Characterizing the Pleiotropic Architecture of Impulsivity and Its Links to Psychopathology and Neurodevelopment.
Mallard TT., Tubbs JD., Jennings M., Zhang Y., Gustavson DE., Grotzinger AD., Westwater ML., Williams CM., Fortgang RG., Elson SL., Fontanillas P., Davis LK., Raznahan A., Tucker-Drob EM., Choi KW., Ge T., Smoller JW., Palmer AA., Sanchez-Roige S.
OBJECTIVE: Impulsivity is a complex mental construct and a core feature of many psychiatric and neurological conditions. The aim of this study was to formally model the genetic architecture of eight impulsive traits, identifying their shared and distinct genetic influences, to advance our biological understanding of impulsivity. METHODS: The authors analyzed genetic data from up to 133,517 individuals using novel multivariate genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) approaches. Bioinformatic analyses were conducted to identify gene expression patterns and neurobiological correlates, and polygenic score analyses were used to examine the ways in which genetic liability for impulsivity relates to clinical outcomes. RESULTS: The analyses revealed pervasive pleiotropy that largely counters theories of impulsivity as a unitary construct. GWAS and TWAS analyses identified 18 loci and 93 genes, respectively, that have diverse effects on self-regulation, including a hotspot at 17q21.31 that harbors genes involved in neurodevelopmental and neurodegenerative disorders. Bioinformatic analyses revealed that many biological correlates have divergent effects on impulsive traits, including upregulated gene expression during early neurodevelopment and altered cortical morphometry of the inferior frontal gyrus in adulthood. Polygenic score analyses suggest that liability for impulsivity may canalize across development, as polygenic influences on clinical outcomes tended to operate via shared pathways early in life but not in adulthood. CONCLUSIONS: These findings provide new insights into the pleiotropic architecture of impulsivity, its multifaceted biology, and its diverse relationships with mental health. The study underscores the importance of considering impulsivity as a genetically heterogeneous construct and highlights key neurodevelopmental pathways that shape its expression across the lifespan.