title: Population structure, differential bias and genomic control in a large-scale, case-control association study.
abstract: The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of exposure. In genetics the first of these, in the form of population structure, has dominated recent debate. Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method by applying a variable downweighting to each SNP.
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, CB2 2XY, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Clayton
authors.forename: Neil M
authors.initials: NM
authors.lastname: Walker
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pask
authors.forename: Jason D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Maier
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Smink
authors.forename: Alex C
authors.initials: AC
authors.lastname: Lam
authors.forename: Nigel R
authors.initials: NR
authors.lastname: Ovington
authors.forename: Helen E
authors.initials: HE
authors.lastname: Stevens
authors.forename: Sarah
authors.initials: S
authors.lastname: Nutland
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.forename: Malek
authors.initials: M
authors.lastname: Faham
authors.forename: Martin
authors.initials: M
authors.lastname: Moorhead
authors.forename: Hywel B
authors.initials: HB
authors.lastname: Jones
authors.forename: Matthew
authors.initials: M
authors.lastname: Falkowski
authors.forename: Paul
authors.initials: P
authors.lastname: Hardenbol
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Willis
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000293:Adolescent; D015982:Bias; D016022:Case-Control Studies; D004247:DNA / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics*; D005189:False Positive Reactions; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D004247:DNA