New Alcohol-related Genes Suggest Shared Genetic Mechanisms with Neuropsychiatric Disorders

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

Citing Articles

Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease.

Chen R, Petrazzini B, Duffy A, Rocheleau G, Jordan D, Bansal M Genome Biol. 2025; 26(1):50.

PMID: 40065360 PMC: 11892324. DOI: 10.1186/s13059-025-03518-5.

Characteristics and factors associated with psychotic-like experiences in remission: a cross-sectional study of 4208 college students in China.

Yang X, Wang R, Li Y, Zhou H, Zhou L, Sun M BMJ Open. 2024; 14(10):e084141.

PMID: 39353694 PMC: 11448162. DOI: 10.1136/bmjopen-2024-084141.

Large analysis of genetic manipulations reveals an inverse correlation between initial alcohol resistance and rapid tolerance phenotypes.

Chvilicek M, Seguin A, Lathen D, Titos I, Cummins-Beebee P, Pabon M Genes Brain Behav. 2024; 23(1):e12884.

PMID: 38968320 PMC: 10825885. DOI: 10.1111/gbb.12884.

Genome-wide association studies of lifetime and frequency cannabis use in 131,895 individuals.

Thorpe H, Fontanillas P, Meredith J, Jennings M, Cupertino R, Pakala S medRxiv. 2024; .

PMID: 38947071 PMC: 11213095. DOI: 10.1101/2024.06.14.24308946.

Unsupervised deep representation learning enables phenotype discovery for genetic association studies of brain imaging.

Patel K, Xie Z, Yuan H, Islam S, Xie Y, He W Commun Biol. 2024; 7(1):414.

PMID: 38580839 PMC: 10997628. DOI: 10.1038/s42003-024-06096-7.

References

Wood A, Kaptoge S, Butterworth A, Willeit P, Warnakula S, Bolton T . Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. Lancet. 2018; 391(10129):1513-1523. PMC: 5899998. DOI: 10.1016/S0140-6736(18)30134-X. View

Verhulst B, Neale M, Kendler K . The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Psychol Med. 2014; 45(5):1061-72. PMC: 4345133. DOI: 10.1017/S0033291714002165. View

Schumann G, Liu C, OReilly P, Gao H, Song P, Xu B . KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci U S A. 2016; 113(50):14372-14377. PMC: 5167198. DOI: 10.1073/pnas.1611243113. View

Baik I, Cho N, Kim S, Han B, Shin C . Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr. 2011; 93(4):809-16. DOI: 10.3945/ajcn.110.001776. View

Jackson B, Brocker C, Thompson D, Black W, Vasiliou K, Nebert D . Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 2011; 5(4):283-303. PMC: 3392178. DOI: 10.1186/1479-7364-5-4-283. View

Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J . UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015; 12(3):e1001779. PMC: 4380465. DOI: 10.1371/journal.pmed.1001779. View

McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood A, Teumer A . A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016; 48(10):1279-83. PMC: 5388176. DOI: 10.1038/ng.3643. View

Bulik-Sullivan B, Loh P, Finucane H, Ripke S, Yang J, Patterson N . LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015; 47(3):291-5. PMC: 4495769. DOI: 10.1038/ng.3211. View

Evangelou E, Ioannidis J . Meta-analysis methods for genome-wide association studies and beyond. Nat Rev Genet. 2013; 14(6):379-89. DOI: 10.1038/nrg3472. View

10.

Evangelou E, Warren H, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H . Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet. 2018; 50(10):1412-1425. PMC: 6284793. DOI: 10.1038/s41588-018-0205-x. View

11.

Do C, Tung J, Dorfman E, Kiefer A, Drabant E, Francke U . Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet. 2011; 7(6):e1002141. PMC: 3121750. DOI: 10.1371/journal.pgen.1002141. View

12.

Pankratz N, Beecham G, DeStefano A, Dawson T, Doheny K, Factor S . Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. Ann Neurol. 2012; 71(3):370-84. PMC: 3354734. DOI: 10.1002/ana.22687. View

13.

Okbay A, Baselmans B, De Neve J, Turley P, Nivard M, Fontana M . Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat Genet. 2016; 48(6):624-33. PMC: 4884152. DOI: 10.1038/ng.3552. View

14.

Couch F, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker K . Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 2013; 9(3):e1003212. PMC: 3609646. DOI: 10.1371/journal.pgen.1003212. View

15.

Ikram M, Fornage M, Smith A, Seshadri S, Schmidt R, Debette S . Common variants at 6q22 and 17q21 are associated with intracranial volume. Nat Genet. 2012; 44(5):539-44. PMC: 3618290. DOI: 10.1038/ng.2245. View

16.

van der Harst P, Zhang W, Mateo Leach I, Rendon A, Verweij N, Sehmi J . Seventy-five genetic loci influencing the human red blood cell. Nature. 2012; 492(7429):369-75. PMC: 3623669. DOI: 10.1038/nature11677. View

17.

Samuel A, Rubinstein A, Azar T, Livne Z, Kim S, Inbal A . Six3 regulates optic nerve development via multiple mechanisms. Sci Rep. 2016; 6:20267. PMC: 4731751. DOI: 10.1038/srep20267. View

18.

Liu J, van Sommeren S, Huang H, Ng S, Alberts R, Takahashi A . Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015; 47(9):979-986. PMC: 4881818. DOI: 10.1038/ng.3359. View

19.

Speliotes E, Willer C, Berndt S, Monda K, Thorleifsson G, Jackson A . Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010; 42(11):937-48. PMC: 3014648. DOI: 10.1038/ng.686. View

20.

Teslovich T, Musunuru K, Smith A, Edmondson A, Stylianou I, Koseki M . Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466(7307):707-13. PMC: 3039276. DOI: 10.1038/nature09270. View