Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

Hang Zhou; Rachel L. Kember; Joseph D. Deak; Heng Xu; Sylvanus Toikumo; Kai Yuan; Penelope A. Lind; Leila Farajzadeh; Lu Wang; Alexander S. Hatoum; Jessica Johnson; Hyunjoon Lee; Travis T. Mallard; Jiayi Xu; Keira J.A. Johnston; Emma C. Johnson; Trine Tollerup Nielsen; Marco Galimberti; Cecilia Dao; Daniel F. Levey; Cassie Overstreet; Enda M. Byrne; Nathan A. Gillespie; Scott Gordon; Ian B. Hickie; John B. Whitfield; Ke Xu; Hongyu Zhao; Laura M. Huckins; Lea K. Davis; Sandra Sanchez-Roige; Pamela A.F. Madden; Andrew C. Heath; Sarah E. Medland; Nicholas G. Martin; Tian Ge; Jordan W. Smoller; David M. Hougaard; Anders D. Børglum; Ditte Demontis; John H. Krystal; J. Michael Gaziano; Howard J. Edenberg; Arpana Agrawal; Hongyu Zhao; Amy C. Justice; Murray B. Stein; Henry R. Kranzler; Joel Gelernter; Million Veteran Program

doi:10.1038/s41591-023-02653-5

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

Hang Zhou^*, Rachel L. Kember, Joseph D. Deak, Heng Xu, Sylvanus Toikumo, Kai Yuan, Penelope A. Lind, Leila Farajzadeh, Lu Wang, Alexander S. Hatoum, Jessica Johnson, Hyunjoon Lee, Travis T. Mallard, Jiayi Xu, Keira J.A. Johnston, Emma C. Johnson, Trine Tollerup Nielsen, Marco Galimberti, Cecilia Dao, Daniel F. LeveyCassie Overstreet, Enda M. Byrne, Nathan A. Gillespie, Scott Gordon, Ian B. Hickie, John B. Whitfield, Ke Xu, Hongyu Zhao, Laura M. Huckins, Lea K. Davis, Sandra Sanchez-Roige, Pamela A.F. Madden, Andrew C. Heath, Sarah E. Medland, Nicholas G. Martin, Tian Ge, Jordan W. Smoller, David M. Hougaard, Anders D. Børglum, Ditte Demontis, John H. Krystal, J. Michael Gaziano, Howard J. Edenberg, Arpana Agrawal, Hongyu Zhao, Amy C. Justice, Murray B. Stein, Henry R. Kranzler, Joel Gelernter^*, Million Veteran Program

^*Corresponding author for this work

Department of Biomedicine - Forskning og uddannelse, Skou-bygningen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

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 in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer.

Original language	English
Journal	Nature Medicine
Volume	29
Issue	12
Pages (from-to)	3184-3192
Number of pages	9
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-023-02653-5
Publication status	Published - Dec 2023

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Zhou, H., Kember, R. L., Deak, J. D., Xu, H., Toikumo, S., Yuan, K., Lind, P. A., Farajzadeh, L., Wang, L., Hatoum, A. S., Johnson, J., Lee, H., Mallard, T. T., Xu, J., Johnston, K. J. A., Johnson, E. C., Nielsen, T. T., Galimberti, M., Dao, C., ... Million Veteran Program (2023). Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals. Nature Medicine, 29(12), 3184-3192. https://doi.org/10.1038/s41591-023-02653-5

@article{58e3e4d673d94fef9754101154229a48,

title = "Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals",

abstract = "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 in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer.",

author = "Hang Zhou and Kember, {Rachel L.} and Deak, {Joseph D.} and Heng Xu and Sylvanus Toikumo and Kai Yuan and Lind, {Penelope A.} and Leila Farajzadeh and Lu Wang and Hatoum, {Alexander S.} and Jessica Johnson and Hyunjoon Lee and Mallard, {Travis T.} and Jiayi Xu and Johnston, {Keira J.A.} and Johnson, {Emma C.} and Nielsen, {Trine Tollerup} and Marco Galimberti and Cecilia Dao and Levey, {Daniel F.} and Cassie Overstreet and Byrne, {Enda M.} and Gillespie, {Nathan A.} and Scott Gordon and Hickie, {Ian B.} and Whitfield, {John B.} and Ke Xu and Hongyu Zhao and Huckins, {Laura M.} and Davis, {Lea K.} and Sandra Sanchez-Roige and Madden, {Pamela A.F.} and Heath, {Andrew C.} and Medland, {Sarah E.} and Martin, {Nicholas G.} and Tian Ge and Smoller, {Jordan W.} and Hougaard, {David M.} and B{\o}rglum, {Anders D.} and Ditte Demontis and Krystal, {John H.} and Gaziano, {J. Michael} and Edenberg, {Howard J.} and Arpana Agrawal and Hongyu Zhao and Justice, {Amy C.} and Stein, {Murray B.} and Kranzler, {Henry R.} and Joel Gelernter and {Million Veteran Program}",

year = "2023",

month = dec,

doi = "10.1038/s41591-023-02653-5",

language = "English",

volume = "29",

pages = "3184--3192",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "12",

}

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, Zhao, H, Justice, AC, Stein, MB, Kranzler, HR, Gelernter, J & Million Veteran Program 2023, 'Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals', Nature Medicine, vol. 29, no. 12, pp. 3184-3192. https://doi.org/10.1038/s41591-023-02653-5

TY - JOUR

T1 - Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

AU - Zhou, Hang

AU - Kember, Rachel L.

AU - Deak, Joseph D.

AU - Xu, Heng

AU - Toikumo, Sylvanus

AU - Yuan, Kai

AU - Lind, Penelope A.

AU - Farajzadeh, Leila

AU - Wang, Lu

AU - Hatoum, Alexander S.

AU - Johnson, Jessica

AU - Lee, Hyunjoon

AU - Mallard, Travis T.

AU - Xu, Jiayi

AU - Johnston, Keira J.A.

AU - Johnson, Emma C.

AU - Nielsen, Trine Tollerup

AU - Galimberti, Marco

AU - Dao, Cecilia

AU - Levey, Daniel F.

AU - Overstreet, Cassie

AU - Byrne, Enda M.

AU - Gillespie, Nathan A.

AU - Gordon, Scott

AU - Hickie, Ian B.

AU - Whitfield, John B.

AU - Xu, Ke

AU - Zhao, Hongyu

AU - Huckins, Laura M.

AU - Davis, Lea K.

AU - Sanchez-Roige, Sandra

AU - Madden, Pamela A.F.

AU - Heath, Andrew C.

AU - Medland, Sarah E.

AU - Martin, Nicholas G.

AU - Ge, Tian

AU - Smoller, Jordan W.

AU - Hougaard, David M.

AU - Børglum, Anders D.

AU - Demontis, Ditte

AU - Krystal, John H.

AU - Gaziano, J. Michael

AU - Edenberg, Howard J.

AU - Agrawal, Arpana

AU - Zhao, Hongyu

AU - Justice, Amy C.

AU - Stein, Murray B.

AU - Kranzler, Henry R.

AU - Gelernter, Joel

AU - Million Veteran Program

PY - 2023/12

Y1 - 2023/12

N2 - 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 in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer.

AB - 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 in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights—together with neuroscience, biology and data science—closer.

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U2 - 10.1038/s41591-023-02653-5

DO - 10.1038/s41591-023-02653-5

M3 - Journal article

C2 - 38062264

AN - SCOPUS:85178897331

SN - 1078-8956

VL - 29

SP - 3184

EP - 3192

JO - Nature Medicine

JF - Nature Medicine

IS - 12

ER -

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals

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