A Genome‐Wide Search for Genes That Relate to a Low Level of Response to Alcohol

Abstract

Background:The low level of response (LR) to alcohol is genetically influenced in both humans and animals, and a low LR is a characteristic of offspring of alcoholics that has been reported to predict alcoholism 10 and 15 years later. The genes that contribute to a low LR have not yet been identified.Methods: A 12-item questionnaire that measures LR, the Self Rating of the Effects of Alcohol (SRE) instrument, was filled out by 745 individuals from the Collaborative Study on the Genetics of Alcoholism (COGA) for whom genetic material was available. These subjects were genotyped by using 336 markers with an average heterozygosity of 0.74 and an average intermarker distance of 10.5 cM. Both quantitative and qualitative nonparametric, sib-pair analyses were carried out for the SRE measure related to early drinking experiences.Results: Correlations of SRE scores across related individuals were significant and between 0.16 and 0.22 for most values, compared with nonsignificant correlations of 0.03 or less among unrelated individuals. Linkage analyses performed by using the FIRST 5 variables (first five times alcohol is consumed) identified four chromosomal regions with lod scores Ն2.0 whose maximum was also near a marker. One of these chromosomal regions previously was linked to alcohol dependence in the COGA sample.Conclusions: These data document the familial nature of a low LR to alcohol as measured by the SRE and suggest several chromosomal regions that might contribute to the phenomenon.

A genome wide search for alcoholism susceptibility genes

“…Dick et al [2002] using a derived phenotype based on a principal component analysis of DSM-IIIR items and scales from the Tridimensional Personality Questionnaire (TPQ) reported evidence for linkage (LOD = 3.3) to a region that included marker D1S518. Finally, using low level of alcohol response as a phenotype, Schuckit et al [2001] found support for linkage at D1S1588.…”

Confirmation and fine mapping of the chromosome 1 alcohol dependence risk locus

“…Two previous large genetic linkage studies in the US population by the COGA group had presented strong evidence for the presence of a gene predisposing to alcohol dependence in this area of chromosome 1. [1][2][3][4][5] We genotyped a set of closely spaced STR markers, encompassing the approximate 1-LOD support interval of the linkage region, in a collection of European-American nuclear families. The markers were tested for transmission disequilibrium using the TDTPHASE program.…”

“…[1][2][3][4] The COGA linkage study consisted of an initial sample of 225 alcohol-dependent sibpairs and a replication sample of 266 sibpairs drawn from extended pedigrees with a high density of alcohol dependence. The families were collected in the United States, and the subjects were largely European-American.…”

Genomewide linkage study in the Irish affected sib pair study of alcohol dependence: evidence for a susceptibility region for symptoms of alcohol dependence on chromosome 4

“…This region has also been implicated in association-based genome scans of illicit drug abuse conducted in samples of European and African ancestry (Uhl et al, 2002). 32 Several studies have not reported any significant linkage to this region of chromosome 4, including: a study of AD in multiplex families, 7 preliminary reports of AD samples collected in the UK 33 and Sweden, 34 a study of alcohol craving in the Mission Indian sample, 35 and two studies of ethanol response based on self-report among the initial COGA sample 36 and on physiological measures in a sib pair sample. 9 The latter study reported some evidence (LODs 1.3-1.4) for linkage to regions B40 cM away from our peak (at 60 and 180 cM) which could overlap with the region we identified given the wide confidence intervals surrounding linkage peaks.…”