GENETIC, EPIGENETIC AND DNA BIOBANK STUDIES

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 socalled 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. LIST OF PUBLICATIONS/MANUSCRIPTS I. Melas PA, Rogdaki M, Lennartsson A, Björk K, Qi H, Witasp A, Werme M, Wegener G, Mathé AA, Svenningsson P, Lavebratt C. Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression. Int J Neuropsychopharmacol. 2011 Jun 20:1-11. II. Sjöholm LK, Melas PA, Forsell Y, Lavebratt C. PreproNPY Pro7 protects against depression despite exposure to environmental risk factors. J Affect Disord. 2009 Nov; 118(1-3):124-30. III. Melas PA, Lennartsson A, Vakifahmetoglu-Norberg H, Åberg E, Werme M, Rogdaki M, Mannervik M, Brené S, Wegener G, Mathé AA, Lavebratt C. Allele-specific epigenetic programming of neuropeptide Y (Npy) in depression-like states. Manuscript. IV. Melas PA, Mannervik M, Mathé AA, Lavebratt C. Neuropeptide Y: Identification of a novel rat mRNA splice-variant that is downregulated in the hippocampus and the prefrontal cortex of a depression-like model. Peptides. 2012 Mar 3. V. Melas PA, Wei Y, Wong CCY, Sjöholm LK, Åberg E, Mill J, Schalling M, Forsell Y, Lavebratt1 C. Monoamine oxidase A (MAOA) gene-environment and epigenetic associations with depression in females, and MAOA’s action as a mediator of the association between childhood adversities and hypermethylation of the glucocorticoid receptor. Manuscript. VI. Melas PA, Sjöholm LK, Forsner T, Edhborg M, Juth N, Forsell Y, Lavebratt C. Examining the public refusal to consent to DNA biobanking: empirical data from a Swedish population-based study. J Med Ethics. 2010 Feb; 36(2):93-8. LIST OF ADDITIONAL PUBLICATIONS/MANUSCRIPTS I. Melas PA, Rogdaki M, Ösby U, Schalling M, Lavebratt C, Ekström TJ. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. FASEB J. 2012 Mar 16. II. Melas PA, Georgsson Öhman S, Juth N, Bui TH. Information Related to Prenatal Genetic Counseling: Interpretation by Adolescents, Effects on Risk Perception and Ethical Implications. J Genet Couns. 2011 Oct 25. III. Amstadter AB, Balachandar V, Bergen SE, Ceulemans S, Christensen JH, Cole J, Dagdan E, De Luca V, Ducci F, Tee SF, Hartz S, Keers R, Medland S, Melas PA, Mühleisen TW, Ozomaro U, Pidsley R, Scott AP, Sha L, Talati A, Teltsh O, Videtic A, Wang K, Wong CC, Delisi LE. Selected summaries from the XVII World Congress of Psychiatric Genetics, San Diego, California, USA, 4-8 November 2009. Psychiatr Genet. 2010 Oct; 20(5):229-68. IV. Melas PA, Tartani E, Edhborg M, Forsner T, Forsell Y. Mental health literacy about depression and schizophrenia among Swedish adolescents Manuscript.