ALDH2 is associated to alcohol dependence and is the major genetic determinant of “daily maximum drinks” in a GWAS study of an isolated rural chinese sample
ABSTRACT Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum P = 4.73 × 10(-8) ) and two AD-related phenotypes: flushing response (minimum P = 4.75 × 10(-26) ) and maximum drinks in a 24-hr period (minimum P = 1.54 × 10(-16) ). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females-despite familial enrichment for AD-for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor. © 2013 Wiley Periodicals, Inc.
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ABSTRACT: Background We report a GWAS of nicotine dependence (ND) defined on the basis of scores on the Fagerström Test for Nicotine Dependence (FTND) in European-American (EA) and African-American (AA) populations. Methods Our sample, from that used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime: 2,114 EA and 2,602 AA subjects, and an additional 927 AA and 2,003 EA subjects from the SAGE project (via dbGAP). GWAS analysis considered FTND score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a SNP subset. Results In EAs, one chromosome 7 intergenic region was genomewide-significant (GWS): rs13225753, p=3.48x10-8 (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 basepairs (minimal p=4.74x10-10). Two chromosome 8 regions were associated: p=4.45x10-8 at DLC1 SNP rs289519 (unadjusted), and p=1.10x10-9 at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with ND and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p=1.46x10-7) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase (eNOS) and AMP activated protein kinase (AMPK) pathways in EAs. Conclusions The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.Biological Psychiatry 09/2014; 77(5). DOI:10.1016/j.biopsych.2014.08.025 · 9.47 Impact Factor
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ABSTRACT: Background/Aims: Alcohol dependence is a common severe psychiatric disorder with a multifactorial etiology. Since the completion of the human genome project and with the increased availability of high-throughput genotyping, multiple genetic risk factors for substance-related disorders, including alcohol dependence, have been identified, but not all results could be replicated. Methods: We systematically review the clinical literature on genetic risk factors for alcohol dependence and alcohol-related phenotypes, including candidate gene-based studies, linkage studies and genome-wide association studies (GWAS). Results: Irrespectively of the methodology employed, the most robust findings regarding genetic risk factors for alcohol dependence concern genetic variations that affect alcohol metabolism. GWAS confirm the importance of the alcohol dehydrogenase gene cluster on chromosome 4 in the genetic risk for alcohol dependence with multiple variants that exert a small, but cumulative influence. A single variant with strong influence on individual risk is the aldehyde dehydrogenase 2 ALDHD2*2 variant common in Asian populations. Other robust associations have been found with previously uncharacterized genes like KIAA0040, and such observations can lead to the identification of thus far unknown signaling pathways. Converging evidence also points to a role of glutamatergic, dopaminergic and serotonergic neurotransmitter signaling in the risk for alcohol dependence, but effects are small, and gene-environment interactions further increase the complexity. Conclusion: With few exceptions like ALDH2*2, the contribution of individual genetic variants to the risk for alcohol-related disorders is small. However, the concentration of risk variants within neurotransmitter signaling pathways may help to deepen our understanding of the underlying pathophysiology and thereby contribute to develop novel therapeutic strategies. (C) 2014 S. Karger AG, BaselNeuropsychobiology 01/2014; 70(2):77-94. DOI:10.1159/000364826 · 2.30 Impact Factor
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ABSTRACT: Understanding and correctly utilizing relatedness among samples is essential for genetic analysis; however, managing sample records and pedigrees can often be error prone and incomplete. Data sets ascertained by random sampling often harbor cryptic relatedness that can be leveraged in genetic analyses for maximizing power. We have developed a method that uses genome-wide estimates of pairwise identity by descent to identify families and quickly reconstruct and score all possible pedigrees that fit the genetic data by using up to third-degree relatives, and we have included it in the software package PRIMUS (Pedigree Reconstruction and Identification of the Maximally Unrelated Set). Here, we validate its performance on simulated, clinical, and HapMap pedigrees. Among these samples, we demonstrate that PRIMUS can verify reported pedigree structures and identify cryptic relationships. Finally, we show that PRIMUS reconstructed pedigrees, all of which were previously unknown, for 203 families from a cohort collected in Starr County, TX (1,890 samples). Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.The American Journal of Human Genetics 11/2014; 95(5):553-64. DOI:10.1016/j.ajhg.2014.10.005 · 10.99 Impact Factor