Polymorphism in sex steroid-related genes. Effects on hormone levels and behavior

Sammanfattning: Genetic factors are important for variations between individuals with respect to most humantraits and diseases. Sex steroids are of profound importance for reproduction, metabolism,cardiovascular function and bone formation. They are potent regulators of their ownsynthesis as well as of that of other hormones, including prolactin. They also exert markedinfluence on the brain, and are hence of probable importance for various normal behaviors,including sexual activity and aggression, as well as for a number of neuropsychiatricdisorders.The purpose of this thesis was to explore how various aspects of the human phenotypemay be influenced by genetic variants polymorphisms - in genes encoding proteins ofimportance for the synthesis and metabolism of sex steroids, receptors for sex steroids, andcoregulators of these receptors. The studies were focused on the possible influence of sexsteroid-related genes on brain and behavior. In addition, effects on hormone levels in serumwere analyzed.Observations: 1) Repeat polymorphisms in the genes encoding the androgen receptor(AR) and the estrogen receptor (ER) beta were associated with serum levels of androgens inwomen. 2) The same ER beta repeat polymorphism, as well as a single nucleotidepolymorphism (SNP) in the progesterone receptor (PR) gene, earlier shown to be ofimportance for the expression of this gene, were associated with serum levels of prolactin. 3)A repeat polymorphism in the gene encoding ER alpha was associated with personality traitsrelated to anxiety and irritability in women. 4) The same variant of the PR genepolymorphism that was associated with prolactin levels was also associated with panicdisorder in women but not in men. 5) A SNP in the ER beta gene was associated with anearly age of onset of Parkinson s disease, but not with the disease per se. 6) In spite of thefact that is well established that women with premenstrual dysphoric disorder displayaberrant brain responsiveness to sex steroids, no differences between patients with thiscondition and controls with respect to a large number of polymorphisms in sex steroidrelatedgenes were observed.Conclusions: All the studies were based on a priori hypotheses regarding the possiblerelationship between the studied genes and the various aspects of the phenotype beinginvestigated. A number of possible associations were found, as described above, none ofwhich had been reported in the literature before. Whereas some of these findings havesubsequently been confirmed in independent studies, or are more or less in line with findingsreported by other researchers, such as the associations between the AR gene and androgenlevels, and between the ER alpha gene and personality traits, others should be regarded aspreliminary until replicated in other populations. The main conclusion of this thesis is thatsex steroid-related genes may be relevant candidates not only for the study of traits anddisorders that are obviously related to sex steroids, such as those related to reproduction,but also for further studies of inter-individual differences with respect to normal behavior aswell as with respect to the susceptibility to various neuropsychiatric disorders.