Researchers at Yale University School of Medicine, along with colleagues, have discovered 29 genetic variants associated with drinking disorders. The genome-wide analysis, published in the journal Nature Neuroscience, reported that 19 of the identified genes were previously unknown as autonomous risk factors for problematic alcohol use (PAU), whereas 10 had been previously identified as risk factors.
According to senior author Yale University’s Joel Gelernter, Foundations Fund Professor of Psychiatry and Professor of Genetics and Neuroscience, “the new data triple the number of known genetic risk loci associated with problematic alcohol use”.
Problems with alcohol? 29 gene variants may explain why
— Neuroscience News (@NeuroscienceNew) May 25, 2020
The Genetic Basis of Alcohol Misuse
Alcohol use and alcohol use disorder (AUD) are among the major causes of death and disability around the world. Genome-wide association studies (GWAS), which involve various assessments and measures, have been used to identify the potential risk genes associated with problematic drinking and alcohol use disorder, however mainly for European populations. Quantity-frequency measures of drinking, such as the Alcohol Use Disorders Identification Test–Consumption (AUDIT-C), occasionally reveal alcohol consumption in the normal range. These tests are genetically different from AUD and the measures used for problematic drinking, such as the Alcohol Use Disorders Identification Test–Problems (AUDIT-P), which highlight a vast set of divergent genetic correlations.
The approximate single-nucleotide polymorphism-based heritability (SNP- based heritability), represented as h2, of alcohol use disorder varies from 5.6 to 10%. A single-nucleotide polymorphism is the replacement of a single nucleotide that happens at a precise position in the genome, where every variation exists at a level of 0.5% from person to person within the population. Currently, more than 10 risk variants have been significantly mapped to numerous risk genes in several studies, includin
g ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide), ALDH2 (Aldehyde Dehydrogenase 2 Family Member, but only within certain Asian samples), ADH1C (Alcohol Dehydrogenase 1C (class I), Gamma Polypeptide), GCKR (Glucokinase Regulator), CRHR1 (Corticotropin Releasing Hormone Receptor 1) and SLC39A8 (Solute Carrier Family 39 Member 8).
Considering the extensive polygenicity (inheritance of a trait controlled by two or more genes) underlying alcohol use disorder and Alcohol Use Disorders Identification Test–Problems, the researchers hypothesized that additional risk locations could also be identified as potential risk factors by increasing sample size, which is also the general design for genome-wide association studies (GWAS) of heterogeneous complex traits.
New Genetic Variants for Alcohol Use Disorder Identified
For their study, researchers classified both alcohol use disorder and Alcohol Use Disorders Identification Test–Problems (AUD and AUDIT-P) as problematic alcohol use (PAU). For identifying novel risk variants and increase their understanding of the genetic designs of PAU, the study involved a genome-wide meta-analysis of AUD and AUDIT-P among 435,563 individuals of European ancestry. Data was obtained from the following datasets: MVP (an enormous bio-bank with more than 750,000 subjects (313,977 subjects were used for this study) with rich phenotypic data assessed via questionnaires and electronic health records (EHRs), PGC (collaborative consortium leading efforts to gather smaller cohorts) and UKB (population-level cohort with the largest available samples of AUDIT-P data). The researchers observed shared genetic variants among the individuals that met the criteria for problematic alcohol use.
The meta-analysis revealed 29 independent variants, 19 of which were novel, with 0.059–0.113 of the variation in phenotype explained in different cohorts or meta-analyses. Moreover, an analysis of functionality and heritability showed consistent enrichments in areas of the brain and in the evolutionarily conserved regulatory regions of the genome, which provides a significant biological understanding into the etiology of PAU. Variations involving gene expressions in the brain have been characterized as a vital risk for PAU, whereas enrichments in regulatory regions highlight specific brain tissues associated with the causative genes. Using Mendelian randomization (MR), the research team also investigated how a single genetically influenced trait affected another genetically linked trait.
Furthermore, researchers established that PAU had a significant genetic correlation with 138 other traits, of which the most common correlations were with substance use and substance-related disorders, major depressive disorder, schizophrenia and various other neuropsychiatric traits.
University of Yale’s Hang Zhou, an associate research scientist in psychiatry and lead author commented on the results: “This gives us ways to understand causal relations between problematic alcohol use traits such as psychiatric states, risk-taking behavior, and cognitive performance”.
Results of the study offer considerable information for future studies involving the biological basis of problematic alcohol use and the role of each risk variant. The researchers hope that this new knowledge will help develop ‘personalized treatment/medicine’ for PAU, facilitating the identification of patients that might be most responsive to treatment or to a specific medication regimen. Also, the specific interactions identified between 16 genes and 325 drugs also highlight their importance as potential targets for ‘precision medicine’.
“With these results, we are also in a better position to evaluate individual-level risk for problematic alcohol use,” Professor Gelernter concluded.