Molecular markers of stress

Using data from the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) Consortium study of major depressive disorder (MDD)on 11,670 Han Chinese women, this thesis describes an investigation on the etiology of MDD, a psychiatric disease that has eluded previous genetic studies as well as investigations of its mechanistic underpinnings. It asks: what happens during stress, how may it contribute to the risk of developing MDD, and why does it increase the risk of MDD in some people but not others. It presents three main findings. First, a GWAS on MDD conducted on 10,640 samples (5,303 cases and 5,337 controls) in the CONVERGE dataset found two genome wide significant associations with MDD, one lying at the 5' side of SIRT1, and the other in an intron of LHPP. Both signals have been replicated in a completely independent cohort of severe MDD cases and matched controls from Northern China, making them the first replicated association loci for MDD to date. Second, I found there are more copies of mtDNA in cases of MDD than controls and while the increase can be induced by stress, it is contingent on the depressed state. Further analyses of results from animal experiments showed stress increases mtDNA levels in a dose-dependent, reversible and tissue specific way that is mediated partly by stress steroids. Third, the total amount of heteroplasmy was found to increase with increasing mtDNA levels, and therefore is higher in cases of MDD than controls, consistent with a change in mitochondrial function observed in animal models of chronic stress. All three findings suggest stress causes changes in mtDNA, and this change may be larger in cases of MDD than controls. This difference between cases and controls may be due to differences in their regulation of mtDNA levels and sequence mutation during stress, and this may be genetically determined. This study provides a new perspective to the etiology of depression, suggesting it may have origins in metabolic regulation.