Researchers have identified 579 locations in the human genome associated with a predisposition to self-regulation-related behaviors, including addiction and child behavioral problems. With data from 1.5 million people of European descent, the effort is considered to be one of the largest genome-wide association studies to date.
The study, publishing August 26, 2021 in
Nature Neuroscience, was conducted by a consortium of researchers at 17 institutions in the United States and the Netherlands, including Abraham Palmer, PhD, professor and vice chair of basic research, and Sandra Sanchez-Roige, PhD, assistant professor, both in the Department of Psychiatry at University of California San Diego School of Medicine. The consortium is led by Palmer, Danielle Dick, PhD, Virginia Commonwealth University; Philipp Koellinger, PhD, University of Wisconsin-Madison and Vrije Universiteit Amsterdam; and Kathryn Paige Harden, PhD, University of Texas at Austin.
“Genes hold the instructions for making our brains,” Palmer said. “Subtle differences in those instructions create different brains that lead to different behaviors, even when confronted with the same environmental inputs. For example, different brains can be more or less impulsive. Over a lifetime, those little differences can shape the events of our lives in profound ways.”
The researchers examined the relationship between genetically predicted externalizing behaviors — a wide range of actions and disorders related to self-regulation — and a variety of medical outcomes. The results shows that a genetic predisposition to higher externalizing behavior was significantly associated with numerous psychiatric and somatic health problems.
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The researchers constructed a genetic risk score — a number that reflects a person’s overall genetic propensity based on how many risk variants they carry — to predict a range of behavioral, medical and social outcomes, including education levels, obesity, opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. These actions and disorders, related to self-regulation, are collectively known as “externalizing” behaviors.
“This study illustrates that genes don’t code for a particular disorder or outcome; there are no genes ‘for’ substance use disorder or ‘for’ behavior problems,” Dick said. “Instead, genes influence the way our brains are wired, which can make us more at risk for certain outcomes. In this case, we find that there are genes that broadly influence self-control or impulsivity, and that this predisposition then confers risk for a variety of life outcomes.”
Characterizing the genetic contributions to self-regulation is helpful because it permits researchers to better understand why some people are more predisposed to externalizing behaviors, predict who is at greatest risk for negative outcomes, prevent problems and intervene effectively.
The researchers hope that by providing a greater understanding of how genetic differences contribute to vulnerability, the study will also reduce stigma and blame surrounding externalizing behaviors. The researchers noted, however, that having a higher risk profile isn’t necessarily a bad thing.
“For example, CEOs, entrepreneurs and fighter pilots are often higher on risk-taking,” Dick said. “DNA is not destiny. We all have unique genetic codes, and we’re all at risk for something; but understanding one’s predisposition can be empowering — it can help individuals understand their strengths, and their potential challenges, and act accordingly.”
The study took a unique approach. Instead of relying on traditional disease diagnoses, the researchers focused on self-reported behaviors and experiences, such as age at first sexual experience and problematic consequences of alcohol use.
“These self-reported traits are easier to measure at scale in the general population, and they correlate strongly with the disease states of our interest — in this case, externalizing psychopathology or behavioral self-regulation,” Sanchez-Roige said. “This is a revolutionary way to study psychiatric genetics.”
The study focused on individuals of European ancestry because that was the source of data most readily available to the team.
“One of our next goals is to repeat these analyses in non-European populations so we can better understand the genetic factors that influence externalizing behaviors in other ancestry groups,” Palmer said. “We expect the specific genetic predictors to be different, because those are shaped by random mutations and patterns of human migration, but we hypothesize that the underlying biology of behavioral inhibition is common across all people and may even have similarities with other species.”
Co-authors include: Richard Karlsson Linnér, Ronald de Vlaming, Jorim J. Tielbeek, Vrije Universiteit Amsterdam; Travis T. Mallard, James W. Madole, Andrew D. Grotzinger, Elliot M. Tucker-Drob, University of Texas at Austin; Peter B. Barr, Morgan N. Driver, Virginia Commonwealth University; Holly E. Poore, Irwin D. Waldman, Emory University; Emma C. Johnson, Washington University; Mengzhen Liu, Scott Vrieze, University of Minnesota; Sara Brin Rosenthal, Trey Ideker, UC San Diego; Hang Zhou, Joel Gelernter, Yale University and VA CT Healthcare System; Rachel L. Kember, Henry R. Kranzler, University of Pennsylvania and Crescenz VA Medical Center; Joëlle A. Pasman, Radboud University Nijmegen; Karin J.H. Verweij, University of Amsterdam; Dajiang J. Liu, Penn State University; COGA Collaborators; Kathleen Mullan Harris, University of North Carolina at Chapel Hill.
Funding for this research came, in part, from the National Institutes of Health (grants R01AA015416, R01DA050721, K02AA018755, U10AA008401, P50AA0022527, R01HD092548, R01HD083613, R01AA026281, P50DA037844, P01HD031921, R01HD073342, R01HD060726, U10AA008401, S10RR025141, UL1TR002243, UL1TR000445, UL1RR024975, U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711, RC2MH089983, RC2MH089924), European Research Council (grant 647648 EdGe), Jacobs Foundation, Brain and Behavior Foundation (grant 27676) and California Tobacco-Related Disease Research Program (grants 28IR-0070, T29KT0526).