Skip to main content
Login | Suomeksi | På svenska | In English

Browsing by Subject "X-chromosomal variants"

Sort by: Order: Results:

  • Mielikäinen, Lotta (2022)
    Sex determination in humans occurs via the sex chromosomes, X and Y. Females carry two X chromosomes while males are XY individuals. Due to this X chromosome distribution the expression of X-linked genes is balanced with a process called X chromosome inactivation (XCI) where one of the X chromosomes is silenced, selected either randomly or preferentially, in early female embryogenesis. X-linked disorders are more prevalent in males as, generally, in females the effects of a disease-causing variant in other of the X chromosomes can be compensated with the normal allele on the other X whereas male express the allele on their only X chromosome. However, cases of heterozygous females manifesting an assumed recessive X-linked disorder have been reported although the symptoms are usually milder in these cases than in males. One suggested reason behind this is a skewed XCI where the majority of female’s cells express the mutated allele. The main goal of this thesis was to examine how often heterozygous female carriers have symptoms of X-linked disorders. To achieve this goal, likely pathogenic and pathogenic X-chromosomal variants were retrieved from the ClinVar database and their global allele frequencies were examined from The Genome Aggregation Database (gnomAD). The genetic and phenotypic data of 500,000 individuals from the UK Biobank (UKB) were used to conduct genetic association analyses between the ClinVar variants and quantitative traits related to their reported phenotypes. The associations were tested in males and in females separately to allow for examination of sex-specific effects and inheritance models via the comparison of effect sizes. 89 (likely) pathogenic variants were detected from UKB, and the majority of these were extremely rare with minor allele frequency below 0.01% in the global population. 11 and 27 of them were selected for the association analyses for the male and female populations of UKB, respectively, after filtering out variants that did not meet requirements such as enough carriers. One to five quantitative traits were chosen for each variant resulting in 28 tests among males and 87 among females. These analyses showed few significant associations while the majority of the tested variants were observed to have no effects on the chosen trait. The most statistically significant association was observed with variant rs137852591 on the gene AR (androgen receptor) in males. The variant was related to lower muscle mass and shorter height that are associated partial androgen insensitivity syndrome reported in ClinVar for this variant. Nominally significant associations were seen with this variant and the same traits in heterozygous females suggesting that there might be, indeed, symptoms of the syndrome in females as well. Additionally, in both sexes variants on gene G6PD seemed related to traits that are characteristics of glucose 6 phosphate dehydrogenase deficiency. The limitations of these databases must be taken into account when conducting studies utilizing them. However, this thesis demonstrated that heterozygous female carriers may have symptoms of X-linked disorders assumed to have recessive inheritance pattern. In the future, a wider set of phenotypes could be used to investigate the impacts of the X-linked variants more broadly.