Identifying Genes and Loci for Complex Diseases: Examples from Primary Open Angle Glaucoma and Schizophrenia.

Abstract

This purpose of this dissertation is to progress towards identification of disease genes and loci for primary open-angle glaucoma (POAG) and schizophrenia. In studying schizophrenia, we conducted a genome-wide linkage scan in 479 subjects from 129 Afrikaner families; Afrikaners are a founder population from South Africa. Conducting a MOD score analysis, we were able to replicate a schizophrenia locus on chromosome 13q34 in subjects with broadly defined schizophrenia, which includes schizoaffective disorder- depressive subtype and schizoaffective disorder- bipolar subtype (MOD score = 3.76). We also detected a locus on chromosome 1p36 in subjects classified with a more narrowly defined form of schizophrenia that include schizoaffective disorder- depressive subtype, but not bipolar subtype (MOD score = 3.21). We conducted two separate studies looking for POAG genes and loci. In the first study, we replicated the GLC1I locus on chromosomes 15q11-13. We initially tested 167 European American individuals in 25 multiplex open-angle glaucoma families and detected a LOD score of 1.01 at 14.3 cM. However when we used ordered subset analysis, we found that by including only the 14 families with earlier average ages at diagnosis (average=50.6 years ±5.4 years), there is evidence for linkage to GLC1I (LOD score = 2.09; p-value = 0.021). In the third and final study, we tested whether glaucoma severity is associated with variants in the promoter region of a known glaucoma gene, myocilin (MYOC). There have been conflicting reports regarding the relationship between glaucoma severity and the -1000CG MYOC promoter SNP, also designated mt1. This study tested for an association in subjects from the Collaborative Initial Glaucoma Treatment Study (CIGTS); a longitudinal study where the subjects were reevaluated every six months. We found that there was not evidence for an association between -1000CG and visual field mean deviation (p=0.98) or intraocular pressure (p=0.52) across the study period in the CIGTS population. There was also no evidence of association between two other MYOC promoter SNPs, -1075GA and -1081AG, and mean deviation or intraocular pressure. In describing these studies, this dissertation illustrates methods and techniques that can be applied to the study of genetics of other complex diseases.PhDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/63652/1/awoodrof_1.pd