Not Only Gene Discovery: Genome-wide Association Studies and Polygenic Risk Scores as Tools to Dissect the Heterogeneity of Major Depressive Disorder

Abstract

Large-scale genome-wide association studies (GWASs) based on biobanks and meta-analyses of many cohorts have revolutionized our ability to investigate the polygenic architecture of psychiatric disorders and traits. This has been possible because of national and international collaborations such as the Psychiatric Genomics Consortium (PGC) ( 1 Sullivan P.F. Agrawal A. Bulik C.M. Andreassen O.A. Borglum A.D. Breen G. et al. Psychiatric genomics: An update and an agenda. Am J Psychiatry. 2018; 175: 15-27 Crossref PubMed Scopus (292) Google Scholar ). While combining cohorts with different characteristics and various phenotypic assessments led to uncovering hundreds of loci associated with major depressive disorder (MDD) ( 2 Levey D.F. Stein M.B. Wendt F.R. Pathak G.A. Zhou H. Aslan M. et al. Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat Neurosci. 2021; 24: 954-963 Crossref PubMed Scopus (47) Google Scholar ), this has limited our ability to investigate the genetic heterogeneity of MDD. Owing to the massive sample sizes required to identify the small individual effects of single risk loci, it is not useful to directly compare gene discovery of GWASs of different MDD subtypes because the sample size available for each subtype is a primary driver of a GWAS’s statistical power. Indeed, although minimal phenotyping may reduce the specificity of MDD loci identified by GWASs ( 3 Cai N. Revez J.A. Adams M.J. Andlauer T.F.M. Breen G. Byrne E.M. et al. Minimal phenotyping yields genome-wide association signals of low specificity for major depression. Nat Genet. 2020; 52: 437-447 Crossref PubMed Scopus (92) Google Scholar ), sample size still trumps phenotyping when focusing only on gene discovery. SEE CORRESPONDING ARTICLE ON PAGE 227 The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between SubtypesBiological PsychiatryVol. 92Issue 3PreviewMajor 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. Full-Text PDF