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BackgroundMajor 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.MethodsThe 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.ResultsWe 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.ConclusionsUntil 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.

Original publication

DOI

10.1016/j.biopsych.2021.10.021

Type

Journal article

Journal

Biological psychiatry

Publication Date

08/2022

Volume

92

Pages

227 - 235

Addresses

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.

Keywords

Humans, Genetic Predisposition to Disease, Depression, Depressive Disorder, Major, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Australia, Genome-Wide Association Study