Sparse whole genome sequencing identifies two loci for major depressive disorder

Abstract

Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide ¹ , poses a major challenge to genetic analysis. To date no robustly replicated genetic loci have been identified ² , despite analysis of more than 9,000 cases ³ . Using low coverage genome sequence of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified and replicated two genome-wide significant loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P-value = 2.53×10 ⁻¹⁰) the other in an intron of the LHPP gene (P = 6.45×10 ⁻¹²). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.