TY - JOUR

T1 - Evaluation of type 2 diabetes genetic risk variants in Chinese adults

T2 - findings from 93,000 individuals from the China Kadoorie Biobank

AU - Gan, Wei

AU - Walters, Robin G

AU - Holmes, Michael V

AU - Bragg, Fiona

AU - Millwood, Iona Y

AU - Banasik, Karina

AU - Chen, Yiping

AU - Du, Huaidong

AU - Iona, Andri

AU - Mahajan, Anubha

AU - Yang, Ling

AU - Bian, Zheng

AU - Guo, Yu

AU - Clarke, Robert J

AU - Li, Liming

AU - McCarthy, Mark I

AU - Chen, Zhengming

AU - China Kadoorie Biobank Collaborative Group

PY - 2016

Y1 - 2016

N2 - AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have discovered many risk variants for type 2 diabetes. However, estimates of the contributions of risk variants to type 2 diabetes predisposition are often based on highly selected case-control samples, and reliable estimates of population-level effect sizes are missing, especially in non-European populations.METHODS: The individual and cumulative effects of 59 established type 2 diabetes risk loci were measured in a population-based China Kadoorie Biobank (CKB) study of 93,000 Chinese adults, including >7,100 diabetes cases.RESULTS: Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function, demonstrated significant interactions with several measures of adiposity (BMI, waist circumference [WC], WHR and percentage body fat [PBF]; all p interaction < 1 × 10(-4)), with a greater effect being observed in leaner adults.CONCLUSIONS/INTERPRETATION: Our study provides further evidence of shared genetic architecture for type 2 diabetes between Europeans and East Asians. It also indicates that even very large GWAS meta-analyses may be vulnerable to substantial inflation of effect size estimates, compared with those observed in large-scale population-based cohort studies.ACCESS TO RESEARCH MATERIALS: Details of how to access China Kadoorie Biobank data and details of the data release schedule are available from www.ckbiobank.org/site/Data+Access .

AB - AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have discovered many risk variants for type 2 diabetes. However, estimates of the contributions of risk variants to type 2 diabetes predisposition are often based on highly selected case-control samples, and reliable estimates of population-level effect sizes are missing, especially in non-European populations.METHODS: The individual and cumulative effects of 59 established type 2 diabetes risk loci were measured in a population-based China Kadoorie Biobank (CKB) study of 93,000 Chinese adults, including >7,100 diabetes cases.RESULTS: Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function, demonstrated significant interactions with several measures of adiposity (BMI, waist circumference [WC], WHR and percentage body fat [PBF]; all p interaction < 1 × 10(-4)), with a greater effect being observed in leaner adults.CONCLUSIONS/INTERPRETATION: Our study provides further evidence of shared genetic architecture for type 2 diabetes between Europeans and East Asians. It also indicates that even very large GWAS meta-analyses may be vulnerable to substantial inflation of effect size estimates, compared with those observed in large-scale population-based cohort studies.ACCESS TO RESEARCH MATERIALS: Details of how to access China Kadoorie Biobank data and details of the data release schedule are available from www.ckbiobank.org/site/Data+Access .

U2 - 10.1007/s00125-016-3920-9

DO - 10.1007/s00125-016-3920-9

M3 - Journal article

C2 - 27053236

VL - 59

SP - 1446

EP - 1457

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 7

ER -