NEW YORK – Researchers have tied 19 novel genetic risk variants to problematic drinking in a new genome-wide meta-analysis.
While a number of risk variants have previously been linked to alcohol use disorder and problematic drinking, researchers led by Yale School of Medicine's Joel Gelernter conducted a meta-analysis of more than 435,000 individuals to search for additional risk loci. Alcohol use is a leading risk factor for death, leading to 2.8 million deaths in 2016, according to a Global Burden of Disease Study.
As they reported in Nature Neuroscience on Monday, the researchers identified 19 novel variants associated with alcohol use disorder or problematic drinking. The researchers further traced the effect of these variants to certain brain tissues. They additionally uncovered genetic correlations between problematic alcohol use (PAU) and other substance abuse issues, as well as psychiatric disorders.
"The new data triple the number of known genetic risk loci associated with problematic alcohol use," Gelernter said in a statement.
For their meta-analysis, the researchers combined data from four datasets to generate a cohort of 435,563 individuals. The datasets relied on slightly different definitions of problematic drinking — such as alcohol use disorder and alcohol use with medical consequences — though the researchers noted that there was a high correlation between the labels.
Through this, they identified 29 variants independently associated with problematic drinking, 19 of which were novel.
Eleven of these variants were situated in gene regions, including PDE4B, THSD7B, and ADH1B, among others. Additionally, 10 of the novel variants have been associated with other alcohol-linked traits, including a variant in VRK2 and one in FUT2.
Through a gene-based association analysis, the researchers further identified 66 genes, 46 of which are novel, that were associated with PAU at genome-wide significance. These included the alcohol dehydrogenase genes ADH4, ADH5, and ADH7, which the researchers noted expands the alcohol-metabolizing gene associations.
Based on published genome-wide association study summary statistics, the researchers uncovered 138 traits that were significantly correlated with PAU. These included smoking and cannabis use, as well as psychiatric conditions like major depressive disorder.
Using tissues and data from the GTEx consortium, the researchers additionally found 103 gene-tissue associations for these PAU-linked genes. C1QTNF4, for example, was expressed in 18 tissues, including brain, gastrointestinal, adipose, and liver tissue. The expression of 34 genes was significantly associated with PAU, including ADH1B, ADH4, ADH5, C1QTNF4, GCKR, and DRD2.
After developing a polygenic risk score for PAU, the researchers noted that the score was also associated with alcohol-related disorders as well as with tobacco use and other respiratory and psychiatric conditions. They tested this risk score in three different samples to find it was significantly associated with alcohol dependence in all three. A Mendelian randomization analysis further suggested that there were causal relationships between these behaviors and the risk of problematic alcohol use.
"With these results, we are also in a better position to evaluate individual-level risk for problematic alcohol use," Gelernter said.
The researchers additionally found interactions between 16 of the genes they identified and 325 drugs, suggesting that some could serve as targets for drugs to manage or treat PAU.