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.