Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder
Sonja LaBianca, Isabell Brikell, Dorte Helenius, Robert Loughnan, Joel Mefford, Clare E. Palmer, Rebecca L. Walker, Jesper R. Gådin, Morten Dybdahl Krebs, Vivek Appadurai, Morteza Vaez, Esben Agerbo, Marianne Giørtz Pedersen, Anders D. Børglum, David M. Hougaard, Ole Mors, Merete Nordentoft, Preben Bo Mortensen, Kenneth S. Kendler, Terry L. Jernigan, Daniel H. Geschwind, Andrés Ingason, Andrew Dahl, Noah Zaitlen, Søren Dalsgaard, Thomas Werge, Andrew J. Schork
Abstract
Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic heterogeneity in ADHD, helping us to understand its etiology and providing a model for studies of other disorders. Genome-wide analyses yield insights into the polygenic effects contributing to clinical heterogeneity in attention deficit hyperactivity disorder, advancing understanding of its genetic etiology and serving as a model for future studies in other complex disorders.