{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:49:58Z","timestamp":1766051398979,"version":"3.48.0"},"posted":{"date-parts":[[2025,12,15]]},"group-title":"Genetic and Genomic Medicine","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Alcohol use disorder (AUD) is a serious psychiatric condition associated with negative health and psychosocial consequences, comprising core symptoms of compulsive heavy drinking that impairs daily functioning. Genetic factors play a major role in AUD etiology, estimated to explain around 50% of variation in risk. Despite being a major global public health concern, the vast majority of genetic and epidemiological studies of AUD have been restricted to samples of European ancestry living in high-income countries. Using data from the Chitwan Valley Family Study, we perform the first comprehensive genetic study of AUD in a unique Nepalese sample of 10,032 individuals. We find significantly lower estimates of narrow-sense heritability (0.21, SE=0.06) compared to prior estimates from European and North American contexts. We also identified a novel genome-wide significant locus on chromosome 4 (lead SNP rs4323051,\n                  <jats:italic>p<\/jats:italic>\n                  =1.2e-8) in a region that determines MNS blood group status. Suggestive evidence of replication was found in a small South Asian genome-wide association study (GWAS), but not from a larger trans-ancestry GWAS. Polygenic scores for problematic alcohol use derived from an external trans-ancestry study explained 1.1% of variance in liability to AUD among males in the CVFS sample. This is the largest study of AUD in a South Asian ancestry sample and the first in a low-income country setting. Our results demonstrate the potential for careful phenotyping in ancestrally and socio-culturally diverse populations to yield novel insights into AUD etiology, while highlighting the need for larger efforts to replicate these findings and further improve cross-contextual polygenic prediction.\n                <\/jats:p>","DOI":"10.64898\/2025.12.13.25342207","type":"posted-content","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T01:15:26Z","timestamp":1765847726000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic Architecture of Alcohol Use Disorder in Nepal"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6671-6816","authenticated-orcid":false,"given":"Justin D.","family":"Tubbs","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixuan","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin","family":"Tsuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary T.","family":"Yohannes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Younga H.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily M.","family":"Madsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirgha J.","family":"Ghimire","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Hermosilla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karmel W.","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan W.","family":"Smoller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William G.","family":"Axinn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025121801451411000_2025.12.13.25342207v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31775-1"},{"key":"2025121801451411000_2025.12.13.25342207v1.2","doi-asserted-by":"crossref","first-page":"525","DOI":"10.3350\/cmh.2024.0835","article-title":"Global epidemiology of alcohol-related liver disease, liver cancer, and alcohol use disorder, 2000-2021","volume":"31","year":"2025","journal-title":"Clin. 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