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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

2 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	56
Nummer	2
Sider (fra-til)	234-244
Antal sider	11
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-023-01593-7
Status	Udgivet - feb. 2024

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10.1038/s41588-023-01593-7

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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

@article{ef2e35b5907f4d60b175a532bb6a94f7,

title = "Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder",

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.",

keywords = "Attention Deficit Disorder with Hyperactivity/genetics, Autism Spectrum Disorder/genetics, Humans, Multifactorial Inheritance/genetics",

author = "Sonja LaBianca and Isabell Brikell and Dorte Helenius and Robert Loughnan and Joel Mefford and Palmer, {Clare E} and Rebecca Walker and G{\aa}din, {Jesper R} and Morten Krebs and Vivek Appadurai and Morteza Vaez and Esben Agerbo and Pedersen, {Marianne Gi{\o}rtz} and B{\o}rglum, {Anders D} and Hougaard, {David M} and Ole Mors and Merete Nordentoft and Mortensen, {Preben Bo} and Kendler, {Kenneth S} and Jernigan, {Terry L} and Geschwind, {Daniel H} and Andr{\'e}s Ingason and Dahl, {Andrew W} and Noah Zaitlen and S{\o}ren Dalsgaard and Werge, {Thomas M} and Schork, {Andrew J}",

note = "{\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2024",

month = feb,

doi = "10.1038/s41588-023-01593-7",

language = "English",

volume = "56",

pages = "234--244",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

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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, bind 56, nr. 2, s. 234-244. https://doi.org/10.1038/s41588-023-01593-7

TY - JOUR

T1 - Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder

AU - LaBianca, Sonja

AU - Brikell, Isabell

AU - Helenius, Dorte

AU - Loughnan, Robert

AU - Mefford, Joel

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

PY - 2024/2

Y1 - 2024/2

N2 - 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.

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.

KW - Attention Deficit Disorder with Hyperactivity/genetics

KW - Autism Spectrum Disorder/genetics

KW - Humans

KW - Multifactorial Inheritance/genetics

U2 - 10.1038/s41588-023-01593-7

DO - 10.1038/s41588-023-01593-7

M3 - Journal article

C2 - 38036780

SN - 1061-4036

VL - 56

SP - 234

EP - 244

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

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