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ASTN1 and alcohol dependence: Family‐based association analysis in multiplex alcohol dependence families
Author(s) -
Hill Shirley Y.,
Weeks Daniel E.,
Jones Bobby L.,
Zezza Nicholas,
Stiffler Scott
Publication year - 2012
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.32048
Subject(s) - genetics , single nucleotide polymorphism , linkage disequilibrium , haplotype , international hapmap project , biology , genetic linkage , alcohol dependence , minor allele frequency , genetic association , allele , gene , genotype , alcohol , biochemistry
A previous genome‐wide linkage study of alcohol dependence (AD) in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The ASTN1 gene is in this region, a gene previously reported to be associated with substance abuse, bipolar disorder and schizophrenia. Using the same family data consisting of 330 individuals with phenotypic data and DNA, finer mapping of a 26 cM region centered on D1S196 was undertaken using SNPs with minor allele frequency (MAF) ≥ 0.15 and pair‐wise linkage disequilibrium (LD) of r 2 < 0.8 using the HapMap CEU population. Significant FBAT P ‐values for SNPs within the ASTN1 gene were observed for four SNPs (rs465066, rs228008, rs6668092, and rs172917), the most significant, rs228008, within intron 8 had a P ‐value of 0.001. Using MQLS, which allows for inclusion of all families, we find three of these SNPs with MQLS P ‐values < 0.003. In addition, two additional neighboring SNPs (rs10798496 and rs6667588) showed significance at P = 0.002 and 0.03, respectively. Haplotype analysis was performed using the haplotype‐based test function of FBAT for a block that included rs228008, rs6668092, and rs172917. This analysis found one block (GCG) over‐transmitted and another (ATA) under‐transmitted to affected offspring. Linkage analysis identified a region consistent with the association results. Family‐based association analysis shows the ASTN1 gene significantly associated with alcohol dependence. The potential importance of the ASTN1 gene for AD risk may be related its role in glial‐guided neuronal migration. © 2012 Wiley Periodicals, Inc.