title: Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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 .
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital Campus, Old Road, Headington, Oxford, OX3 7LJ, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Gan
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Robin G
authors.initials: RG
authors.lastname: Walters
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Bragg
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Iona Y
authors.initials: IY
authors.lastname: Millwood
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital Campus, Old Road, Headington, Oxford, OX3 7LJ, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Karina
authors.initials: K
authors.lastname: Banasik
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Huaidong
authors.initials: H
authors.lastname: Du
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Andri
authors.initials: A
authors.lastname: Iona
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital Campus, Old Road, Headington, Oxford, OX3 7LJ, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Anubha
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Chinese Academy of Medical Sciences, Dong Cheng District, Beijing, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Chinese Academy of Medical Sciences, Dong Cheng District, Beijing, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Clarke
authors.affiliation: Chinese Academy of Medical Sciences, Dong Cheng District, Beijing, People's Republic of China.|School of Public Health, Peking University Health Sciences Center, Beijing, People's Republic of China.
authors.forename: Liming
authors.initials: L
authors.lastname: Li
authors.affiliation: Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital Campus, Old Road, Headington, Oxford, OX3 7LJ, UK. mark.mccarthy@drl.ox.ac.uk.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.|National Institute of Health Research Oxford Biomedical Research Centre, Oxford, UK. mark.mccarthy@drl.ox.ac.uk.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK. zhengming.chen@ctsu.ox.ac.uk.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000328:Adult; D044466:Asian People; D018070:Biological Specimen Banks; D002681:China / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055105:Waist Circumference / Q000235:genetics / Q000502:physiology
keywords: Biobank; Chinese; Genetic risk score; Population-based cohort studies; Type 2 diabetes; Winner’s curse