Do polygenic indices capture “direct” effects on child externalizing behavior? Within-family analyses in two longitudinal birth cohorts
Abstract
Abstract Behaviors and disorders characterized by difficulties with self-regulation, such as problematic substance use, antisocial behavior, and symptoms of attention-deficit/hyperactivity disorder (ADHD), incur high costs for individuals, families, and communities. These externalizing behaviors often appear early in the life course and can have far-reaching consequences. Researchers have long been interested in direct measurements of genetic risk for externalizing behaviors, which can be incorporated alongside other known risk factors to improve efforts at early identification and intervention. In a preregistered analysis drawing on data from the Environmental Risk (E-Risk) Longitudinal Twin Study ( N =862 twins) and the Millennium Cohort Study (MCS; N =2,824 parent-child trios), two longitudinal cohorts from the UK, we leveraged molecular genetic data and within-family designs to test for genetic effects on externalizing behavior that are unbiased by the common sources of environmental confounding. Results are consistent with the conclusion that an externalizing polygenic index (PGI) captures causal effects of genetic variants on externalizing problems in children and adolescents, with an effect size that is comparable to those observed for other established risk factors in the research literature on externalizing behavior. Additionally, we find that polygenic associations vary across development (peaking from age 5-10 years), that parental genetics (assortment and parent-specific effects) and family-level covariates affect prediction little, and that sex differences in polygenic prediction are present but only detectable using within-family comparisons. Based on these findings, we believe that the PGI for externalizing behavior is a promising means for studying the development of disruptive behaviors across child development. Significance Statement Externalizing behaviors/disorders are important but difficult to predict and address. Twin models have suggested that externalizing behaviors are heritable (∼80%), but it has been difficult to measure genetic risk factors directly. Here, we go beyond heritability studies by quantifying genetic liability for externalizing behaviors using a polygenic index (PGI) and employing within-family comparisons to remove sources of environmental confounding typical of such polygenic predictors. In two longitudinal cohorts, we find that the PGI is associated with variation in externalizing behaviors within families, and the effect size is comparable to established risk factors for externalizing behaviors. Our results suggest that genetic variants associated with externalizing behaviors, unlike many other social-science phenotypes, primarily operate through direct genetic pathways.
Authors 16
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Peter T. Tanksley corresponding
The University of Texas at Austin
Affiliation as printed
Department of Psychology, The University of Texas at Austin, Austin, TX, USA
Population Research Center, The University of Texas at Austin, Austin, TX, USA
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Rutgers, The State University of New Jersey
Affiliation as printed
Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Newark, NJ, USA
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Duke University · University of Edinburgh
Affiliation as printed
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Department of Psychology, University of Edinburgh, Edinburgh, UK
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Affiliation as printed
Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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University of California San Diego
Affiliation as printed
Department of Psychiatry, University of California San Diego, San Diego, CA, USA
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Harvard University · Massachusetts General Hospital
Affiliation as printed
Department of Psychiatry, Harvard Medical School, Boston, MA, USA
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
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Max Planck Institute for Human Development · The University of Texas at Austin
Affiliation as printed
Department of Psychology, The University of Texas at Austin, Austin, TX, USA
Max Planck Institute for Human Development, Berlin, Germany
Population Research Center, The University of Texas at Austin, Austin, TX, USA
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Affiliation as printed
Department of Economics, Leiden Law School, Leiden University, the Netherlands
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Affiliation as printed
Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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University of California San Diego
Affiliation as printed
Department of Psychiatry, University of California San Diego, San Diego, CA, USA
Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
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University of California San Diego · Vanderbilt University Medical Center
Affiliation as printed
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Department of Psychiatry, University of California San Diego, San Diego, CA, USA
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Affiliation as printed
Department of Psychology, Emory University, Atlanta, GA, USA
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Rutgers, The State University of New Jersey
Affiliation as printed
Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Newark, NJ, USA
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Duke University · King's College London · University of Oslo
Affiliation as printed
Center for the Study of Population Health & Aging, Duke University Population Research Institute, Durham, NC, USA
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Department of Psychology, University of Oslo, Oslo, Norway
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
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Duke University · King's College London · University of Oslo
Affiliation as printed
Center for the Study of Population Health & Aging, Duke University Population Research Institute, Durham, NC, USA
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
Department of Psychology, University of Oslo, Oslo, Norway
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
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The University of Texas at Austin
Affiliation as printed
Department of Psychology, The University of Texas at Austin, Austin, TX, USA
Population Research Center, The University of Texas at Austin, Austin, TX, USA
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