Linkage and Association Studies of Alcoholism
Phenotypes in the COGA Study
Ying Liu
Mentor: Nancy Lim Saccone
Abstract
Alcoholism is one of the most common and costly health problems in the United States. It is
defined by compulsive, excessive use of alcohol in spite of negative consequences. Numbers of
previous studies demonstrated that alcoholism is a complex genetic disorder and shaped by genegene as well as gene-environment interactions. This report is aimed to test the associations
between specific genetic variations on chromosome 7 under the previous linkage peak area and
an alcoholism phenotype, MAXDRINKS, defined in the COGA study. Prior to analyses, the
MAXDRINKS phenotype was log transformed and adjusted for the effect of gender. It turns out
that the normality of MAXDRNKS distribution was significantly improved after log
transformation and a clear age-sex cohort effect was also observed for this trait. Total 81 SNPs
spanning 8 candidate genes on chromosome 7 were genotyped in 262 severely affected COGA
families. Family-based association tests, both for single-marker and sliding-window haplotype
analyses, were performed by using FBAT/HBAT, QTDT and UNPHASED packages. In addition,
linkage disequilibrium patterns and block structures were also examined by using Haploview.
Among the total 11 SNPs which showed moderate association with MAXDRNKS (P < 0.05), 5
and 3 SNPs are within or flanking the CHRM2 and REELIN genes, respectively. Although no
extensive linkage disequilibrium patterns were found for both CHRM2 and REELIN genes,
haplotype analyses results for REELIN gene revealed that 3 haplotypes were significantly
associated with MAXDRNKS. However, the biological importance of different haplotypes
remains to be addressed. Finally, we also tested the association between two non-synonymous
coding SNPs of TAS2R38, a bitter taster receptor gene on chromosome 7, with MAXDRNKS,
but found no evidence of significant association either as single loci or as a haplotype. Taken
together, these results supported the previous findings of association between CHRM2 gene and
both alcoholism and major depressive syndrome, and also suggested new evidence for REELIN’s
role in the risk of alcoholism. It will be valuable to examine these finding in other family sets
with different ethnic background or in population-based case-control studies.