title: Contrasting multi-site genotypic distributions among discordant quantitative phenotypes: the APOA1/C3/A4/A5 gene cluster and cardiovascular disease risk factors.
abstract: Most tests of association between DNA sequence variation and quantitative phenotypes in samples of randomly chosen individuals rely on specification of genotypic strata followed by comparison of phenotypes across these strata. This strategy often succeeds when phenotypic differences are caused by one or two single nucleotide polymorphisms (SNPs) among the surveyed markers. However, when multiple-SNP haplotypes account for observed phenotypic variation, identification of the best partitioning requires examination of an inordinate number of SNP combinations. An alternative approach is to rank individuals by their phenotypic measures and ask whether attributes of the genotypic variation show a non-random distribution along this phenotypic ranking. One simple version of this strategy selects the top and bottom tails of the distribution, and then tests whether genotypes from these two samples are drawn from a single population. This framework does not require the recovery of phased haplotypes and allows contrasts between large numbers of sites at once. We use a method based on this approach to identify associations between plasma triglyceride level, a risk factor for cardiovascular disease, and multi-site genotypes located in the APOA1/C3/A4/A5 cluster of apolipoprotein genes in unrelated individuals (1,071 African-American females, 780 African-American males, 1,036 European-American females, and 930 European-American males) sampled from four US cities as part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Method performance is investigated using simulations that model genealogical variation and different genetic architectures. Results indicate that this multi-site test can identify genotype-phenotype associations with reasonable power, including those generated by some simple epistatic models.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA. payseur@wisc.edu
authors.forename: Bret A
authors.initials: BA
authors.lastname: Payseur
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Clark
authors.forename: James
authors.initials: J
authors.lastname: Hixson
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Charles F
authors.initials: CF
authors.lastname: Sing
mesh_terms: D000328:Adult; D001741:Black or African American; D016632:Apolipoprotein A-I / Q000235:genetics*; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III / Q000235:genetics*; D001054:Apolipoproteins A / Q000235:genetics*; D044383:Black People; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008957:Models, Genetic; D005810:Multigene Family; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood; D014481:United States / Q000453:epidemiology; D044465:White People
chemical_list: C505693:APOA1 protein, human; C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D014280:Triglycerides; C022205:apolipoprotein A-IV