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

Background Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder but little is known about the genetic characterisation of this heterogeneity. Understanding the genetic etiology of MDD can be challenging as large sample sizes are needed for gene discovery – often achieved with a trade-off in the depth 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 depression GWAS to date and subsequently used polygenic scores (PGS) 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 show that a PGS for depression explains 5.7% of variance in MDD liability in our sample. Lastly, we find 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 discovery of novel loci, we provide support for differential pathways to illness models that recognize both the overlap with other common psychiatric disorders, as well as pathophysiological differences.