Major depression
(MD), considered to be the most frequently encountered form of mental
illness and a leading cause of disability worldwide (Kessler, 2013) poses
a major challenge to genetic analysis. To date no robustly replicated
genetic loci have been identified (Flint, 2014;Levinson, 2014),
despite analysis of more than 9,000 cases (Major Depressive Disorder
Working Group of the Psychiatric, 2013). Using low coverage genome
sequence of 5,303 Chinese women with recurrent MD selected to reduce
phenotypic heterogeneity, and 5,337 screened
controls, we identified and replicated two genome-wide significant
loci contributing to risk of MD on chromosome 10: one locus
near to the SIRT1 gene (P-value = 4.91x10-10)
the other in an intron of the LHPP gene (P
= 4.91x10-12). Analysis
of a subset of 4,509 cases with melancholia yielded an increase
in genetic signal at SIRT1, but not LHPP. Exclusion of 668
cases reporting childhood sexual abuse, a strong environmental risk
factor for MD, led to increased odds ratios at both loci
and detection of another genome wide significant locus, near
SLC25A37, a mitochondrial ion transporter on chromosome 8 (P = 4.2x10-8).
Genome-wide analysis of rare exonic variants
showed that cases have a small but significant enrichment
of deleterious coding variants (P = 0.003) due in part to mutations
in genes involved in mitochondrial biology (P = 0.009), consistent
with the involvement of SIRT1 and SLC25A37 in mitochondrial function. Our
results demonstrate the complexity of genetic effects contributing to
MD, attributable to the disease’s etiologic heterogeneity, and suggest
that the pathogenesis of MD includes a mitochondrial origin.
