New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Alcoholism is a multifactorial trait that is manifested by genes (genotype), epigenetic factors (epigenome), environmental effects (alcohol consumption, frequently accompanied by smoking), endogenous influences (e.g. eventually heart and liver disease), and probably each person’s microbiome (primarily gut flora; contribution of bacterial metabolism). In a study comprising 195 countries and territories, excessive alcohol consumption was found to be responsible for ~2.2% and ~6.8% of age-standardized deaths of women and men, respectively. Most genetic studies of alcohol consumption focus on alcohol dependency — although the population burden of alcohol-related disease mainly reflects a broader range of behaviors associated with alcohol consumption. Small decreases in alcohol consumption could have major public health benefits, as well as on rates of mortality.

Unfortunately, genetic studies of alcoholism to date have robustly identified only a small number of associated genetic variants; these include a mutant allele (in Asians) of aldehyde dehydrogenase-2 (ALDH2) gene plus variants in the aldehyde dehydrogenase (ADH) gene family — a group of enzymes that participate in the metabolism of aldehydes — including a cluster of genes on chromosome 4q23 (ADH1B, ADH1C, ADH5, ADH6 and ADH7). Authors [see attached article] report a genome-wide association studies (GWAS) meta-analysis of alcohol intake among individuals of European ancestry [taken from the UK Biobank (UKB), the Alcohol Genome-Wide Consortium (AlcGen), and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus (CHARGE+) consortia].

The UKB is a prospective cohort study comprising ~500,000 individuals recruited between ages 40 yr and 69 yr; participants were asked to report their average weekly and monthly alcohol consumption through a self-completed touchscreen questionnaire. On the basis of these reports, authors then calculated the alcohol intake in grams per day.

The meta-analysis included 480,842 people of European descent, attempting to characterize the genetic architecture (i.e. the underlying genetic basis of a trait and its properties of variability; phenotypic variation for quantitative traits is, at the most basic level, the result of segregation of alleles at quantitative trait loci) of alcohol intake. Authors identified 46 new common genetic loci and investigated their potential functional importance — using magnetic resonance imaging (MRI) data and gene expression studies. Note that, high on the list of statistical signifiance, is SLC39A8 (P = 1.3e–15), a gene encoding a cation influx transporter (which is expressed in embryonic stem cells, and every cell-type examined except perhaps skin; endogenous SLC39A8 substrates include manganese, zinc, selenium and cobalt). Authors also note that — many of these identified genetic pathways are not only associated with alcohol consumption — but are genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.


Nat Hum Behav 29 Jul 2019; doi: 10.1038/s41562-019-0653-z [Epub ahead of print]

This entry was posted in Gene environment interactions. Bookmark the permalink.