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Genetics of schizophrenia: candidate genes and positional cloning analysis
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Title
Genetics of schizophrenia: candidate genes and positional cloning analysis
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Title
Candidate genes and positional cloning analysis
Name
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Saviouk
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Viatcheslav
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Viatcheslav Saviouk
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Matise
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Tara
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Advisory Committee
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Tara Matise
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chair
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Brzustowicz
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Linda
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Advisory Committee
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Linda Brzustowicz
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internal member
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Chiu
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Chi-hua
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Advisory Committee
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Chi-hua Chiu
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internal member
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Firestein
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Bonnie
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Advisory Committee
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Bonnie Firestein
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outside member
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Rutgers University
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Graduate School - New Brunswick
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theses
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2008
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2008-10
Language
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English
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electronic
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xi, 228 pages
Abstract
Schizophrenia (SZ) is a multifactorial phenotype. Candidate gene approach and positional cloning are the primary methods for elucidating its etiology.
We genotyped two TNF gene SNPs (-G308A, -G238A) and analyzed the haplotype structure in 24 Canadian families. Our results demonstrate that there is evidence for association (P=0.026) of a specific haplotype with SZ with a Trimhap test. Stratifying the 22 families with genome scan data by TNF promoter haplotypes followed by reanalysis of linkage to SZ, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 demonstrated a significant increase in LOD from 0.15 to 3.01.
The synapsin 2 (Syn2) gene is implicated in synaptogenesis, neurotransmitter release, and the localization of nitric oxide synthase. 37 pedigrees of Northern European ancestry from the NIMH HGI collection were used in this study. Four microsatellites and twenty SNPs were genotyped. Linkage (FASTLINK) and association (TRANSMIT, PDTPHASE) were evaluated. A maximum HLOD of 1.93 was observed at D3S3434. Significant results were obtained for association with SZ using TRANSMIT (p=0.0000005) and PDTPHASE (p=0.014) using single marker analyses. Haplotype analysis provided a single haplotype that is significantly associated with SZ using TRANSMIT ([less than] 0.00000001) and PDTPHASE (p=0.02).
The results of a linkage scan for SZ in the NIMH HGI Chinese family collection were reported by Faraone et al. with the largest NPL z score of 2.88 for D10S2327. We have reanalyzed the genome using the posterior probability of linkage (PPL). We split the sample into two subsets: those without any family members with affective diagnoses (SZ subgroup); and those with SZ, schizoaffective disorder, and bipolar disorder (HET subgroup). Genotypes were cleaned using PEDCHECK and SIMWALK. Sample specific genetic maps were constructed. SZ and HET groups were analyzed by four-point PPL analysis, and the results from each group were combined via pooling and sequential updating. The results confirmed the linkage peak on 10q22 with a PPL of 32.1% after updating. In addition we observed a peak of 30.5% over D3S1311 on 3q29 coming primarily from the HET group. Our results confirmed previous and yielded novel linkage findings in this family sample.
We genotyped two TNF gene SNPs (-G308A, -G238A) and analyzed the haplotype structure in 24 Canadian families. Our results demonstrate that there is evidence for association (P=0.026) of a specific haplotype with SZ with a Trimhap test. Stratifying the 22 families with genome scan data by TNF promoter haplotypes followed by reanalysis of linkage to SZ, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 demonstrated a significant increase in LOD from 0.15 to 3.01.
The synapsin 2 (Syn2) gene is implicated in synaptogenesis, neurotransmitter release, and the localization of nitric oxide synthase. 37 pedigrees of Northern European ancestry from the NIMH HGI collection were used in this study. Four microsatellites and twenty SNPs were genotyped. Linkage (FASTLINK) and association (TRANSMIT, PDTPHASE) were evaluated. A maximum HLOD of 1.93 was observed at D3S3434. Significant results were obtained for association with SZ using TRANSMIT (p=0.0000005) and PDTPHASE (p=0.014) using single marker analyses. Haplotype analysis provided a single haplotype that is significantly associated with SZ using TRANSMIT ([less than] 0.00000001) and PDTPHASE (p=0.02).
The results of a linkage scan for SZ in the NIMH HGI Chinese family collection were reported by Faraone et al. with the largest NPL z score of 2.88 for D10S2327. We have reanalyzed the genome using the posterior probability of linkage (PPL). We split the sample into two subsets: those without any family members with affective diagnoses (SZ subgroup); and those with SZ, schizoaffective disorder, and bipolar disorder (HET subgroup). Genotypes were cleaned using PEDCHECK and SIMWALK. Sample specific genetic maps were constructed. SZ and HET groups were analyzed by four-point PPL analysis, and the results from each group were combined via pooling and sequential updating. The results confirmed the linkage peak on 10q22 with a PPL of 32.1% after updating. In addition we observed a peak of 30.5% over D3S1311 on 3q29 coming primarily from the HET group. Our results confirmed previous and yielded novel linkage findings in this family sample.
Note
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Ph.D.
Note
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Includes bibliographical references (p. 111-125).
Subject
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Topic
Microbiology and Molecular Genetics
Subject
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Topic
Schizophrenia--Genetic aspects
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17563
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doi:10.7282/T3K64JCH
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ETD doctoral
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The author owns the copyright to this work.
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Open
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Viatcheslav Saviouk
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Copyright holder
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Rutgers University. Graduate School - New Brunswick
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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