A research team that included five BBRF grantees has reported results of a large study relating DNA variations to the risk of problematic alcohol use (PAU). The study nearly tripled the number of known locations (called “loci”) in the human genome where variations in the DNA sequence are thought to correspond with significantly increased risk of problematic drinking.

The study also quantified significant correlations between problematic drinking and a large number of other traits, notably including substance use as well as psychiatric diagnoses such as depression, schizophrenia, bipolar disorder, and ADHD.

Problematic drinking refers to what researchers term “pathological” alcohol use: physiological dependence and/or significant psychological, social, or medical impacts. It is related to, but distinct from, chronic or regular alcohol use, which is often but not always pathological.

The team’s senior member was Joel Gelernter, M.D., of Yale University. First author of the paper in Nature Neuroscience reporting the team’s results was Hang Zhou, Ph.D., also of Yale, whose 2018 BBRF Young Investigator grant project sought to extend understanding of genetic susceptibility for comorbid major depression and substance use disorders.

In recent years, Drs. Gelernter, Zhou and others have published a steady stream of new research results examining genetic risk for alcohol use disorder, opioid use disorder and other conditions. Several of these studies have taken advantage of a valuable new sample of individuals whose genetics, health history, and habits have been documented in great detail: the VA’s Million Veteran Program (MVP), which continues to enroll participants.

The new study on the genetics of problematic drinking included over 200,000 individuals enrolled in the MVP—and over 435,000 people overall. All were of European ancestry. Everyone in the large sample had been part of a genome-wide association study (GWAS), used to discover statically significant associations between commonly occurring DNA variations in individuals and illness risk across populations. The current study was a meta-analysis of several existing GWAS studies, a method in which researchers achieve greater statistical power by combining results. In this case, two subsets of the MVP sample were combined with one from the Psychiatric Genomics Consortium and one from the UK Biobank. Several other independent cohorts were used to confirm results of the meta-analysis.

Past research has established that pathological drinking has a genetic component. Estimates are that about half of an individual’s risk for PAU is inherited. Prior to the current meta-analysis, variations in 10 genome locations had been statistically correlated with alcohol use disorder. Every human genome contains some number of unique variations. The question in mapping “risk” areas is: where do the variations occur, within the 23 chromosomes? And which commonly occurring variations can be correlated with disorders, such as problematic drinking? Variations can be as small as a single DNA “letter” (the human genome is 3 billion pairs of letters in length), or can involve deletion or repetition of large “chunks” of DNA letters. Variations, when they occur in sensitive spots, can cause a critical gene or genes to malfunction, or to cease working altogether. Some variations occur in genome locations that don’t contain genes but rather sequences that regulate the way our 21,000+ genes function.

A number of the genes previously associated with problematic drinking affect enzymes used by the body to metabolize alcohol. Others are related to different mechanisms: one important variation occurs in the gene that encodes one of the cellular receptors for the neurotransmitter dopamine.

The new meta-analysis by Drs. Gelernter, Zhou and colleagues was statistically powerful enough to expand the number of known PAU-related genome locations to 29, 19 of which are new. Eleven of the new areas where DNA variations correlate with significant increase in risk for PAU are within genes; others are in regulatory regions. Some of the newly discovered variants are related to other alcohol-related traits, including quantity and frequency of alcohol consumption.

Certain PAU-related variations showed associations with multiple traits. In other words, people with elevated risk are also more likely to have other alcohol-related disorders including alcoholism, as well as tobacco-use disorder, and other substance addiction disorders. They are also more likely to be at elevated risk for depression, schizophrenia, bipolar disorder, and ADHD among other conditions. There was a correlation between PAU and people who had smoked regularly at some point in their life. People who score well on cognitive performance tests and with greater educational attainment were found to be at lower than average risk of problematic drinking.

“Central to PAU risk,” the researchers noted, are PAU-linked genetic variants that affect gene expression in cells of the brain. The study also found that 16 PAU-associated genes interact biochemically with 325 known drug compounds. These, the team said, provide clues for potential future treatments to control or prevent PAU in certain individuals, based on their genetic profile.

Future studies “will be required to delineate the biology and function associated with each [genetic] risk variant,” the team suggested. “We anticipate that knowledge of the functional effects of the variants will contribute eventually to personalized treatment of PAU, facilitating identification of individuals with PAU who may be most treatment-responsive or for whom a specific medication may be most effective.” The team also placed a high priority on enrolling more African-Americans and people of non-European ancestry to broaden the applicability of the results.

The team also included Abraham Palmer, Ph.D., a 2006 and 2003 BBRF Young Investigator; Renato Polimanti, Ph.D., a 2015 BBRF Young Investigator; Daniel Levey, Ph.D., a 2019 BBRF Young Investigator; and Sandra Sanchez-Roige, Ph.D., a 2018 BBRF Young Investigator.