Glycans and ageDealing with non-linear correlations

Lucija KlarićGenos Ltd.

Lucija Klarić

Relationship between age and glycans

Local correction for age and sex- linear age/sex correction vs local age/sex correction- local age/sex correction – general additive models with smooth function

(R package: mgcv)

Local correction for age and sexResiduals after age and sex correction in Korcula cohort

Local correction for age and sexResiduals after age and sex correction in Korcula cohort

Materials and methods• 2 cohorts:– Korcula

• 851 individuals• 316751 SNPs (typed)• 77 glycans (UPLC)

– Vis• 808 individuals• 308996 SNPs (typed)• 77 glycans (UPLC)

• GWAS – GenABEL package for R• Meta analysis – MetABEL package for R

Comparison GWAS Korcula: Linear vs Local Correction

SNP glycan p (Linear) p (Local)rs6764279 IGP29 4.68E-31 2.59E-31rs6764279 IGP35 5.49E-19 7.30E-19rs6764279 IGP32 3.10E-17 2.39E-17rs6764279 IGP15 9.69E-17 2.05E-16rs12366899 IGP41 2.80E-16 2.40E-16rs12366899 IGP1 3.09E-15 3.38E-15rs6444193 IGP29 2.09E-14 3.92E-14rs6939603 IGP41 3.28E-14 1.56E-14rs6764279 IGP28 3.73E-14 5.77E-14rs6939603 IGP1 9.47E-14 3.68E-14rs6764279 IGP24 2.93E-13 3.95E-13rs11621121 IGP42 1.02E-12 2.07E-11rs12366899 IGP19 1.38E-12 2.15E-13

Comparison Meta analysis: Linear vs Local Correction

SNP glycan p (Linear) p (Local) chi (Linear) chi (Local) chi Lin/Locrs6764279 IGP29 9.07E-59 1.46E-58 261.27 260.32 1.004rs6764279 IGP15 2.24E-36 5.10E-35 158.65 152.43 1.041rs6764279 IGP35 9.90E-35 9.00E-35 151.11 151.30 0.999rs6764279 IGP32 1.78E-29 2.63E-30 127.09 130.88 0.971rs6764279 IGP28 4.34E-29 2.02E-28 125.31 122.26 1.025rs6444193 IGP29 2.49E-25 6.23E-25 108.15 106.33 1.017rs6764279 IGP24 6.00E-24 4.76E-23 101.85 97.74 1.042rs4686837 IGP29 1.04E-19 7.36E-20 82.53 83.22 0.992rs909674 IGP39 2.52E-18 6.64E-18 76.24 74.32 1.026rs909674 IGP40 3.84E-18 9.26E-18 75.40 73.66 1.024rs11621121IGP59 1.29E-16 5.09E-15 68.47 61.22 1.118rs12366899IGP41 3.19E-16 2.60E-16 66.69 67.08 0.994

Concluding remarks

• Most p-values are lower in linear correction than local correction for age

• Linear age correction outperformes local age correction– possible reason: local correction corrects better only

few people (~50 people from 40-50 years of age)• Associations of SNPs and glycans are quite robust• Residuals of local correction for age and sex are

not related to age

Monogalactosylated IgG glycans in agingβ4GalT-I (Beta-1,4-galactosyltransferase 1) • adds galactose to GlcNAc residues• interacts preferentially with 1,6-arm

FA2[6]G1 FA2[3]G1FA2B[6]G1 FA2B[3]G1

Monogalactosylated structures with Gal on 1,6 arm decrease with age.Monogalactosylated structures with bisecting GlcNAc with Gal on 1,3 or 1,6 arm increase with age.

Monogalactosylated IgG glycans in aging

Monogalactosylated structures with Gal on 1,6 arm decrease with age.Monogalactosylated structures with bisecting GlcNAc with Gal on 1,3 or 1,6 arm increase with age.

Glycan KOR (n=915) ORCADES (n=2035) Twins (n=1261) VIS (n=906)R p R p R p R p

FA2[6]G1 -0.193 6.49E-08 -0.171 1.92E-12 -0.028 6.86E-03 -0.231 2.71E-11FA2[3]G1 0.010 3.91E-01 0.024 3.89E-08 0.008 2.30E-03 -0.061 9.06E-02FA2B[6]G1 0.141 2.33E-07 0.335 4.69E-46 0.183 2.79E-10 0.043 1.69E-01FA2B[3]G1 0.264 1.05E-17 0.481 4.31E-113 0.314 3.77E-27 0.247 5.36E-14

Table 1. Associations of glycans with age (UPLC)

Monogalactosylated IgG glycans in aging

Table 2. Correlation of age and glycans measured by different methods in Vis population (500 subjects).

Glycan UPLC xCGE-LIF

(Total IgG) (Total IgG)R p R p

FA2[6]G1 -0,303 8,19E-11 -0,218 3,69E-06FA2[3]G1 -0,094 4,91E-02 -0,026 5,79E-01FA2B[6]G1 -0,021 6,63E-01 0,012 8,01E-01FA2B[3]G1 0,254 6,37E-08 0,302 8,86E-11

Glycan MALDI-TOF-MS LC-ESI-MS

IgG1 IgG2&3 IgG1 IgG2&3R p R p R p R p

FA2[6]G1FA2[3]G1

-0,506 4,64E-30 -0,568 4,35E-39 -0,088 6,50E-02 -0,390 1,58E-17

FA2B[6]G1FA2B[3]G1

-0,154 1,15E-03 -0,412 1,49E-19 -0,008 8,72E-01 -0,247 1,48E-07

Monogalactosylated IgG glycans in aging