Genetic Analysis of Complex and Mendelian Diseases

This work describes approaches for discovering genetic variants that contribute to the etiology of human diseases with complex and simple modes of inheritance through the use of linkage analysis, genome-wide association analysis, and massively parallel sequencing (MPS). The studies contained in this work illustrate both the capabilities and limitations of these approaches. The two GWA studies in this work illustrated how reducing genetic and population heterogeneity could increase the ability to detect associations with genome-wide significance. The first, a GWA study of idiopathic Parkinson's disease (IPD), was able to detect an association signal that approached genome-wide significance across chromosome 12q12, including the LRRK2 locus (average p-value=4.85 x 10-6), which has been implicated in IPD by several linkage studies. The second, a pilot GWA study of dystonia, identified an association with genome-wide significance at RNF213. The second half of this work employed MPS approaches to investigate the genetics of familial presentations of disease. The first, a study of a family with an atypical presentation of frontotemporal dementia with amyotrophic lateral sclerosis, was unable to detect an obvious deleterious mutation despite sequencing the exomes of 10 individuals and the whole genome of 1 individual in this family. The exome sequencing data from this family were used to perform a multipoint linkage analysis, which potentially implicated chromosome 9q in this family. In this region, all affected family members shared a synonymous mutation in CRB2, a gene in the gamma-secretase pathway. The final study featured a genome-wide linkage analysis of a pedigree affected with a microcoria myopathy and a combined whole genome and whole exome sequencing analysis of this pedigree and 7 unrelated individuals. The linkage analysis found a multipoint LOD score of 1.8 on Chromosome 5q35. Exome sequencing detected a missense mutation shared by the affected family members in C5orf60: c.97C>T (p.P33S) that was also found in an exome from an unrelated subject. Another missense mutation in C5orf60, c.64G>C (p.D22H), was present in the exomes from 5 of the unrelated subjects. These results suggest that mutations in C5orf60 are a novel cause of microcoria and also corroborate the genetic heterogeneity of this condition.Doctor of Philosoph