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| PMID |
|
|
| TITLE |
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| The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes. |
|
| ABSTRACT |
|
| BACKGROUND |
NlmCategory: 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 |
NlmCategory: METHODS |
| 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. |
| RESULTS |
NlmCategory: RESULTS |
| 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. |
| CONCLUSIONS |
NlmCategory: CONCLUSIONS |
| 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. |
| Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2021/04/09 |
| revised |
2021/09/21 |
| accepted |
2021/10/24 |
| entrez |
2021/12/20 05:39 |
| pubmed |
2021/12/21 06:00 |
| medline |
2021/12/21 06:00 |
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| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Mitchell BL |
|
Mitchell |
Brittany L |
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. |
| Campos AI |
|
Campos |
Adrian I |
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. |
| Whiteman DC |
|
Whiteman |
David C |
DC |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Olsen CM |
|
Olsen |
Catherine M |
CM |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Gordon SD |
|
Gordon |
Scott D |
SD |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Walker AJ |
|
Walker |
Adam J |
AJ |
|
Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. |
| Dean OM |
|
Dean |
Olivia M |
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. |
| Berk M |
|
Berk |
Michael |
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. |
| Hickie IB |
|
Hickie |
Ian B |
IB |
|
Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia. |
| Medland SE |
|
Medland |
Sarah E |
SE |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Wray NR |
|
Wray |
Naomi R |
NR |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, Australia. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
| Byrne EM |
|
Byrne |
Enda M |
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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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: Biological psychiatry |
| ISOABBREVIATION: Biol Psychiatry |
| YEAR: 2021 |
| MONTH: Nov |
| DAY: 02 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1873-2402 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Biol Psychiatry |
| COUNTRY: United States |
| ISSNLINKING: 0006-3223 |
| NLMUNIQUEID: 0213264 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GENERAL NOTE |
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| KEYWORDS |
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| KEYWORD |
| Genetics |
| Genome-wide association study |
| Heterogeneity |
| Major depressive disorder |
| Polygenic risk scores |
| Psychiatry |
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| MESH HEADINGS |
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