Вісник проблем біології і медицини (Apr 2019)
GENETICS OF MAJOR DEPRESSIVE DISORDER
Abstract
Major depressive disorder (MDD) is prevalent psychiatric disease with hereditary liability. It develops as a interaction result of genetic components and certain environmental factors. According to the results of the WHO investigation, the average global prevalence of major depressive disorder is 5%. There is a regional variation of this index, so that low prevalence is found in East and South-East Asia and sub-Saharan Africa, whereas higher prevalence is found in North and South America, North Africa and some European countries. Women have 1.5- 2.0 times risk of developing depression compared with men. Depression is more common among young people than among old people. The results of population study show that in family generations there is not clear pattern of inheritance of major depressive disorder, and it may appear in the family even when ancestral patients in the pedigree are absent. The depression inheritance is negligible and is about 40%. Thus, in the disorder development certain environmental factors are predominant: negative experiences in childhood, adverse life events, etc. The risk of developing depression may be increased in a presence of some nonmental diseases diabetes, obesity, and cardiovascular disease. The liability to depression is determined by a complex set of genes, each of which separately has a little effect. In addition, the set and the intensity of symptom expressions of different patients with major depression are varied extremely, making it difficult to determine the clear boundary between disorder and health. To study moleculargenetic mechanisms of MDD four methods are used: genome-wide linkage analysis, selection of candidate genes, genome-wide association studies, and resequencing. These methods allowed to identify 3 genomic regions (3p25- p26, 12q22-q24, 15q25-q26) and 10 genes (APOE, C5orf20, DRD4, GNB3, MTHFR, NPV, SLC6A2, SLC6A3, SLC6A4, TNF) that were associated with depression. Among the candidate genes, three genes associated with stress responses to be most attracted: DRD4, NPY, and SLC6A2. The DRD4 gene (11p15.5) encodes one in protein subunits of the dopamine receptor. This receptor participates in regulation of emotion and complex behavior. The NPY gene (7p15.3) encodes a neuropeptide Y, which is an active neurotransmitter in the central nervous system, and has an effect on cortical excitability, stress response, dietary, daily rhythms, and cardiovascular function. The SLC6A2 gene (16q12.2) encodes a noradrenaline neurotransmitter, which provides a reverse movement of this hormone through the presynaptic membrane after the stressful period passed. The method of genome-wide association allows to detect such damages of genome-wide DNA as these: single nucleotide polymorphisms (SNPs), single nucleotide variants (SNVs), small insertions/deletions (In/Del) and copy number variations (CNVs), part of which may be associated with depression. There were identified 4 SNPs: in the genes SLC6A15 and GPHN, in the region 16p11.2 and in the 5q21 noncoding region, which resides with the closest gene NUDT12, and 5 CNVs in the regions 7p21.3, 15q26.3, 15q35.1, 16p11.2 and 18p11.32. Due to resequencing it was determined the association of MDD with a number of SNPs 6 in the gene BDNF, 2 in the gene AANAT and 1 in the gene LIPG. The BDNF gene (11p14.1) is related to the development of the central nervous system. It encodes the neurotrophic brain factor a protein that stimulates and supports neurons development. The product of the AANAT gene (17q25.1) is involved in sleep regulation, as a key enzyme of the melatonin pathway. It is necessary to admit that we known about the genetic bases of liability to MDD still not enough. The study of these bases is restrained by lack of sufficient knowledge of the main links of complex network of neurophysiologic processes and biological pathway of MDD development.
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