Associations Between a Genetic Liability Toward Externalizing and Behavioral Outcomes Spanning Toddlerhood Through Early Adulthood in Five Developmental Cohorts - 04/06/25

Doi : 10.1016/j.jaac.2025.04.010

Maia Choi, MS ^a,^⁎ , Holly E. Poore, PhD ^a, Sarah J. Brislin, PhD ^a, Peter B. Barr, PhD ^b,^c, Fazil Aliev, PhD ^a, Stephanie Zellers, PhD ^d, Gretchen R.B. Saunders, PhD ^e, Jessica E. Salvatore, PhD ^a, Scott I. Vrieze, PhD ^e, K. Paige Harden, PhD ^f, Abraham A. Palmer, PhD ^g, Anu Raevuori, MD, PhD ^d, Antti Latvala, PhD ^d,
COGA Collaborators
Danielle M. Dick, PhD ^a,^⁎
^a Rutgers University, Piscataway, New Jersey
^b Veteran’s Affairs New York Harbor Healthcare System, New York, New York
^c SUNY Downstate Health Sciences University, Brooklyn, New York
^d University of Helsinki, Helsinki, Finland
^e University of Minnesota, Minneapolis, Minnesota
^f University of Texas, Austin, Texas
^g University of California San Diego, San Diego, California

^∗Correspondence to Maia Choi, MS, and Danielle Dick, PhD, 671 Hoes Lane W, Piscataway, NJ 08854671 Hoes Lane WPiscatawayNJ08854

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Wednesday 04 June 2025

Abstract

Objective

Understanding how genetic risk unfolds across development will be important for using genetics to inform prevention and early intervention. The current study leverages information from 5 large datasets to characterize behavioral manifestations of a genetic liability toward externalizing from ages 6 months to 26 years.

Method

We used polygenic scores (PGS) derived from a multivariate genome-wide association study (GWAS) of externalizing that identified hundreds of significantly associated genetic variants (EXT_PGS) to estimate associations of genetic liability with relevant phenotypes within and across developmental periods, ranging from toddlerhood to early adulthood. We used data from 5 population- and family-based datasets spanning 3 countries.

Results

The EXT_PGS was significantly associated with a breadth of externalizing phenotypes from toddlerhood to early adulthood. Higher EXT_PGS was consistently associated with measures of impulsivity from early adolescence to early adulthood. Individuals with higher EXT_PGS were more likely to experience conduct problems and symptoms of oppositional defiant and attention-deficit/hyperactivity disorders. Furthermore, the EXT_PGS was associated with higher levels of substance use and problems beginning in early adolescence through early adulthood, including alcohol and illicit drug use. There was minimal evidence for sex interactions.

Conclusion

A genetic liability toward externalizing is associated a wide array of behaviors and psychiatric/substance use outcomes beginning as early as childhood and through emerging adulthood. The early emergence and breadth of behaviors associated with a genetic liability toward externalizing could inform prevention and intervention.

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Key words : externalizing, development, polygenic, behavioral undercontrol, substance use

Plan

Personality and Behavioral Traits

Behavior Problems

Substance Use and Problems

Height

Phenotypes Not Included in Meta-Analyses

EXT_PGS by Sex Interactions

Discussion

CRediT authorship contribution statement

	The Externalizing Consortium has been supported by the National Institute on Alcohol Abuse and Alcoholism (R01AA015416 – administrative supplement to Danielle Dick), and the National Institute on Drug Abuse (R01DA050721 to Danielle Dick). Additional funding for investigator effort has been provided by K02AA018755, U10AA008401, P50AA022537 to Danielle Dick, as well as a European Research Council Consolidator Grant (647648 EdGe to Koellinger). The content is solely the responsibility of the authors and does not necessarily represent the official views of the above funding bodies. AddHealth: This research uses data from Add Health, funded by grant P01 HD31921 (Harris) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), with cooperative funding from 23 other federal agencies and foundations. Add Health is currently 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. Add Health was designed by J. Richard Udry, Peter S. Bearman, and Kathleen Mullan Harris at the University of North Carolina at Chapel Hill. ALSPAC: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (grant-acknowledgements.pdf). Genomewide genotyping data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from23andMe. FinnTwin 12: This work was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award numbers R01AA015416, R01AA09203, K02AA018755, and K01AA024152; and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278, and 264146). COGA: 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). MCTFR: This work was supported by NIH grants DA042755, DA046413, AA009367, MH066140, DA005147, DA013240, DA036216, AA023974, DA037904, and DA038065. The funding sources contributed to data collection, but not to study design or hypothesis.
	Data Sharing: Data are available through the individual studies.
	The Externalizing Consortium Principal Investigators: Danielle M. Dick, Philipp Koellinger, K. Paige Harden, Abraham A. Palmer. Lead Analysts: Richard Karlsson Linnér, Travis T. Mallard, Peter B. Barr, Sandra Sanchez-Roige. Significant Contributors: Irwin Waldman. externalizing.rutgers.edu/. 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. cogastudy.org/
	The Externalizing Consortium would like to thank the following groups for making the research possible: 23andMe, Add Health, Vanderbilt University Medical Center’s BioVU, Collaborative Study on the Genetics of Alcoholism (COGA), the Psychiatric Genomics Consortium’s Substance Use Disorders working group, UK10K Consortium, UK Biobank, and Philadelphia Neurodevelopmental Cohort. 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.
	This publication is the work of the authors and Maia Choi and Danielle Dick will serve as guarantors for the contents of this paper.
	Disclosure: Maia Choi has received a T32 fellowship funding from the National Institute on Drug Abuse. Holly E. Poore has received funding from the National Institute on Drug Abuse. Sarah J. Brislin has received funding from the National Institute on Drug Abuse, National Institute on Mental Health, National Institute on Alcohol Abuse and Alcoholism, and the Brain & Behavior Research Foundation. Peter B. Barr has received funding from National Institute on Drug Abuse, National Institute on Mental Health, and the National Institute on Alcohol Abuse and Alcoholism. Fazil Aliev has received funding from National Institute on Drug Abuse, National Institute of Health, and the National Institute on Alcohol Abuse and Alcoholism. Stephanie Zellers has received funding for an upcoming project from the Yrjö Jahnsson Foundation and is currently supported by the Broad Trauma Initiative at the Broad Institute of MIT and Harvard, as well as via the iRISE consortium which is a Horizon Europe funded project. Stephanie Zellers also received various research fellowships from the University of Minnesota Department of Psychology during her doctoral studies (2017-2022). Gretchen Saunders has received funding from the National Institute on Drug Abuse. Jessica Salvatore has received additional funding from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the National Center for Advancing Translational Science. Scott Vrieze has received funding from the National Institute on Drug Abuse. K. Paige Harden has received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She has received royalties from books published by Princeton University Press (The Genetic Lottery: Why DNA Matters for Social Equality) and contracted by Random House (title to be determined), and royalties from undergraduate course materials (Introduction to Psychology) from the University of Texas at Austin. She has received honoraria from Trinity University, Furman University, University of California at Santa Barbara, University of Colorado at Boulder, MD Anderson Hospital, and Brain Bar for speaking engagements. Abraham A. Palmer has received funding from the National Institutes of Health: National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism, National Institute on Deafness and Other Communication Disorders, National Institute of Mental Health, National Institute of General Medical Sciences, National Eye Institute; the Tobacco-Related Disease Research Program (administered by the University of California, Office of the President); the UC San Diego Stein Institute for Research on Aging; the National Science Foundation. Anu Raevuori reports receiving a research grant from Gyllenberg foundation, a lecture fee from Lundbeck Pharmaceutical, and holding an equity ownership in Meru Health Inc. Antti Latvala was funded by the Research Council of Finland. Danielle M. Dick has received funding from National Institute on Drug Abuse, National Center for Advancing Translational Sciences, the National Institute on Alcohol Abuse and Alcoholism. Danielle Dick is a co-founder of Thrive Genetics, Inc, and a member of the advisory board of Seek Health Group, Inc. She owns stock in both companies. Danielle Dick has reported being on the Advisory Board for the Seek Women’s Health Company. She is also a co-founder of the company, Thrive Genetics, Inc. She owns stock in both companies. She receives royalties from authoring the book, The Child Code: Understanding Your Child’s Unique Nature for Happier, More Effective Parenting, published by Avery, an imprint of the Penguin group.