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© FIMM - Institute for Molecular Medicine Finland www.fimm.fi
Thermo-Fisher ESHG 2019 Seminar
Gothenburg, June 16, 2019
FinnGen: a platform for drug targetdevelopment and precision medicine
Samuli Ripatti
Institute For Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki
Public Health, Faculty of Medicine, University of Helsinki
The Broad Institute of MIT and Harvard
@samrip
@CoECDG
Disclaimer
› Thermo Fisher Scientific and its affiliates are not endorsing, recommending, or promoting any
use or application of Thermo Fisher Scientific products presented by third parties during this
seminar. Information and materials presented or provided by third parties are provided as-is
and without warranty of any kind, including regarding intellectual property rights and reported
results. Parties presenting images, text and material represent they have the rights to do so. If
applicable; modify as appropriate, (for which you must have a signed speaker engagement
agreement) including if free products/support were provided: Speaker was provided travel and
hotel support by Thermo Fisher Scientific for this presentation, but no remuneration
Presentation namedd.mm.yyyy 2
Y O U R T E S T B E D F O R N E X T G E N E R A T I O N R E S E A R C H & I N N O V A T I O N
INNOVATIVE STUDY DESIGNS
POPULATION ISOLATE
HEALTHREGISTERS
BIOBANKS GENOME DATA
+ ++
4
EARLY SETTLEMENT • 2000-10 000 years ago• South and Coast
LATE SETTLEMENT• 16th century• multiple bottle necks
EXPANSION • 18th century – population 250 000• Today – population 5.4 million
EARLY
SETTLEMENT
LATE
SETTLEMENT
5
GRACILE (death in infancy)
LAAHD (intrauterine death)
FSH-RO (fertility disturbance)
EPMR (progressive retardation)
PEHO (progressive retardation)
TMD (muscle disease) dominant
RAPADILINO (growth disturbance with malformations)
LCCS (intrauterine death)
IOSCA, OHAHA (progressive retardation)
CHS (progressive retardation)
vLINCL (progressive retardation)
HYDROLET (intrauterine death)
SALLA (progressive retardation)
MKS (intrauterine death)
MEB (severe retardation)
TCD, CHM (eye disease), X -recessive
INCL (progressive retardation)
HOGA (eye disease)
DTD (growth disturbance)
JNCL (progressive retardation)
CHH (growth disturbance)
MUL (growth disturbance)
FAF (eye, nerve and skin disease) dominant
USH3 (ear and eye disease)
PLOSL (progressive retardation)
AGU (progressive retardation)
CLD (watery diarrhea)
NKH (severe retardation)
LPI (metabolic disease)
CCD (watery diarrhea)
APECED (autoimmune polyendocrinopathy)
RESCH, RS (eye disease), X- recessive
PME (neurological disease)
SMB12 (anemia)
CNA2 (eye disease)
CNF (kidney disease)
56... 58... 60... 62... 64... 66... 68... 70... 72... 74... 76... 78... 80... 82... 84 ...86... 88... 90... 92... 94... 96... 98
Finnish Disease Heritage
Recessive diseases enriched in
Finland
6
Finnish bottleneck boosts the frequency of a subset of high impact variants
• Risk effects• Tens of Mendelian diseases
• AKT2 knockouts ↑insulin level and ↑T2D risk
• TOP3B and SETD1A in schizophrenia and learning disabilities
• Protective effects• Knockouts of SLC30A8 T2D risk ↓ by 65%
• Knockouts of LPA CAD risk ↓ by 20%
• RNF186 truncating variant with ulcerative colitis risk ↓ by 70%
POPULATION ISOLATE
7
500 000 individuals
~1O % of the population
500 000 individualsCombined
genotype and register data
National Health Register data
Association analyses
Axiom GWA array
Imputation
FinnGen
8
FinnGen partners
9
National registers
Hospital discharge
Hospital procedure
Outpatient visit
Outpatient procedure
Primary care
Primary care procedure
Cancer register
Cause of death
Drug purchase
Drug reimbursement
Register data for
administration
Register data for
administration
Register data for
administration
All data harmonized
Interconnected by the 11 digit person number
10
Constructing disease endpoints
Hospital or outpatientdischarge registry
Hospital or outpatient discharge registry
Procedure code:
Cause of death
Drug reimbursement
Cause of death
ICD: I21, I22
Coronary bypass surgery
ICD: I20-I25
ICD: G30, F00
ATC: NO6D
ICD: G30, F00contributing
Case
Coronary heart disease Alzheimer’s
Existing hospital labvalues
11
FINNGEN1 Chip
540,008
Imputation grid
57,008
Partner content
116,402
Finnish rare coding
14,900
Clinvar pathogenic
10,800
HLA + KIR
4,600
Pharmacogenetic
736,145
FINNGEN1
Thermo Fisher, Axiom
12
• Latest data freeze 146 000 individuals• Imputed to a Finnish reference panel 8000 haplotypes
13
Breast cancerLocus does not exist in 37 build
Known:IGFBP5, same lead
Info 0.74
Known: KCNU1Risk for T2D
Known.long LD
Novel rare Finn enriched
Known.FGFR2
Known.CCDN1.Same lead variant
Known.NTN4.Same lead variant
Not in GWAS but clinvar!!Finn specific PTV
Known.TOX3
Known.ZNRF3. Same lead
14
PALB2 locus
Top variant intronic
Frameshift in perfect LD
PRS
PALB2
NoneCHEK2
CHEK2 + PRS
PALB2 + PRS
PRS = PRS >90th percentile, only women
HR 95% CI
None 1.00
CHEK2 1.94 1.45-2.61
PRS 2.41 2.19-2.65
PALB2 4.89 3.34-7.17
CHEK2 & PRS 6.32 4.37-9.13
PALB2 & PRS 14.17 4.54-44.20
Nina Mars: C16.4, Monday @ 13-14:30
16
UK Biobank ~400k (another 80k non-European)
Biobank Japan ~200k
FinnGen ~150k (+50k every 6 months)
HUNT ~70k
Estonian Biobank ~50k (soon 100k)
Generation Scotland ~30k
Michigan ~40k
BioME (MSSM) ~32k
Colorado ~32k
Partners ~20k (soon 25k)
UCLA ~14k
Likely additional participants:
BioVU (120K)
deCODE (250K)
China Kadoorie (100K)
Wei Zhou, Masa Kanai, Juha KarjalainenCristen Willer, Ben Neale
Looking forward:Global Biobank Meta-Analysis
17
Asthma
Biobank Japan8,204 cases, 10 loci
UK Biobank 26,332 cases, 31 loci Combined
52,194 cases, 52 loci
Finngen12,071 cases, 8 loci
HUNT 5,587 cases, 3 loci
Wei Zhou, Masa Kanai, Juha Karjalainen
18
Towards next steps in population health
• Finnish medical data, genomes and technology combined with global collaboration will advance
• Genetic discoveries
• Public health interventions that prevent disease
• Identifying individuals at high-risk to make early detection and prevention more efficient
19
Acknowledgements