title: Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders.
abstract: Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abbreviated Max Drinks), a significantly heritable phenotype (h(2)  = 0.32 ± 0.05; P = 4.61 × 10(-14)) with a strong genetic correlation with AUD (ρg  = 0.99 ± 0.13) for the San Antonio Family Study (n = 1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD = 4.17; P = 5.85 × 10(-6)) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P = 4.04 × 10(-3)), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P = 2.14 × 10(-4)), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific.
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Mark Z
authors.initials: MZ
authors.lastname: Kos
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.forename: Rene
authors.initials: R
authors.lastname: Olvera
authors.forename: D Reese
authors.initials: DR
authors.lastname: McKay
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Quillen
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.forename: Xiang-Ding
authors.initials: XD
authors.lastname: Chen
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.forename: Ravi
authors.initials: R
authors.lastname: Duggirala
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D058068:Endophenotypes; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D055815:Young Adult
keywords: AUD; SNP association; alcohol dependence; endophenotype ranking value (ERV); pleiotropy; variance components linkage analysis