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theses

Schizophrenia is a major neuropsychiatric disorder that affects approximately one percent of the general population. Although the etiology of schizophrenia is unknown, family, twin and adoption studies have demonstrated that schizophrenia is a predominantly genetic disorder with a very high heritability. We previously reported highly significant evidence of linkage to chromosome 1q21-23, identified NOS1AP as the candidate gene from this region contributing to risk for schizophrenia in our sample, and identified three SNPs with strong evidence of association to schizophrenia. These SNPs were tested for regulatory functions using a Dual Luciferase Reporter Assay. rs12742393 demonstrated regulatory activity and produced significant allelic expression differences in two different human neural cell lines. Further statistical analysis of eight SNPs in strong LD with rs12742393 identified a haplotype block of four SNPs in complete LD with each other (rs4557949-rs11584803-rs4145621-rs12084492) with strong evidence of association to schizophrenia. Additional statistical analysis revealed that a haplotype of rs12742393 and this block produced stronger evidence for association than rs12742393 alone. rs4145621 already has been tested for regulatory activity and produced no evidence of being a functional variant. The focus of this thesis was to evaluate the regulatory activity of two of these SNPs within this haplotype, rs12084492 and rs4557949. We performed Dual-Luciferase Reporter Assays to test for regulatory function of each SNP individually and in combination with rs12742393 using two different cell lines, PFSK-1 and SK-N-MC, and using different cell confluence levels. Our results suggest that both SNPs are not functional variants. Evaluation of rs11584803 is necessary to completely test our initial hypothesis.

ETD_5043

M.S.

Includes bibliographical references

by Carmen Ramirez

doi:10.7282/T39Z92ZB

ETD graduate

The author owns the copyright to this work.