title: The aggregate effect of dopamine genes on dependence symptoms among cocaine users: cross-validation of a candidate system scoring approach.
abstract: Genome-wide studies of psychiatric conditions frequently fail to explain a substantial proportion of variance, and replication of individual SNP effects is rare. We demonstrate a selective scoring approach, in which variants from several genes known to directly affect the dopamine system are considered concurrently to explain individual differences in cocaine dependence symptoms. 273 SNPs from eight dopamine-related genes were tested for association with cocaine dependence symptoms in an initial training sample. We identified a four-SNP score that accounted for 0.55% of the variance in a separate testing sample (p = 0.037). These findings suggest that (1) limiting investigated SNPs to those located in genes of theoretical importance improves the chances of identifying replicable effects by reducing statistical penalties for multiple testing, and (2) considering top-associated SNPs in the aggregate can reveal replicable effects that are too small to be identified at the level of individual SNPs.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO 80309-0447, USA. jaime.derringer@colorado.edu
authors.forename: Jaime
authors.initials: J
authors.lastname: Derringer
authors.forename: Robert F
authors.initials: RF
authors.lastname: Krueger
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.forename: Fazil
authors.initials: F
authors.lastname: Aliev
authors.forename: Richard A
authors.initials: RA
authors.lastname: Grucza
authors.forename: Scott
authors.initials: S
authors.lastname: Saccone
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Victor M
authors.initials: VM
authors.lastname: Hesselbrock
authors.forename: John R
authors.initials: JR
authors.lastname: Kramer
authors.forename: Peng
authors.initials: P
authors.lastname: Lin
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Neuman
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
mesh_terms: D000293:Adolescent; D000328:Adult; D019970:Cocaine-Related Disorders / Q000235:genetics*; D004298:Dopamine / Q000235:genetics*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011954:Receptors, Dopamine / Q000235:genetics*
chemical_list: D011954:Receptors, Dopamine; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine