title: Informed conditioning on clinical covariates increases power in case-control association studies.
abstract: Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1 × 10(-9)). The improvement varied across diseases with a 16% median increase in χ(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America. nzaitlen@hsph.harvard.edu
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.forename: Bogdan
authors.initials: B
authors.lastname: Pasaniuc
authors.forename: Marilyn
authors.initials: M
authors.lastname: Cornelis
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.forename: Samuela
authors.initials: S
authors.lastname: Pollack
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: David J
authors.initials: DJ
authors.lastname: Friedman
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Aage
authors.initials: A
authors.lastname: Haugen
authors.forename: Joachim
authors.initials: J
authors.lastname: Heinrich
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Olaide Y
authors.initials: OY
authors.lastname: Raji
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.forename: David
authors.initials: D
authors.lastname: Scherf
authors.forename: Sophia
authors.initials: S
authors.lastname: Steer
authors.forename: Martin
authors.initials: M
authors.lastname: Walshaw
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Waters
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
authors.forename: Shanbeh
authors.initials: S
authors.lastname: Zienolddiny
authors.forename: Eric Tchetgen
authors.initials: ET
authors.lastname: Tchetgen
authors.forename: Christopher
authors.initials: C
authors.lastname: Haiman
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Debra A
authors.initials: DA
authors.lastname: Schaumberg
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Benjamin
authors.initials: B
authors.lastname: Voight
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
mesh_terms: D000367:Age Factors; D015992:Body Mass Index; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005163:Factor Analysis, Statistical; D005260:Female; D056726:Genetic Association Studies / Q000706:statistics & numerical data*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012907:Smoking