 C/A or A/A

CD38 positive, rs3778076 C/CCD38 positive, rs3778076 C/A or A/A

427 121 25 4 053 11 2 0 0202 21 2 0 032 2 0 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

Supplementary Figure 14: Kaplan-Meier plot showing time to first treatment (TTFT)for CLL patients stratified by CD38 status and SNP genotype for rs736456 (a) andrs3778076 (b). P values are obtained from pairwise log-rank tests for survival curves, with falsediscovery rate (FDR) corrections for multiple testing. For simplicity, p values are only shown for thecomparisions of SNP genotypes within the same prognostic factor stratum. TTFT is defined as thetime from diagnosis of CLL to treatment or last follow-up without treatment. Patients censored atlast follow-up are indicated by a cross. The number of patients in each group at each timepoint areindicated in the table. All statistical tests were two-sided.

14

a

++ ++ + ++++ +++++++++++++++++++++++++++++++++++++++++ + ++++++++++++++++++ ++ +

++++ ++ ++

+++++++

+ +++ ++ ++

+ +

++ + + +++

++++++++++++ + ++++++ + + ++

++ + +++

P = 1.4 × 10−3P = 0.03

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20Time in years

Surv

ival p

roba

bilit

y

Strata++

++

≤ 3.5mg/L, rs736456 A/A≤ 3.5mg/L, rs736456 G/A or G/G

>3.5mg/L, rs736456 A/A>3.5mg/L, rs736456 G/A or G/G

144 88 36 8 252 20 5 1 071 30 10 3 119 4 0 0 0---- 0 5 10 15 20

Time in years

Stra

ta

Number of patients at risk

b

++ ++ + +++++++++++++++++++++++++++++++++++++++++++++++++++++ +++ ++++++++++++++++++++++++ +

+++ +++ ++

+

++

+

+

+++ ++++++++++++++

+++ ++++++ + ++

+

+ + + +

+ +

P = 2.4 × 10−4P = 0.22

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20Time in years

Surv

ival p

roba

bilit

y

Strata++

++

≤ 3.5mg/L, rs3778076 C/C≤ 3.5mg/L, rs3778076 C/A or A/A

>3.5mg/L, rs3778076 C/C>3.5mg/L, rs3778076 C/A or A/A

174 102 39 8 224 7 3 1 073 29 9 3 118 5 1 0 0---- 0 5 10 15 20

Time in years

Stra

ta

Number of patients at risk

Supplementary Figure 15: Kaplan-Meier plot showing time to first treatment (TTFT) forCLL patients stratified by β2 Microglobulin and SNP genotype for rs736456 (a) andrs3778076 (b). P values are obtained from pairwise log-rank tests for survival curves, with falsediscovery rate (FDR) corrections for multiple testing. For simplicity, p values are only shown for thecomparisions of SNP genotypes within the same prognostic factor stratum. TTFT is defined as thetime from diagnosis of CLL to treatment or last follow-up without treatment. Patients censored atlast follow-up are indicated by a cross. The number of patients in each group at each timepoint areindicated in the table. High serum β2 microglobulin is defined as > 3.5 mg/L. All statistical testswere two-sided.

15

a

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++ +++++++++++++++++++++ + ++ ++++ + +

+++++++++++++

+++++++++ + ++ + + ++ + + +

++

+++

++

P = 9.93 × 10−3P = 0.48

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

Normal, rs736456 A/ANormal, rs736456 G/A or G/G

Abnormal, rs736456 A/AAbnormal, rs736456 G/A or G/G

298 64 16 2 086 13 5 2 026 2 0 0 013 0 0 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

b

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++++++++++++++++++++ ++ ++ ++++ + + +

+++

++

++

+ +

++

++

+ + +

P = 9.14 × 10−4P = 0.27

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Surv

ival p

roba

bilit

y

Strata++

++

Normal, rs3778076 C/CNormal, rs3778076 C/A or A/A

Abnormal, rs3778076 C/CAbnormal, rs3778076 C/A or A/A

345 70 19 4 045 7 2 0 037 2 0 0 03 0 0 0 0---- 0 10 20 30 40

Time in years

Stra

ta

Number of patients at risk

Supplementary Figure 16: Kaplan-Meier plot showing time to first treatment (TTFT)for CLL patients stratified by TP53 status and SNP genotype for rs736456 (a) andrs3778076 (b). P values are obtained from pairwise log-rank tests for survival curves, with falsediscovery rate (FDR) corrections for multiple testing. For simplicity, p values are only shown forthe comparisions of SNP genotypes within the same prognostic factor stratum. TTFT is defined asthe time from diagnosis of CLL to treatment or last follow-up without treatment. Patients censoredat last follow-up are indicated by a cross. The number of patients in each group at each timepointare indicated in the table. Abnormal is defined as a 17p deletion by FISH or a TP53 mutation bySanger sequencing. It should be noted that TP53 status is not routinely determined in patients withearly stage CLL. As such, the cohort tested for TP53 has an over-representation of patients withprogressive CLL. All statistical tests were two-sided.

16

a

++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++ +++ ++ ++++ + +

+

++

+++++

+ + +

++ + +

+ + +

Log−rankP=6.74×10−5P=6.74×10−5P=6.74×10−5P=6.74×10−5P=6.74×10−5P=6.74×10−5

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Sur

viva

l pro

babi

lity

rs736456++

+A/A

G/A

G/G

195 85 16 2 0

36 11 3 2 0

3 0 0 0 0−−−

0 10 20 30 40Time in years

rs73

6456

Number of patients at risk

b

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

++++++ +++ ++ ++++ + + +

++

+

+

+

+

+ +Log−rankP=7.87×10−5P=7.87×10−5P=7.87×10−5P=7.87×10−5P=7.87×10−5P=7.87×10−5

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Sur

viva

l pro

babi

lity

rs3778076++

C/C

A/C

214 90 17 4 0

22 7 2 0 0−−0 10 20 30 40

Time in years

rs37

7807

6

Number of patients at risk

17

c

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ ++++++ +++ ++ +++ + +

+ ++

+++

++++++ +

++

++ + ++ + +

+

+Log−rankP=3.42×10−7P=3.42×10−7P=3.42×10−7P=3.42×10−7P=3.42×10−7P=3.42×10−7

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40Time in years

Sur

viva

l pro

babi

lity

Number of risk alleles++

+no risk variant

one risk variant

two or more risk variants

178 79 15 2 0

49 16 3 2 0

7 1 1 0 0−−−

0 10 20 30 40Time in yearsN

umbe

r of

ris

k al

lele

s

Number of patients at risk

Supplementary Figure 17: Survival curves in low-risk CLLs by rs736456 (a) rs3778076 (b)and risk allele groups of rs736456 and rs3778076 (c). Low-risk CLL is defined as Binet stageA patients with mutated IGHV and CD38 negativity (N=236). Numbers do not match 236 becausers736456 genotypes are missing for 2 patients. Log-rank test is used to examine if survival curvesdiffer by genotypes and risk allele group. All statistical tests were two-sided.

18

rs34676223

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rs34676223

0.2

0.4

0.6

0.8

r2

ZNF436

ZNF436−AS1

TCEA3

ASAP3 E2F2

LOC101928163

ID3 MDS2 RPL11 ELOA

ELOA−AS1

PITHD1

LYPLA2

GALE

HMGCL

FUCA1

23.7 23.8 23.9 24 24.1Position on chr1 (Mb)

Supplementary Figure 18: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs34676223. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

19

rs41271473

0

2

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8

10

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g 10(

P)

0

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bination rate (cM/M

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rs41271473

0.2

0.4

0.6

0.8

r2

HIST3H2A

HIST3H2BB

MIR4666A

RNF187

BTNL10

MIR7641−2

RHOU

DUSP5P1

228.7 228.8 228.9 229 229.1Position on chr1 (Mb)

Supplementary Figure 19: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs41271473. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

20

rs3770745

0

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8

10

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g 10(

P)

0

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100

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bination rate (cM/M

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rs3770745

0.2

0.4

0.6

0.8

r2

EIF2AK2

SULT6B1

CEBPZOS

CEBPZ

NDUFAF7

PRKD3 QPCT

37.4 37.5 37.6 37.7 37.8Position on chr2 (Mb)

Supplementary Figure 20: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs3770745. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

21

rs13401811

0

2

4

6

8

10

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g 10(

P)

0

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100

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bination rate (cM/M

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rs13401811

0.2

0.4

0.6

0.8

r2

LOC105373553

BUB1

SNORD132

ACOXL

ACOXL−AS1

111.4 111.5 111.6 111.7 111.8Position on chr2 (Mb)

Supplementary Figure 21: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs13401811. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

22

rs17483466

0

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4

6

8

10

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g 10(

P)

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rs17483466

0.2

0.4

0.6

0.8

r2

ACOXL

ACOXL−AS1

BCL2L11

MIR4435−2HG

111.6 111.7 111.8 111.9 112Position on chr2 (Mb)

Supplementary Figure 22: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs17483466. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

23

rs9308731

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rs9308731

0.2

0.4

0.6

0.8

r2

ACOXL

ACOXL−AS1

BCL2L11

MIR4435−2HG

MIR4435−1

MIR4435−2

111.7 111.8 111.9 112 112.1Position on chr2 (Mb)

Supplementary Figure 23: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs9308731. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

24

rs3769825

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P)

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0.2

0.4

0.6

0.8

r2

FAM126B

NDUFB3

CFLAR

CFLAR−AS1

CASP10

CASP8

ALS2CR12 TRAK2

STRADB

C2CD6

201.9 202 202.1 202.2 202.3Position on chr2 (Mb)

Supplementary Figure 24: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs3769825. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

25

rs13397985

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rs13397985

0.2

0.4

0.6

0.8

r2

FBXO36

SLC16A14

SP110

SP140

SP140L SP100

230.9 231 231.1 231.2 231.3Position on chr2 (Mb)

Supplementary Figure 25: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs13397985. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

26

rs757978

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rs757978

0.2

0.4

0.6

0.8

r2

PPP1R7

ANO7

HDLBP

SEPT2

FARP2

MIR3133

STK25

BOK−AS1

BOK

THAP4

ATG4B

DTYMK

242.2 242.3 242.4 242.5 242.6Position on chr2 (Mb)

Supplementary Figure 26: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs757978. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

27

rs9880772

0

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rs9880772

0.2

0.4

0.6

0.8

r2

EOMES LINC01981

27.6 27.7 27.8 27.9 28Position on chr3 (Mb)

Supplementary Figure 27: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs9880772. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

28

rs1274963

0

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6

8

10

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P)

0

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rs1274963

0.2

0.4

0.6

0.8

r2

SCN11A

WDR48

GORASP1

TTC21A

MIR6822

CSRNP1

XIRP1 CX3CR1 CCR8

SLC25A38

39 39.1 39.2 39.3 39.4Position on chr3 (Mb)

Supplementary Figure 28: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs1274963. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

29

rs10936599

0

2

4

6

8

10

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g 10(

P)

0

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bination rate (cM/M

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rs10936599

0.2

0.4

0.6

0.8

r2

MECOM TERC

ACTRT3

MYNN

LRRC34

LRRIQ4

LRRC31

SAMD7

LOC100128164

SEC62

169.3 169.4 169.5 169.6 169.7Position on chr3 (Mb)

Supplementary Figure 29: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs10936599. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

30

rs10028805

0

2

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6

8

10

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g 10(

P)

0

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bination rate (cM/M

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rs10028805

0.2

0.4

0.6

0.8

r2

BANK1

102.5 102.6 102.7 102.8 102.9Position on chr4 (Mb)

Supplementary Figure 30: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs10028805. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

31

rs898518

0

2

4

6

8

10

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g 10(

P)

0

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rs898518

0.2

0.4

0.6

0.8

r2

SGMS2

LOC101929595

CYP2U1

HADH LEF1

LEF1−AS1

108.8 108.9 109 109.1 109.2Position on chr4 (Mb)

Supplementary Figure 31: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs898518. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

32

rs57214277

0

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10

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P)

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rs57214277

0.2

0.4

0.6

0.8

r2

ENPP6 LOC728175

LOC102723766

IRF2

185.1 185.2 185.3 185.4 185.5Position on chr4 (Mb)

Supplementary Figure 32: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs57214277. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

33

rs31490

0

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rs31490

0.2

0.4

0.6

0.8

r2

SLC12A7

CTD−3080P12.3

SLC6A19

SLC6A18

TERT

MIR4457

CLPTM1L

LINC01511

SLC6A3 LPCAT1

MIR6075

SDHAP3

1.1 1.2 1.3 1.4 1.5Position on chr5 (Mb)

Supplementary Figure 33: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs31490. For each study, allelic dosage was estimated forthe minor allele at each variant position and included in a Cox proportional hazard model to estimatehazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis ifthey had results from all six studies. Study-specific single nucleotide polymorphism (SNP) effectswere combined in a fixed effect model using an inverse-variance-weighted method. The upper panelshows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values) on they-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively, and arecoloured according to their linkage disequilibrium (pairwise r2) with the CLL etiological risk variantbased on the 1000 Genomes European panel. Reference genes in the region are shown in the lowerpanel, with arrows indicating transcript direction, dense blocks representing exons and horizontallines representing introns.

34

rs872071

0

2

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P)

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0.4

0.6

0.8

r2

LOC285766 DUSP22 IRF4 EXOC2

HUS1B

0.2 0.3 0.4 0.5 0.6Position on chr6 (Mb)

Supplementary Figure 34: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs872071. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

35

rs73718779

0

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P)

0

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rs73718779

0.2

0.4

0.6

0.8

r2

MYLK4

WRNIP1

SERPINB1

MIR4645

SERPINB9P1

LOC101927730

SERPINB9

SERPINB6

LINC01011

NQO2

HTATSF1P2

LOC101927759

RIPK1

BPHL

TUBB2A

LOC100507194

2.8 2.9 3 3.1 3.2Position on chr6 (Mb)

Supplementary Figure 35: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs73718779. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

36

rs674313

0

2

4

6

8

10

−lo

g 10(

P)

0

20

40

60

80

100

Recom

bination rate (cM/M

b)

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rs674313

0.2

0.4

0.6

0.8

r2

LOC101929163

C6orf10

HCG23

BTNL2

HLA−DRA

HLA−DRB5

HLA−DRB6

HLA−DRB1

HLA−DQA1

HLA−DQB1

HLA−DQB1−AS1

HLA−DQA2

MIR3135B

HLA−DQB2

HLA−DOB

TAP2

PSMB8

PSMB8−AS1

TAP1

PSMB9

32.4 32.5 32.6 32.7 32.8Position on chr6 (Mb)

Supplementary Figure 36: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs674313. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

37

rs210142

0

2

4

6

8

10

−lo

g 10(

P)

0

20

40

60

80

100

Recom

bination rate (cM/M

b)

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rs210142

0.2

0.4

0.6

0.8

r2

KIFC1

PHF1

CUTA

SYNGAP1

MIR5004

ZBTB9 BAK1

GGNBP1

LINC00336

ITPR3

LOC101929188

UQCC2

MIR3934

IP6K3 LEMD2

MLN

33.3 33.4 33.5 33.6 33.7Position on chr6 (Mb)

Supplementary Figure 37: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs210142. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

38

rs3800461

0

2

4

6

8

10

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g 10(

P)

0

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100

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bination rate (cM/M

b)

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rs3800461

0.2

0.4

0.6

0.8

r2

RPS10−NUDT3

RPS10 PACSIN1

SPDEF C6orf106

LOC101929243

SNRPC UHRF1BP1

TAF11

ANKS1A

34.4 34.5 34.6 34.7 34.8Position on chr6 (Mb)

Supplementary Figure 38: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs3800461. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

39

rs2236256

0

2

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10

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g 10(

P)

0

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100

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bination rate (cM/M

b)

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rs2236256

0.2

0.4

0.6

0.8

r2

OPRM1

IPCEF1

CNKSR3

154.3 154.4 154.5 154.6 154.7Position on chr6 (Mb)

Supplementary Figure 39: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs2236256. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

40

rs17246404

0

2

4

6

8

10

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g 10(

P)

0

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bination rate (cM/M

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rs17246404

0.2

0.4

0.6

0.8

r2

GPR37

C7orf77

POT1

POT1−AS1

124.3 124.4 124.5 124.6 124.7Position on chr7 (Mb)

Supplementary Figure 40: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs17246404. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

41

rs2456449

0

2

4

6

8

10

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g 10(

P)

0

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bination rate (cM/M

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rs2456449

0.2

0.4

0.6

0.8

r2

PCAT1 PCAT2

PRNCR1

CASC19

CCAT1

CASC21

CASC8

CCAT2

POU5F1B

128 128.1 128.2 128.3 128.4Position on chr8 (Mb)

Supplementary Figure 41: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs2456449. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

42

rs1679013

0

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P)

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rs1679013

0.2

0.4

0.6

0.8

r2

CDKN2A−AS1

CDKN2A

CDKN2B−AS1

CDKN2B

DMRTA1

22 22.1 22.2 22.3 22.4Position on chr9 (Mb)

Supplementary Figure 42: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs1679013. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

43

rs4406737

0

2

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6

8

10

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P)

0

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rs4406737

0.2

0.4

0.6

0.8

r2

LIPK

LIPN

LIPM

ANKRD22

STAMBPL1

ACTA2−AS1

ACTA2

FAS

FAS−AS1

MIR4679−2

MIR4679−1

CH25H

LIPA

90.6 90.7 90.8 90.9 91Position on chr10 (Mb)

Supplementary Figure 43: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs4406737. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

44

rs61904987

0

2

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6

8

10

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P)

0

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0.2

0.4

0.6

0.8

r2

ANKK1

DRD2

MIR4301

TMPRSS5 ZW10

CLDN25

USP28

113.3 113.4 113.5 113.6 113.7Position on chr11 (Mb)

Supplementary Figure 44: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs61904987. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

45

rs735665

0

2

4

6

8

10

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g 10(

P)

0

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rs735665

0.2

0.4

0.6

0.8

r2

MIR4493 GRAMD1B

SCN3B

ZNF202

123.2 123.3 123.4 123.5 123.6Position on chr11 (Mb)

Supplementary Figure 45: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs735665. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

46

rs10735079

0

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10

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P)

0

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100

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bination rate (cM/M

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rs10735079

0.2

0.4

0.6

0.8

r2

RPH3A

MIR1302−1 OAS1

OAS3

OAS2

DTX1

RASAL1

CFAP73

DDX54

MIR7106

RITA1

113.2 113.3 113.4 113.5 113.6Position on chr12 (Mb)

Supplementary Figure 46: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs10735079. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

47

rs8024033

0

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8

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P)

0

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rs8024033

0.2

0.4

0.6

0.8

r2

GPR176 EIF2AK4

SRP14

SRP14−AS1

BMF BUB1B

BUB1B−PAK6

PAK6

C15orf56

ANKRD63

PLCB2

INAFM2

C15orf52

PHGR1

DISP2

40.2 40.3 40.4 40.5 40.6Position on chr15 (Mb)

Supplementary Figure 47: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs8024033. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

48

rs7169431

0

2

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6

8

10

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g 10(

P)

0

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bination rate (cM/M

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rs7169431

0.2

0.4

0.6

0.8

r2

NEDD4 RFX7

56.1 56.2 56.3 56.4 56.5Position on chr15 (Mb)

Supplementary Figure 48: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs7169431. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

49

rs7176508

0

2

4

6

8

10

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g 10(

P)

0

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40

60

80

100

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bination rate (cM/M

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rs7176508

0.2

0.4

0.6

0.8

r2

DRAIC PCAT29 LINC00593

69.8 69.9 70 70.1 70.2Position on chr15 (Mb)

Supplementary Figure 49: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs7176508. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

50

rs783540

0

2

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10

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g 10(

P)

0

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100

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bination rate (cM/M

b)

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rs783540

0.2

0.4

0.6

0.8

r2

GOLGA6L10

GOLGA6L17P

GOLGA6L9

UBE2Q2P2

GOLGA2P10

LOC727751

RPS17

CPEB1

CPEB1−AS1

AP3B2

LOC338963

ACTG1P17

SNHG21

FSD2

SCARNA15

WHAMM

83.1 83.2 83.3 83.4 83.5Position on chr15 (Mb)

Supplementary Figure 50: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs783540. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

51

rs391525

0

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P)

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rs391525

0.2

0.4

0.6

0.8

r2

GSE1

GINS2

C16orf74

MIR1910

EMC8

LOC101928557

COX4I1

IRF8

MIR6774

85.7 85.8 85.9 86 86.1Position on chr16 (Mb)

Supplementary Figure 51: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs391525. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

52

rs305065

0

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8

10

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g 10(

P)

0

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bination rate (cM/M

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rs305065

0.2

0.4

0.6

0.8

r2

C16orf74

MIR1910

EMC8

LOC101928557

COX4I1

IRF8

MIR6774

85.8 85.9 86 86.1 86.2Position on chr16 (Mb)

Supplementary Figure 52: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs305065. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

53

rs305061

0

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g 10(

P)

0

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bination rate (cM/M

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rs305061

0.2

0.4

0.6

0.8

r2

C16orf74

MIR1910

EMC8

LOC101928557

COX4I1

IRF8

MIR6774

85.8 85.9 86 86.1 86.2Position on chr16 (Mb)

Supplementary Figure 53: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs305061. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

54

rs1036935

0

2

4

6

8

10

−lo

g 10(

P)

0

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bination rate (cM/M

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rs1036935

0.2

0.4

0.6

0.8

r2

MYO5B

MIR4320

CFAP53

MBD1

CXXC1

SKA1 MAPK4

47.6 47.7 47.8 47.9 48Position on chr18 (Mb)

Supplementary Figure 54: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs1036935. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

55

rs4368253

0

2

4

6

8

10

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g 10(

P)

0

20

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100

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bination rate (cM/M

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rs4368253

0.2

0.4

0.6

0.8

r2

PMAIP1

57.4 57.5 57.6 57.7 57.8Position on chr18 (Mb)

Supplementary Figure 55: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs4368253. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

56

rs4987855

0

2

4

6

8

10

−lo

g 10(

P)

0

20

40

60

80

100

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bination rate (cM/M

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rs4987855

0.2

0.4

0.6

0.8

r2

PHLPP1 BCL2 KDSR

60.6 60.7 60.8 60.9 61Position on chr18 (Mb)

Supplementary Figure 56: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs4987855. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

57

rs7254272

0

2

4

6

8

10

−lo

g 10(

P)

0

20

40

60

80

100

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bination rate (cM/M

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ZFR2 ATCAY

NMRK2

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EEF2

SNORD37

PIAS4

ZBTB7A

MAP2K2 CREB3L3

SIRT6

ANKRD24

EBI3

CCDC94

SHD

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FSD1

3.9 4 4.1 4.2 4.3Position on chr19 (Mb)

Supplementary Figure 57: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs7254272. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

58

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rs11083846

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PNMAL1

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CALM3

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DACT3

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PRKD2

MIR320E

STRN4

FKRP

SLC1A5

SNAR−E

AP2S1 ARHGAP35

47 47.1 47.2 47.3 47.4Position on chr19 (Mb)

Supplementary Figure 58: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs11083846. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

59

rs140522

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50.8 50.9 51 51.1 51.2Position on chr22 (Mb)

Supplementary Figure 59: Regional association plot of TTFT (time to first time treatment)for known CLL etiological risk variant rs140522. For each study, allelic dosage was estimatedfor the minor allele at each variant position and included in a Cox proportional hazard model toestimate hazard ratio (HR) and 95% confidence interval (CI). Variants were included in the meta-analysis if they had results from all six studies. Study-specific single nucleotide polymorphism (SNP)effects were combined in a fixed effect model using an inverse-variance-weighted method. The upperpanel shows SNP coordinates based on genomic build b37/hg19 on the x-axis, and -log10 (P values)on the y-axis. Genotyped and imputed SNPs are represented by diamonds and circles, respectively,and are coloured according to their linkage disequilibrium (pairwise r2) with the CLL etiologicalrisk variant based on the 1000 Genomes European panel. Reference genes in the region are shownin the lower panel, with arrows indicating transcript direction, dense blocks representing exons andhorizontal lines representing introns.

60

ars4752676

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0.2

0.4

0.6

0.8

r2

TACC2 BTBD16 PLEKHA1

MIR3941

ARMS2

HTRA1

123.8 123.9 124 124.1 124.2Position on chr10 (Mb)

b

Fixed−effect (P=3.79×10−8)

0.5 1 2 3

rs4752676,10:124012209 (Phet=0.837; I 2=0%)

GWAS 6

GWAS 5

GWAS 4

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GWAS 2

GWAS 1

156/105

57/29

129/68

152/89

113/34

148/66

C/T

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0.10

0.18

0.10

0.14

0.11

0.10

21.35% 1.61 [1.05, 2.46]

12.75% 1.87 [1.08, 3.26]

17.91% 1.89 [1.19, 3.01]

25.59% 1.97 [1.33, 2.91]

7.36% 1.88 [0.91, 3.90]

15.05% 1.29 [0.78, 2.15]

100.00% 1.74 [1.43, 2.12]1.74 [1.43, 2.12]Random−effect (P=3.79×10−8)

Study No/events Eff/Ref EAF Weight(%) HR [95% CI]

Supplementary Figure 60: Regional and forest plots of rs4752676. TTFT (time to first timetreatment) survival associations in rs4752676 region (a). The upper panel plots SNPs based ongenomic build b37/h19 coordinates on the x-axis, and their -log10(p-values) on the y-axis. Diamondand circle shapes are used for genotyped and imputed SNPs, respectively, with colours according totheir pairwise r2 with the lead SNP based on 1000 Genomes European panel (Nov 2014). Referencegenes in the region are shown in the lower panel, with arrows indicating transcript direction, denseblocks for exons, and lines for introns. Plot was generated using LocusZoom. Forest plot of rs4752676effect on TTFT by study (b). No/events: No. CLL patients/No. patients receiving treatment (thefirst time); Eff/Ref: effect/reference allele; EAF: frequencies of the effect allele; HR: hazard ratio; CI:confidence interval; Squares denote the per-allele HR, with their size inversely proportional to thevariance of the effect estimates. Pooled HRs derived from both the fixed and random-effect models areshown in diamond shapes, with their corresponding meta p-values indicated in the left parentheses.Format of x-axis label is rsid, chromosome:position(b37), P for Cochran’s Q test (Phet) and I2 forheterogeneity in parenethesis. All statistical tests were two-sided.

61

ars736457

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rs736457

0.2

0.4

0.6

0.8

r2

TACC2 BTBD16 PLEKHA1

MIR3941

ARMS2

HTRA1

123.8 123.9 124 124.1 124.2Position on chr10 (Mb)

b

Fixed−effect (P=3.69×10−8)

0.5 1 2 3

rs736457,10:124012562 (Phet=0.83; I 2=0%)

GWAS 6

GWAS 5

GWAS 4

GWAS 3

GWAS 2

GWAS 1

156/105

57/29

129/68

152/89

113/34

148/66

G/C

G/C

G/C

G/C

G/C

G/C

0.10

0.18

0.10

0.14

0.11

0.10

21.31% 1.60 [1.05, 2.46]

12.73% 1.88 [1.08, 3.26]

18.01% 1.91 [1.20, 3.04]

25.54% 1.96 [1.33, 2.90]

7.35% 1.89 [0.91, 3.91]

15.05% 1.29 [0.77, 2.14]

100.00% 1.74 [1.43, 2.12]1.74 [1.43, 2.12]Random−effect (P=3.69×10−8)

Study No/events Eff/Ref EAF Weight(%) HR [95% CI]

Supplementary Figure 61: Regional and forest plots of rs736457. TTFT (time to first timetreatment) survival associations in rs736457 region (a). The upper panel plots SNPs based on genomicbuild b37/h19 coordinates on the x-axis, and their -log10(p-values) on the y-axis. Diamond andcircle shapes are used for genotyped and imputed SNPs, respectively, with colours according to theirpairwise r2 with the lead SNP based on 1000 Genomes European panel (Nov 2014). Reference genesin the region are shown in the lower panel, with arrows indicating transcript direction, dense blocksfor exons, and lines for introns. Plot was generated using LocusZoom. Forest plot of rs736457 effecton TTFT by study (b). No/events: No. CLL patients/No. patients receiving treatment (the firsttime); Eff/Ref: effect/reference allele; EAF: frequencies of the effect allele; HR: hazard ratio; CI:confidence interval; Squares denote the per-allele HR, with their size inversely proportional to thevariance of the effect estimates. Pooled HRs derived from both the fixed and random-effect models areshown in diamond shapes, with their corresponding meta p-values indicated in the left parentheses.Format of x-axis label is rsid, chromosome:position(b37), P for Cochran’s Q test (Phet) and I2 forheterogeneity in parenethesis. All statistical tests were two-sided.

62

ars11757517

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rs11757517

0.2

0.4

0.6

0.8

r2

NUDT3

RPS10−NUDT3

RPS10 PACSIN1

SPDEF

C6orf106

LOC101929243

SNRPC

UHRF1BP1

34.3 34.4 34.5 34.6 34.7Position on chr6 (Mb)

b

Fixed−effect (P=4.12×10−8)

0.5 1 2 3 4 5

rs11757517,6:34514207 (Phet=0.732; I 2=0%)

GWAS 6

GWAS 5

GWAS 4

GWAS 3

GWAS 2

GWAS 1

156/105

57/29

129/68

152/89

113/34

148/66

T/C

T/C

T/C

T/C

T/C

T/C

0.055

0.079

0.070

0.063

0.044

0.064

23.63% 1.58 [0.94, 2.65]

12.48% 1.54 [0.75, 3.15]

18.14% 2.27 [1.25, 4.11]

20.40% 2.59 [1.48, 4.55]

8.09% 2.75 [1.13, 6.70]

17.26% 2.04 [1.11, 3.76]

100.00% 2.03 [1.58, 2.62]2.03 [1.58, 2.62]Random−effect (P=4.12×10−8)

Study No/events Eff/Ref EAF Weight(%) HR [95% CI]

Supplementary Figure 62: Regional and forest plots of rs11757517. TTFT (time to first timetreatment) survival associations in rs11757517 region (a). The upper panel plots SNPs based ongenomic build b37/h19 coordinates on the x-axis, and their -log10(p-values) on the y-axis. Diamondand circle shapes are used for genotyped and imputed SNPs, respectively, with colours according totheir pairwise r2 with the lead SNP based on 1000 Genomes European panel (Nov 2014). Referencegenes in the region are shown in the lower panel, with arrows indicating transcript direction, denseblocks for exons, and lines for introns. Plot was generated using LocusZoom. Forest plot of rs11757517effect on TTFT by study (b). No/events: No. CLL patients/No. patients receiving treatment (thefirst time); Eff/Ref: effect/reference allele; EAF: frequencies of the effect allele; HR: hazard ratio; CI:confidence interval; Squares denote the per-allele HR, with their size inversely proportional to thevariance of the effect estimates. Pooled HRs derived from both the fixed and random-effect models areshown in diamond shapes, with their corresponding meta p-values indicated in the left parentheses.Format of x-axis label is rsid, chromosome:position(b37), P for Cochran’s Q test (Phet) and I2 forheterogeneity in parenethesis. All statistical tests were two-sided.

63

Supplementary Table 1: Demographic and clinical characteristics of chronic lymphocytic leukemia (CLL) cases

GWAS 1 GWAS 2 GWAS 3 GWAS 4 GWAS 5 GWAS 6 Study 7 P value*

Sex Male 84 86 90 82 31 101 49Female 69 37 62 47 26 55 38 0.128Not available 1 3 0 0 0 0 0

Age ≤ 65 70 49 87 64 32 56 36>65 83 52 58 65 25 100 51 0.002Not available 1 25 7 0 0 0 0

Binet stage A 134 107 126 107 48 87 70B/C 18 18 24 21 9 57 9 4.39 × 10−8

Not available 2 1 2 1 0 12 8

IGHV Mutated 110 97 94 31 1 63 0Unmutated 43 26 50 10 0 46 2 0.003Not available 1 3 8 88 56 47 85

CD38 Negative 98 74 95 89 33 49 54Positive 52 50 29 29 23 28 29 0.023Not available 4 2 28 11 1 79 4

β2 Microglobulin ≤ 3.5 mgL−1 0 40 83 75 0 0 2>3.5mgL−1 0 20 37 32 0 0 2 0.814Not available 154 66 32 22 57 156 83

TP53 status Normal 135 14 30 5 1 139 70Abnormal 3 3 6 2 0 17 9 0.002Not available 16 109 116 122 56 0 8

GWAS, genome-wide association study; *Fishers exact test. All statistical tests were two-sided.

64

Supplementary Table 2: eQTL results for rs736456

SNP ID SNP positionAssessedAllele

Chromosome GeneGene

SymbolGene

PositionP valueeQTLa

PBH

eQTLbZ scoreeQTL

rs736456 124012547 G 10 ENSG00000255624 RP11-564D11.3 124648738 0.07364703 0.3124953 1.7889ENSG00000179988 PSTK 124735463 0.08726587 0.3124953 -1.71ENSG00000107672 NSMCE4A 123725667 0.0961524 0.3124953 1.664ENSG00000095574 IKZF5 124759327 0.13754382 0.320929072 -1.4849ENSG00000154473 BUB3 124919339 0.14812111 0.320929072 1.4463ENSG00000066468 FGFR2 123297910 0.23855749 0.443035339 -1.1785ENSG00000107669 ATE1 123594127 0.41759542 0.562342092 0.8108ENSG00000166033 HTRA1 124247732 0.41771032 0.562342092 -0.8103ENSG00000119965 C10orf88 124702169 0.43257084 0.562342092 0.785ENSG00000196177 ACADSB 124793161 0.72288928 0.854323695 -0.3546ENSG00000138161 CUZD1 124615405 0.9349648 0.96378848 0.0818ENSG00000213185 FAM24B 124623875 0.96378848 0.96378848 0.0455ENSG00000107679 PLEKHA1 124163039 9.90E-17 1.28677E-15 8.3061

eQTL data for genes within 1MB of the risk SNP are shown. eQTL, expression quantitative trait loci; SNP, single nucleotide polymorphism.aUnadjusted P value based on summary-data-based Mendelian randomization (SMR).bBenjamini-Hochberg corrected P value.

65

Supplementary Table 3: eQTL results for rs3778076

SNP ID SNP positionAssessedAllele

Chromosome GeneGene

SymbolGene

PositionP valueeQTLa

PBH

eQTLbZ scoreeQTL

rs3778076 34513266 A 6 ENSG00000112039 FANCE 35427509 0.00083537 0.004646106 -3.3406ENSG00000124507 PACSIN1 34468461 0.00086039 0.004646106 -3.3326ENSG00000198755 RPL10A 35437373 0.01193704 0.05371668 -2.5139ENSG00000023892 DEF6 35277571 0.0367798 0.141864943 2.0884ENSG00000064999 ANKS1A 34958110 0.12283078 0.414553883 -1.5429ENSG00000269490 SBP1 33663335 0.14700276 0.44100828 -1.4501ENSG00000186577 C6orf1 34215702 0.22566553 0.609296931 -1.2115ENSG00000137309 HMGA1 34209329 0.25121634 0.616621925 -1.1473ENSG00000225339 RP11-513I15.6 34251000 0.30347967 0.667102562 1.029ENSG00000220583 RPL35P2 34231269 0.32119753 0.667102562 0.9922ENSG00000065029 ZNF76 35245224 0.35861887 0.691622106 -0.9179ENSG00000137288 MNF1 33672424 0.42347908 0.762262344 -0.8002ENSG00000146197 SCUBE3 35201523 0.47919369 0.779264312 0.7078ENSG00000196114 RP3-391O22.3 34544234 0.4981522 0.779264312 0.6775ENSG00000030110 BAK1 33544174 0.54664175 0.779264312 0.6029ENSG00000161904 LEMD2 33747946 0.61918905 0.779264312 -0.497ENSG00000112033 PPARD 35353151 0.65704258 0.779264312 -0.4439ENSG00000112664 NUDT3 34308224 0.663998 0.779264312 -0.4344ENSG00000124614 RPS10 34389566 0.67404719 0.779264312 -0.4205ENSG00000266509 MIR3934 33665958 0.69535379 0.779264312 0.3916ENSG00000096433 ITPR3 33626436 0.69683235 0.779264312 0.3896ENSG00000007866 TEAD3 35453113 0.72154103 0.779264312 -0.3562ENSG00000204188 GGNBP1 33554159 0.8424192 0.86674062 0.199ENSG00000064995 TAF11 34850710 0.86674062 0.86674062 0.1679ENSG00000065060 UHRF1BP1 34805386 2.49E-140 6.7281E-139 25.2188ENSG00000196821 C6orf106 34609850 2.62E-65 3.53943E-64 17.0668ENSG00000124562 SNRPC 34733377 7.57E-23 6.81399E-22 -9.8399

eQTL data for genes within 1MB of the risk SNP are shown. eQTL, expression quantitative trait loci; SNP, single nucleotide polymorphism.aUnadjusted P value based on summary-data-based Mendelian randomization (SMR).bBenjamini-Hochberg corrected P value.

66

Supplementary Table 4: eQTL results for rs3800461

SNP ID SNP positionAssessedAllele

Chromosome GeneGene

SymbolGene

PositionP valueeQTLa

PBH

eQTLbZ scoreeQTL

rs3800461 34616322 C 6 ENSG00000112039 FANCE 35427509 0.00100401 0.366527794 -3.2894ENSG00000124507 PACSIN1 34468461 0.00367018 0.003137531 -2.9052ENSG00000225339 RP11-513I15.6 34251000 0.00947011 0.010194944 2.5947ENSG00000065029 ZNF76 35245224 0.01256734 0.023675275 2.4959ENSG00000007866 TEAD3 35453113 0.0168943 0.028562136 2.389ENSG00000112664 NUDT3 34308224 0.0313344 0.035196458 2.1529ENSG00000186577 C6orf1 34215702 0.08235187 0.060258462 1.7372ENSG00000269490 SBP1 33663335 0.13823389 0.147056911 -1.4822ENSG00000064995 TAF11 34850710 0.21364682 0.230389817 -1.2436ENSG00000196114 RP3-391O22.3 34544234 0.2492389 0.333823156 1.1523ENSG00000137288 MNF1 33672424 0.27827613 0.386494625 -1.0842ENSG00000161904 LEMD2 33747946 0.33344406 0.438742184 -0.9672ENSG00000266509 MIR3934 33665958 0.4002359 0.481018595 0.8413ENSG00000146197 SCUBE3 35201523 0.40405562 0.481018595 -0.8342ENSG00000137309 HMGA1 34209329 0.55224461 0.627550693 -0.5943ENSG00000096433 ITPR3 33626436 0.60376074 0.656261674 0.519ENSG00000112033 PPARD 35353151 0.79162581 0.824610219 0.2644ENSG00000220583 RPL35P2 34231269 0.98165027 0.98165027 -0.0229ENSG00000124562 SNRPC 34733377 1.04E-60 8.66167E-60 -16.4368ENSG00000064999 ANKS1A 34958110 1.24E-06 0.00000516 -4.8493ENSG00000196821 C6orf106 34609850 3.27E-310 <1.00E-300 41.0453ENSG00000065060 UHRF1BP1 34805386 3.27E-310 <1.00E-300 51.2666ENSG00000023892 DEF6 35277571 4.10E-23 2.56556E-22 9.9014ENSG00000124614 RPS10 34389566 5.19E-05 0.000185439 -4.0468ENSG00000198755 RPL10A 35437373 5.31E-07 2.65445E-06 -5.0148

eQTL data for genes within 1MB of the risk SNP are shown. eQTL, expression quantitative trait loci; SNP, single nucleotide polymorphism.aUnadjusted P value based on summary-data-based Mendelian randomization (SMR).bBenjamini-Hochberg corrected P value.

67