title: Leveraging family history in population-based case-control association studies.
abstract: Population-based epidemiologic studies often gather information from study participants on disease history among their family members. Although investigators widely recognize that family history will be associated with genotypes of the participants at disease susceptibility loci, they commonly ignore such information in primary genetic association analyses. In this report, we propose a simple approach to association testing by incorporating family history information as a "phenotype." We account for the expected attenuation in strength of association of the genotype of study participants with family history under Mendelian transmission. The proposed analysis can be performed using standard statistical software adopting either a meta- or pooled-analysis framework. Re-analysis of a total of 115 known susceptibility single-nucleotide polymorphisms, discovered through genome-wide association studies for several disease traits, indicates that incorporation of family history information can increase efficiency by as much as 40%. Efficiency gain depends on the type of design used for conducting the primary study, extent of family history, and accuracy and completeness of reporting.
authors.affiliation: Public Health Foundation of India, New Delhi, India.
authors.forename: Arpita
authors.initials: A
authors.lastname: Ghosh
authors.forename: Patricia
authors.initials: P
authors.lastname: Hartge
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Amit D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Regina G
authors.initials: RG
authors.lastname: Ziegler
authors.forename: Myrto
authors.initials: M
authors.lastname: Barrdahl
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Sholom
authors.initials: S
authors.lastname: Wacholder
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D004194:Disease / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008432:Mathematical Computing; D015201:Meta-Analysis as Topic; D019683:Penetrance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012107:Research Design; D012984:Software
keywords: disease history in family members; first-degree relatives; meta-analysis; more powerful test for genetic association