Depression : genetic, epigenetic and DNA biobank studies

Sammanfattning: Depression is a disease that has an estimated lifetime prevalence of ~15% and a heritability of ~36%. There is support for a heterogeneous etiology of depression, which includes a) numerous genetic loci, b) various epigenetic contributors, and c) different environmental risk factors. The first five papers included in the present thesis investigate these three disease-contributing categories by studying a) the association of P11, NPY, MAOA and NR3C1, with depression, b) epigenetic marks like DNA methylation and histone modifications, and c) environmental influences, like childhood adversities, that may interact with certain genotypes and modulate the risk of depression. In two of these studies, there is also an attempt to pinpoint some targets and mechanisms of a current antidepressant drug and to examine the molecular effects of novel potential therapeutics. The thesis also includes a paper which investigates reasons behind public refusal to consent to participation in a human genetics repository; a so- called DNA biobank. Achieving high participation rates in DNA biobanks is a prerequisite for the identification of new genetic loci, already known to have small effect sizes, which are associated with complex disorders like depression. However, as addressed in this last paper, solidarity (i.e. the participation in research for the common good) seems to be at stake for DNA biobanks and is an issue that needs to be raised both by the scientific community and national policy-makers. Specifically, the data of this thesis 1) confirm a genetic association between NPY and depression, 2) show the existence of a MAOA x childhood-adversity interaction that increases the risk of depression, 3) demonstrate DNA methylation differences of P11 in depression-like states and of MAOA in depression, 4) verify the effect of childhood trauma on NR3C1 DNA methylation, 5) provide new insights into how Npy is transcriptionally regulated via an allele-specific epigenetic programming and describe an alternatively spliced Npy mRNA variant, 6) suggest that escitalopram (a selective serotonin reuptake inhibitor; SSRI) may exert part of its antidepressant function by affecting the expression of DNA methyltransferases (DNMTs) and DNA methylation levels, 7) support the antidepressant effect of running, and 8) provide awareness of the ethical problems posed by large-scale genomic studies that rely on DNA biobanking.

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