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

Abstract

Alcoholism is a relatively common, chronic, disabling and often treatment-resistant disorder. Evidence from twin and adoption studies indicates a substantial genetic influence, with heritability estimates of 50-60%. We conducted a genome scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD). Most probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected siblings and parents were evaluated by structured interview. A 4 cM genome scan was conducted using 474 families of which most (96%) were comprised by affected sib pairs. Nonparametric and quantitative linkage analyses were conducted using DSM-IV alcohol dependence (AD) and number of DSM-IV AD symptoms (ADSX). Quantitative results indicate strong linkage for number of AD criteria to a broad region of chromosome 4, ranging from 4q22 to 4q32 (peak multipoint LOD = 4.59, P = 2.1 Â 10 À6, at D4S1611). Follow-up analyses suggest that the linkage may be due to variation in the symptoms of tolerance and out of control drinking. There was evidence of weak linkage (LODs of 1.0-2.0) to several other regions, including 1q44, 13q31, and 22q11 for AD along with 2q37, 9q21, 9q34 and 18p11 for ADSX. The location of the chromosome 4 peak is consistent with results from prior linkage studies and includes the alcohol dehydrogenase gene cluster. The results of this study suggest the importance of genetic variation in chromosome 4 in the etiology and severity of alcoholism in Caucasian populations.

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

“…We did not detect these peaks in our analyses. In other samples, however, quantitative indices of alcohol dependence similar to those used here have yielded linkage on chromosome 4 (see Prescott et al 2006 for summary). For instance, in the Irish high-density sample of alcoholics, Prescott and colleagues (2006) report linkage (LOD 4.5) on chromosome 4.…”

Developing a Quantitative Measure of Alcohol Consumption for Genomic Studies on Prospective Cohorts

“…Other studies Bergen et al, 2003;Prescott et al, 2006;Saccone et al, 2000) have used a symptom count of alcohol-dependence (DSMThird Edition, Revised [DSM-III-R; American Psychiatric Association, 1987] or DSM-IV) symptoms or LMAXALC alone as quantitative measures of risk of alcoholism, particularly to identify several regions on chromosome 4 as areas of putative genomic interest. Our measure of alcohol consumption, which is moderately heritable, has three unique advantages over these existing measures.…”

“…A majority of existing genomic studies of alcohol-use disorders, including linkage and genome-wide as well as candidate gene-association studies (Kranzler et al, 1998;Prescott et al, 2006;Reich, 1996), have used DSM-IV-based diagnostic measures of alcohol abuse and/or dependence as their primary phenotypes. The most notable of these may be the Collaborative Study on the Genetics of Alcoholism (Begleiter et al, 1995), which has had considerable success identifying linkage signals and, consequently, identifying genetic variants in candidate genes, using diagnostic alcohol dependence (Edenberg and Foroud, 2006;Edenberg et al, 2004;Foroud et al, 2000;Reich et al, 1998).…”

Genetics of Alcohol Dependence: A Review of Clinical Studies

“…Large-scale linkage studies like the COGA [146] or the study by Long et al [145] in a relatively homogeneous Native American population have pointed to a risk locus on chromosome 4q, which contains the ADH region. Additional evidence for a risk locus on chromosome 4q was found in the Irish Affected Sib Pair Study of Alcohol Dependence that additionally provided weaker, suggestive evidence for linkage on chromosomes 1q, 13q and 22q for alcohol dependence, on 2q, 9q and 19p for symptom count [147]. Further loci identified in the COGA that were replicated in a follow-up [148] include chromosomes 1 and 7.…”