Date: October 14, 2016. 12:00
Location: Auditorium of the CCU
Major depression (MD), the commonest psychiatric disorder and a leading cause of disability worldwide poses a major challenge to genetic analysis. No robustly replicated genetic loci have been identified, despite analysis of more than 9,000 cases. Using low pass whole genome sequence of a sample of 5,303 Chinese women with recurrent MD, selected to reduce known and suspected causes of heterogeneity, and 5,337 screened controls we identified and replicated two genome-wide significant loci that contribute to the risk of MD. The combined sample yielded P-values of P = 4.91E-10 at a locus 5’ to the SIRT1 gene (odds ratio 1.15) and P = 4.91E-12 in an intron of the LHPP gene (odds ratio 1.19). Analysis of the 4,509 cases diagnosed with melancholia, a severe form of MD, yielded an increase in genetic signal at the SIRT1 locus, but not at the LHPP locus. Exclusion of 585 cases who reported childhood sexual abuse, the most potent single risk factor known for MD, led to an increase in genetic signal at both loci and the detection of one more genome wide significant locus, in an intergenic region on chromosome 8 (P = 4.2E-8). Rare variants detected in the exomes were used to show that cases have a small but significant enrichment of deleterious coding variant (P = 0.0026). Our results demonstrate the complexity of genetic effects contributing to the risk of MD, likely due to the disease’s etiologic heterogeneity.