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Exploring functional genetic variants in genes involved in mental disorders

Zhang, Ying
http://rave.ohiolink.edu/etdc/view?acc_num=osu1186433668

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Neuroscience.
My studies are to test the hypothesis that functional polymorphisms of OPRM1 and DRD2 modulate the susceptibility to mental disorders. I first determined whether there is an mRNA allele expression difference between two alleles of OPRM1 and DRD2 in relevant tissue (postmortem brain samples). Primer extension assays (SNaPshot) was used to detect allele-specific mRNA expression in human postmortem brain tissues using indicator SNP A118G for OPRM1 and three SNPs (rs6275, rs6277, and rs6279) for DRD2, respectively. Allelic expression imbalance (AEI) has been revealed for both OPRM1 and DRD2. The main efforts of this project were to search for functional polymorphisms or other factors responsible for the observed AEI of OPRM1 and DRD2. For OPRM1, in vitro studies were conducted to verify the effects of A118G on transcription and translation in transfected CHO cells. As for DRD2, genotyping and association studies were used to scan for polymorphisms correlated with AEI, and one SNP (rs12364283) in the upstream regulatory region of DRD2 was highly associated with AEI and its effects were confirmed by reporter gene assay in HEK and SH-SY5Y cells. Moreover, two highly linked intronic SNPs (rs2283265 and rs1076560) were associated with reduced formation of the DRD2S (short) splice variant relative to DRD2L (long) – two splice variants thought to have distinct roles in dopamine signaling. Consistent with this finding, we found the minor allele of the two intronic SNPs was associated with greater neuronal activity in healthy humans assessed with fMRI during working memory. These results reveal novel functional genetic DRD2 variants which affect its expression and physiology of subcortical and cortical brain regions during working memory, a mechanism that may be relevant to several mental disorders. Another clinical case-control study (Stanley collections, Bethesta, MD) revealed much higher allele frequency of rs12364283 (c2 = 6.89, P = 0.009 (n = 95)) in schizophrenia subjects, which need to be repeated in another cohort with larger sample size. Clarifying the functional relevance of polymorphisms associated with susceptibility to mental disorders provides a foundation for clinical association studies. This study has the potential to improve the prevention, diagnosis and treatment of drug addiction.
Wolfgang Sadée (Advisor)
Laura Bohn (Other)
Howard Gu (Other)
David Saffen (Other)
Allelic expression imbalance; Polymorphism; mu opioid receptor; Dopamine D2 receptor; Gene expression; Splice variants; Working memory

Recommended Citations

Citations

  • Zhang, Y. (2007). Exploring functional genetic variants in genes involved in mental disorders [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1186433668

    APA Style (7th edition)

  • Zhang, Ying. Exploring functional genetic variants in genes involved in mental disorders. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1186433668.

    MLA Style (8th edition)

  • Zhang, Ying. "Exploring functional genetic variants in genes involved in mental disorders." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1186433668

    Chicago Manual of Style (17th edition)

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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.