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 600 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-hour 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.

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

“…In our PheWAS, no relevant results were observed for ADH1B rs1229984 in the ASN sample, which is probably attributable to the power limitations from the small ASN sample available. However, we strongly replicated the protective role of ALDH2 rs671 in drinking behaviors (alcohol intake, p = 3.77*10 -8 ) that is associated with the accumulation of blood acetaldehyde and its resultant aversive effects in this ancestry group (Peng et al, 2014;Quillen et al, 2014), despite the very small sample size.…”

“…PheWAS analyses are considered a useful post-GWAS approach; such analyses can deepen our understanding of the range of phenotypic effects associated with GWASidentified risk alleles (Bush et al, 2016). The risk alleles we studied are recognized has having large effects on nicotine response and alcohol metabolism (The Tobacco and Genetics Consortium, 2010; Gelernter et al, 2014;Quillen et al, 2014). Our results provide strong support for either pleiotropic or consequent, or both, effects of these risk alleles Figure 2 Phenotypic associations of ADH1B rs1229984 in transpopulation meta-analysis (META) and in African (AFR), Asian (ASN), European (EUR), and Hispanic (HISP) samples.…”

“…Consistent with the genetic associations, these variants increase the alcohol oxidization rate, raising acetaldehyde levels and its related aversive symptoms, including facial flushing, nausea, headache, and tachycardia (Edenberg, 2007). Similarly, ALDH rs672 is negatively associated with alcohol use behaviors in Asian populations (this variant is very rare or absent in non-Asian populations) (Quillen et al, 2014) and it causes a complete or nearcomplete lack of acetaldehyde metabolism activity via this pathway (Peng et al, 2014), producing an accumulation of acetaldehyde and consequently its aversive symptoms. It is also recognized that the ADH1B locus is under strong selection in East Asians and a recent study hypothesized an independent evolution of the same locus also in Europeans (Galinsky et al, 2016).…”

Polygenic Risk, Personality Dimensions, and Adolescent Alcohol Use Problems: A Longitudinal Study

“…Although the measures were not identical across studies, AUDIT scores have been shown to be modestly correlated with DSM-IV alcohol dependence symptoms (r = .43) (Conley, 2001). Furthermore, genetic variants underlying alcohol dependence symptoms are likely to overlap with alcohol-related phenotypes (Quillen et al, 2014), and there are genetic factors in common over a wide spectrum of alcohol-related phenotypes . Finally, both samples were fully (FinnTwin12) or predominantly (ALSPAC) White, and thus, the results may not generalize across racial-ethnic samples, indicating the need for the current findings to be replicated.…”

Genetics of Alcohol Use Disorder

“…Park ve arkadaşları bir Doğu Asya örnekleminde kromozom 4q22-q23'teki ADH gen kümesinde çok sayıda nominal anlamlı SNP tespit etmiş, ayrıca ADH7'deki rs1442492 ve rs10516441 ile ALDH2'de rs671 polimorfizmlerini genom çapı anlamlı bulmuşlardır (73). Benzer bir şekilde, Doğu Asyalılarla yapılan başka GWAS çalışmalarında ALDH2*2 varyantı olan rs671 azalmış AKB riski ile ilişkili bulunmuştur (72,74,75). 2 GWAS çalışmasında ADH1B*2 SNP rs1229984 AKB gelişimine karşı koruyucu olarak gösterilmiştir (73,75).…”