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A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency

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Abstract

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

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Data Availability

All data sources are described in the manuscript. No new data were collected. Only data from existing studies or study cohorts were analyzed. Add Health genetic data obtained through dbGaP (Study Accession: phs001367.v1.p1). Instructions on gaining access to Add Health restricted use data can be found at: https://data.cpc.unc.edu/projects/2/view. COGA genetic data available through dbGaP (Study Accession: phs000763.v1.p1). Instructions for access to ALSPAC data available at: http://www.bristol.ac.uk/alspac/researchers/access/.

Code Availability

No custom software was developed in this study. All code is available by request from the corresponding author.

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Acknowledgements

COGA: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, T. Foroud; Scientific Director, A. Agrawal; Translational Director, D. Dick, includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, T. Foroud, Y. Liu, M.H. Plawecki); University of Iowa Carver College of Medicine (S. Kuperman, J. Kramer); SUNY Downstate Health Sciences University (B. Porjesz, J. Meyers, C. Kamarajan, A. Pandey); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield, D. Dick, R. Hart, J. Salvatore); The Children’s Hospital of Philadelphia, University of Pennsylvania (L. Almasy); Icahn School of Medicine at Mount Sinai (A. Goate, P. Slesinger); and Howard University (D. Scott). Other COGA collaborators include: L. Bauer (University of Connecticut); J. Nurnberger Jr., L. Wetherill, X., Xuei, D. Lai, S. O’Connor, (Indiana University); G. Chan (University of Iowa; University of Connecticut); D.B. Chorlian, J. Zhang, P. Barr, S. Kinreich, G. Pandey (SUNY Downstate); N. Mullins (Icahn School of Medicine at Mount Sinai); A. Anokhin, S. Hartz, E. Johnson, V. McCutcheon, S. Saccone (Washington University); J. Moore, F. Aliev, Z. Pang, S. Kuo (Rutgers University); A. Merikangas (The Children’s Hospital of Philadelphia and University of Pennsylvania); H. Chin and A. Parsian are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting- Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).

ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website. This research was specifically funded by NIH AA018333, MRC G0800612/86812, Wellcome Trust and MRC (Core) 076467/Z/05/, NIH 5R01AA018333-05, Wellcome Trust and MRC 092731. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.

Add Health: Add Health is directed by Robert A. Hummer and funded by the National Institute on Aging cooperative agreements U01 AG071448 (Hummer) and U01AG071450 (Aiello and Hummer) at the University of North Carolina at Chapel Hill. Waves I-V data are from the Add Health Program Project, grant P01 HD31921 (Harris) from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), with cooperative funding from 23 other federal agencies and foundations. Add Health was designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill.

High Performance Computing resources provided by the High Performance Research Computing (HPRC) core facility at Virginia Commonwealth University (https://hprc.vcu.edu) and HPC resources hosted by the Virginia Institute for Psychiatric and Behavioral Genetics were used for conducting the research reported in this work.

Funding

This work was supported by the National Institutes of Health (NIH) Grant F31AA029620 (PI: Thomas) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and T32DA015035 (APM) from the National Institute on Drug Abuse (NIDA).

COGA: The Collaborative Study on the Genetics of Alcoholism (COGA) is supported by NIH Grant U10AA008401 (PI: Porjesz).

ALSPAC: A comprehensive list of grants funding is available on the ALSPAC website. This research was specifically funded by NIH AA018333, MRC G0800612/86812, Wellcome Trust and MRC (Core) 076467/Z/05/, NIH 5R01AA018333-05, Wellcome Trust and MRC 092731.

AddHealth: Add Health is funded by the National Institute on Aging cooperative agreements U01 AG071448 (Hummer) and U01AG071450 (Aiello and Hummer) at the University of North Carolina at Chapel Hill. Waves I-V data are from the Add Health Program Project, grant P01 HD31921 (Harris) from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), with cooperative funding from 23 other federal agencies and foundations.

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Authors and Affiliations

  1. Department of Psychology, Virginia Commonwealth University, Box 842018, Richmond, VA, 23284-2018, USA

    Nathaniel S. Thomas

  2. Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA

    Nathan A. Gillespie

  3. Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA

    Grace Chan

  4. Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA, USA

    Grace Chan

  5. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Howard J. Edenberg

  6. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    Howard J. Edenberg

  7. Department of Psychiatry & Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Chella Kamarajan

  8. Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA

    Sally I-Chun Kuo, Danielle M. Dick & Jessica E. Salvatore

  9. Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA

    Alex P. Miller

  10. Department of Psychiatry, Indiana University, Bloomington, IN, USA

    John I. Nurnberger Jr.

  11. Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA

    Jay Tischfield

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  1. Nathaniel S. Thomas
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Contributions

Nathaniel S. Thomas: conceived of the study, conducted statistical analyses, and wrote the manuscript. Nathan A. Gillespie assisted with the design and implementation of the study and provided editorial feedback on the whole manuscript. Grace Chan, Howard J. Edenberg, Chella Kamarajan, Sally I-Chun Kuo, Alex P. Miller, John I. Nurnberger Jr., and Jay Tischfield provided editorial feedback on the whole manuscript. Jessica E. Salvatore and Danielle M. Dick supervised the design and implementation of the study and provided editorial feedback on the whole manuscript. All authors contributed to and have approved the final manuscript.

Corresponding author

Correspondence to Nathaniel S. Thomas.

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Conflicts of Interest/Competing Interests

Nathaniel S. Thomas, Nathan A. Gillespie, Grace Chan, Howard J. Edenberg, Chella Kamarajan, Sally I-Chun Kuo, Alex P. Miller, John I. Nurnberger Jr., Jay Tischfield, Danielle M. Dick, and Jessica E. Salvatore declare that they have no conflicts of interest.

Ethics Approval

Secondary analysis of these data was determined to be qualified for exemption by the Institutional Review Board at Virginia Commonwealth University (HM20024009) according to 45 CFR 46 under exempt category 4 (ii). Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees (http://www.bristol.ac.uk/alspac/researchers/research-ethics/).

Consent to Participate

Written consent was obtained from all participants by each respective study.

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NA.

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Edited by Tinca Polderman

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Danielle M. Dick and Jessica E. Salvatore jointly supervised this work.

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Thomas, N.S., Gillespie, N.A., Chan, G. et al. A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency. Behav Genet 54, 151–168 (2024). https://doi.org/10.1007/s10519-023-10170-x

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