Using whole genome sequencing to identify risk alleles for susceptibility to schizophrenia

Gillian K. Davis
Schizophrenia is a complex idiopathic neuropsychiatric illness that affects approximately 1% of the general population. Family, twin, and adoption studies indicate a high heritability and strong genetic element to the disease with first degree relatives demonstrating an increased risk of about 10% and monozygotic concordance rates as high as 50%. These values represent the probability of developing schizophrenia based on the presence of genetic components. The high heritability has led to
more » ... dual studies and meta-analyses being able to produce significant evidence of linkage to specific locations, but studies that used large number of pedigrees have failed to produce statistically significant linkage results. Genome Wide Association Studies of schizophrenia have also produced similarly mixed results. One interpretation of these mixed linkage and association results is that factors such as small effect size and uncontrolled phenotypic variation require very large samples to overcome. This thesis focuses on a different interpretation: genuine genetic differences between definable subsets can mask both linkage and association, and that this problem is worsened in studies that use large samples where the entire sample is analyzed as if it were a genetically homogenous group. The work presented herein begins with linkage studies performed on 22 medium- sized Canadian pedigrees (n=304 individuals) of German or Celtic descent initially recruited if at least three subjects with schizophrenia were available for study. Association studies were conducted on an expanded sample of 30 pedigrees (n=573). Subjects in this sample have been followed for up to 20 years allowing for continued observation of diagnostic stability. We have identified linkage disequilibrium between schizophrenia and single nucleotide polymorphisms (SNPs) from six discrete genomic regions located under linkage peaks within this sample. We hypothesize that SNPs that generated compelling evidence of association (PPLD|L >= 0.2) [...]
doi:10.7282/t3tt4v31 fatcat:y6ugqyfksfhnxi6ycoo5fqgoye