The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes.

Australia Depression Depressive Disorder, Major / genetics Genetic Predisposition to Disease / genetics Genome-Wide Association Study Humans Multifactorial Inheritance / genetics Polymorphism, Single Nucleotide / genetics
Genetics Genome-wide association study Heterogeneity Major depressive disorder Polygenic risk scores Psychiatry

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 08 2022
Historique:
received: 09 04 2021
revised: 21 09 2021
accepted: 24 10 2021
pubmed: 21 12 2021
medline: 19 7 2022
entrez: 20 12 2021
Statut: ppublish

Résumé

Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery-often achieved with a trade-off in the depth of phenotyping. The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest publicly available depression genome-wide association study to date and subsequently used polygenic scores to investigate genetic heterogeneity across various clinical subtypes of MDD. We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We found that a polygenic score for depression explained 5.7% of variance in MDD liability in our sample. Finally, we found strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course, and various subtypes of MDD. Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with the discovery of novel loci, we provide support for differential pathways to illness models that recognize the overlap with other common psychiatric disorders as well as pathophysiological differences.

Sections du résumé

BACKGROUND
Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery-often achieved with a trade-off in the depth of phenotyping.
METHODS
The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest publicly available depression genome-wide association study to date and subsequently used polygenic scores to investigate genetic heterogeneity across various clinical subtypes of MDD.
RESULTS
We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We found that a polygenic score for depression explained 5.7% of variance in MDD liability in our sample. Finally, we found strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course, and various subtypes of MDD.
CONCLUSIONS
Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with the discovery of novel loci, we provide support for differential pathways to illness models that recognize the overlap with other common psychiatric disorders as well as pathophysiological differences.

Identifiants

DOI: 10.1016/j.biopsych.2021.10.021 PMID: 34924174
pubmed: 34924174
pii: S0006-3223(21)01715-7
doi: 10.1016/j.biopsych.2021.10.021
pii:
doi:

Types de publication

Journal Article Meta-Analysis Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

227-235

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Auteurs

Brittany L Mitchell (BL)

QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia. Electronic address: Brittany.mitchell@qimrberghofer.edu.au.

Adrian I Campos (AI)

QIMR Berghofer Medical Research Institute, Brisbane, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.

David C Whiteman (DC)

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Catherine M Olsen (CM)

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Scott D Gordon (SD)

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Adam J Walker (AJ)

Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia.

Olivia M Dean (OM)

Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia; Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia.

Michael Berk (M)

Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia; Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Australia.

Ian B Hickie (IB)

Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.

Sarah E Medland (SE)

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Naomi R Wray (NR)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, Australia.

Nicholas G Martin (NG)

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Enda M Byrne (EM)

Child Health Research Centre, The University of Queensland, Brisbane, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. Electronic address: Enda.byrne@uq.edu.au.

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Classifications MeSH

questionsmedicales.fr › Régions géographiques › Océanie › Australasie › Australie › The Australian Genetics of Depression Study:...
questionsmedicales.fr › Comportement et mécanismes comportementaux › Émotions › Dépression › The Australian Genetics of Depression Study:...
questionsmedicales.fr › Troubles mentaux › Troubles de l'humeur › Trouble dépressif › Trouble dépressif majeur › The Australian Genetics of Depression Study:...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › The Australian Genetics of Depression Study:...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › The Australian Genetics of Depression Study:...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The Australian Genetics of Depression Study:...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Hérédité multifactorielle › The Australian Genetics of Depression Study:...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › The Australian Genetics of Depression Study:...