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 Walker; Jesper R Gådin; Morten 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 W Dahl; Noah Zaitlen; Søren Dalsgaard; Thomas M Werge; Andrew J Schork

doi:10.1038/s41588-023-01593-7

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 Walker, Jesper R Gådin, Morten 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 JerniganDaniel H Geschwind, Andrés Ingason, Andrew W Dahl, Noah Zaitlen, Søren Dalsgaard, Thomas M Werge, Andrew J Schork

14 Citations (Scopus)

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.

Original language	English
Journal	Nature Genetics
Volume	56
Issue number	2
Pages (from-to)	234-244
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-023-01593-7
Publication status	Published - Feb 2024

Keywords

Attention Deficit Disorder with Hyperactivity/genetics
Autism Spectrum Disorder/genetics
Humans
Multifactorial Inheritance/genetics

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LaBianca, S., Brikell, I., Helenius, D., Loughnan, R., Mefford, J., Palmer, C. E., Walker, R., Gådin, J. R., Krebs, M., Appadurai, V., Vaez, M., Agerbo, E., Pedersen, M. G., Børglum, A. D., Hougaard, D. M., Mors, O., Nordentoft, M., Mortensen, P. B., Kendler, K. S., ... Schork, A. J. (2024). Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder. Nature Genetics, 56(2), 234-244. https://doi.org/10.1038/s41588-023-01593-7

LaBianca, S, Brikell, I, Helenius, D, Loughnan, R, Mefford, J, Palmer, CE, Walker, R, Gådin, JR , Krebs, M, Appadurai, V, Vaez, M, Agerbo, E, Pedersen, MG, Børglum, AD, Hougaard, DM, Mors, O, Nordentoft, M, Mortensen, PB, Kendler, KS, Jernigan, TL, Geschwind, DH, Ingason, A, Dahl, AW, Zaitlen, N, Dalsgaard, S , Werge, TM & Schork, AJ 2024, 'Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder', Nature Genetics, vol. 56, no. 2, pp. 234-244. https://doi.org/10.1038/s41588-023-01593-7

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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.",

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AU - Palmer, Clare E

AU - Walker, Rebecca

AU - Gådin, Jesper R

AU - Krebs, Morten

AU - Appadurai, Vivek

AU - Vaez, Morteza

AU - Agerbo, Esben

AU - Pedersen, Marianne Giørtz

AU - Børglum, Anders D

AU - Hougaard, David M

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Mortensen, Preben Bo

AU - Kendler, Kenneth S

AU - Jernigan, Terry L

AU - Geschwind, Daniel H

AU - Ingason, Andrés

AU - Dahl, Andrew W

AU - Zaitlen, Noah

AU - Dalsgaard, Søren

AU - Werge, Thomas M

AU - Schork, Andrew J

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AB - 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.

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KW - Autism Spectrum Disorder/genetics

KW - Humans

KW - Multifactorial Inheritance/genetics

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Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder

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