Genetic studies of depressive symptoms

Abstract

This thesis is focused on depressive symptoms particularly in late fife. Depressive symptoms are associated with serious negative outcomes a greater level of disability and with excess morbidity and mortality. This thesis includes a series of studies that explore the importance of genetic components on current and past depressive symptoms in a large sub-sample of the Swedish Twin Registry. More specifically gender differences, genetic risk factors, and the role of some genetic variants of candidate genes in the serotonergic system were investigated.

The relative importance of genetic and environmental variance components for depressive symptoms was investigated by means of a twin design. The sex specific heritability estimates (b2) for depressive symptom-, were 14% for males and 29% for females and 23% when constrained to be equal across the sexes. The prevalence of the dichotomous depressed mood variable was 16%. for men and 24% for women with corresponding heritability estimates of 7% for males and 49% for females in the full model and 33% in the best fitting (AE) model constrained to be equal across sexes. These results show that depressive symptoms and depressed mood in the elderly are heritable, with an indication of a higher heritability for women than men.

The novel real-time sequencing method, Pyrosequencing - was evaluated for genotyping of single nucleotide polymorphisms (SNPs) and the first large-scale effort at genotyping using this method was performed. Pyrosequencing genotypes were validated through duplicate analysis of 1022 genotypes against the TaqMan® 5'-nuclease assays. The Pyrosequencing method was highly efficient, robust and accurate in the analysis of SNPs.

The serotonergic system is profoundly associated with mood disorders and there are several serotonergic functions that could contribute to symptoms of depression. Associations between depressed mood and polymorphic variants in the HTR2A gene and the SLC6A4 gene in a sample of 1592 twins were investigated. An increased risk (OR = 2.4) for depressed mood in males associated with a genetic variant of the HTR2A gene was found. These findings might be indicative of a gender difference in the generic composition of depressive symptoms. Monoamine oxidases deaminate biogenic amines like serotonin. The two different forms of the enzyme, MAOA and MAOB are both encoded by genes on the X chromosome. A linkage disequilibrium (LD) map was created by use of nine SNPs to determine the LD structure of the MAO locus. The locus holds two distinct LD blocks, one for each gene, with very few haplotype variants. There was an association with haplotype variants of the MAOA gene and trbc-MAO activity. However, there was no association between either, MAOA or MAOB with depressive symptoms, but an interesting additive effect was observed in females.

Thus, this thesis has demonstrated that genetic variance is important for variation in depressive symptoms and that this variation appears to differ for men and women. Variants of the HTR2A receptor are associated with depressed mood in men but not women. Haplotypes of the MAOA gene are associated with levels of trbc-MAO activity but there was no clear association between variants of the MAO locus with depressive symptoms. Nonetheless, an increased number of symptoms were found with increasing numbers of alleles of certain haplotypes.