Investigating Genetic Heterogeneity in Major Depression Through Item-level Genetic Analyses of the PHQ-9

BackgroundMajor Depressive Disorder (MDD) is a clinically heterogeneous disorder. Previous large-scale genetic studies of MDD have explored genetic risk factors of MDD case-control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity. AimIn this study, we present the results of symptom-level genetic analyses and compare SNP-based heritability (h2 O_SCPCAPSNPC_SCPCAP) and genetic correlations across major depression symptoms. We further investigate genetic correlations with a range of psychiatric disorders and other associated traits. Methods: We have analysed data from the UK biobank and included 148,752 subjects of white British ancestry with genotype data who completed nine items of a self-rated measure of depression: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD score regression analysis was used to calculate SNP-based heritability (h2 O_SCPCAPSNPC_SCPCAP) and genetic correlations (rg) across symptoms and to investigate genetic correlations with 25 external phenotypes. Confirmatory factor analyses were applied to test whether one, two, or three-factor models best fit the pattern of genetic correlations across the nine symptoms. ResultsWe identified 9 novel genome-wide significant genomic loci, with no overlap in loci across depression symptoms. h2 O_SCPCAPSNPC_SCPCAP ranged from 3% (suicidal ideation) to 11% (fatigue). Genetic correlations range from 0.54 to 0.96 (all p < 1.39x10-3) with 30 of 36 correlations being significantly smaller than 1. A 3-factor model provided the best fit to the genetic correlation matrix, with factors representing "psychological", "neurovegetative", and "psychomotor / concentration" symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms. DiscussionPatterns of h2 O_SCPCAPSNPC_SCPCAP and genetic correlations differed across the nine symptoms of depression. Our findings suggest that the large phenotypic heterogeneity observed for MDD is recapitulated at a genetic level. Future studies should investigate how genetic heterogeneity in MDD influences the efficacy of clinical interventions.