Genetic Architecture of Alcohol Use Disorder in Nepal

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, p=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.