Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

Kranzler, H.; Zhou, H.; Kember, R.; Smith, R. V.; Justice, A.; Damrauer, S.; Tsao, P. S.; Klarin, D.; Rader, D. J.; Cheng, Z.; Tate, J. P.; Becker, W. C.; Concato, J.; Xu, K.; Polimanti, R.; Zhao, H.; Gelernter, J.

doi:10.1101/527929

bioRxiv · 10.1101/527929

Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

Kranzler, H.·Zhou, H.·Kember, R.·Smith, R. V.·Justice, A.·Damrauer, S.·Tsao, P. S.·Klarin, D.·Rader, D. J.·Cheng, Z.·Tate, J. P.·Becker, W. C.·Concato, J.·Xu, K.·Polimanti, R.·Zhao, H.·Gelernter, J.

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Abstract

Although alcohol consumption level and alcohol use disorder (AUD) diagnosis are both moderately heritable, their genetic risks and overlap are not well understood. We conducted genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores (reflecting alcohol consumption) and AUD diagnoses from electronic health records (EHRs) in a single, large multi-ancestry Million Veteran Program sample. Meta-analysis across population groups (N = 274,424) identified 18 genome-wide significant loci, 5 of which were associated with both traits and 13 with either AUDIT-C (N = 8) or AUD (N = 5). A significant genetic correlation between the traits reflects this overlap. However, downstream analyses revealed biologically meaningful points of divergence. Cell-type group partitioning heritability enrichment analyses indicated that central nervous system was the most significant cell type for AUDIT-C and the only significant cell type for AUD. Polygenic risk scores (PRS) for both traits were associated with alcohol-related disorders in two independent samples. Genetic correlations for 188 non-alcohol-related traits were significantly different for the two traits, as were the phenotypes associated with the traits polygenic risk scores. We conclude that EHR-derived, longitudinal, repeated measures of alcohol consumption level and AUD diagnosis can facilitate genetic discovery and help to elucidate the relationship between drinking level and AUD risk. Finally, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

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Kranzler, H., Zhou, H., Kember, R., Smith, R. V., Justice, A., Damrauer, S., Tsao, P. S., Klarin, D., Rader, D. J., Cheng, Z., Tate, J. P., Becker, W. C., Concato, J., Xu, K., Polimanti, R., Zhao, H., Gelernter, J.. 2019-01-25. Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424). https://doi.org/10.1101/527929

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