Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N?=?903,147; African, N?=?122,571; Latin American, N?=?38,962; East Asian, N?=?13,551; and South Asian, N?=?1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association...
| Authors | Zhou, H; Kember, RL; Deak, JD; Xu, H; Toikumo, S; Yuan, K; Lind, PA; Farajzadeh, L; Wang, L; Hatoum, AS; Johnson, J; Lee, H; Mallard, TT; Xu, J; Johnston, KJA; Johnson, EC; Nielsen, TT; Galimberti, M; Dao, C; Levey, DF; Overstreet, C; Byrne, EM; Gillespie, NA; Gordon, S; Hickie, IB; Whitfield, JB; Xu, K; Zhao, H; Huckins, LM; Davis, LK; Sanchez-Roige, S; Madden, PAF; Heath, AC; Medland, SE; Martin, NG; Ge, T; Smoller, JW; Hougaard, DM; Børglum, AD; Demontis, D; Krystal, JH; Gaziano, JM; Edenberg, HJ; Agrawal, A; Million Veteran Program; Justice, AC; Stein, MB; Kranzler, HR; Gelernter, J |
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| Journal | NATURE MEDICINE |
| Pages | 3184-3192 |
| Volume | 29 |
| Date | 7/01/2023 |
| Grant ID | R01 MH124851 | NIMH NIH HHS [MH] (United States); T32 AA028259 | NIAAA NIH HHS [AA] (United States); R01 AA007535 | NIAAA NIH HHS [AA] (United States); I01 BX004820 | BLRD VA [BX] (United States); R01 DA054869 | NIDA NIH HHS [DA] (United States); R01 AA013321 | NIAAA NIH HHS [AA] (United States); I01 CX001849 | CSRD VA [CX] (United States); K01 DA051759 | NIDA NIH HHS [DA] (United States); K01 AA030083 | NIAAA NIH HHS [AA] (United States); U54 AA027989 | NIAAA NIH HHS [AA] (United States); K01 AA028292 | NIAAA NIH HHS [AA] (United States); I01 BX003341 | BLRD VA [BX] (United States); R21 CA252916 | NCI NIH HHS [CA] (United States); R01 AA013320 | NIAAA NIH HHS [AA] (United States); R01 AA014041 | NIAAA NIH HHS [AA] (United States); K05 AA017688 | NIAAA NIH HHS [AA] (United States); P50 AA011998 | NIAAA NIH HHS [AA] (United States); UL1 TR001878 | NCATS NIH HHS [TR] (United States); R01 AA007728 | NIAAA NIH HHS [AA] (United States); UL1 TR001863 | NCATS NIH HHS [TR] (United States); R56 DA012854 | NIDA NIH HHS [DA] (United States); R01 HG012354 | NHGRI NIH HHS [HG] (United States); S10 OD018522 | NIH HHS [OD] (United States); S10 OD026880 | NIH HHS [OD] (United States); R01 AA026364 | NIAAA NIH HHS [AA] (United States); U01 MH109514 | NIMH NIH HHS [MH] (United States); DP1 DA054394 | NIDA NIH HHS [DA] (United States); R01 DA012854 | NIDA NIH HHS [DA] (United States); R00 DA023549 | NIDA NIH HHS [DA] (United States); R01 MH124839 | NIMH NIH HHS [MH] (United States); K08 DA019951 | NIDA NIH HHS [DA] (United States); R37 AA007728 | NIAAA NIH HHS [AA] (United States); P50 AA012870 | NIAAA NIH HHS [AA] (United States) |
| Funding Body | |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41591-023-02653-5 |