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Genetic Factors Regulating Expression of Dopaminergic Genes

Barrie, Elizabeth Stofko
http://rave.ohiolink.edu/etdc/view?acc_num=osu1406388433

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Genetic differences are one of the main contributors to diversity in clinical phenotypes. This project identifies and defines genetic factors affecting dopamine dysregulation focusing on three genes in dopamine signaling: DBH, COMT and SNCA. To study this I measure allelic expression, selecting RNA samples from post-mortem human tissue that are heterozygous for a marker SNP, and quantitate the expression of each allele. Dopamine beta-hydroxylase (DBH) encodes an enzyme which converts dopamine to norepinephrine. A promoter SNP, rs1611115 has been associated with low DBH and high dopamine plasma levels; however, underlying mechanisms remain uncertain. I found a tissue-specific effect of rs1611115 in liver, with up to 11 fold differences in allelic and overall mRNA expression (p<0.0004 to 2x10-7 and p<0.0001 respectively), indicating decreased transcription. Interestingly, locus coeruleus and adrenal gland, the main sources of DBH in the body, did not demonstrate this robust effect; only small AEI ratios were detected in these tissues. More frequent than rs1611115 and in linkage disequilibrium with it, a second SNP, rs1108580 was associated with reduced allelic mRNA expression in all tissues tested. This dual mechanism accounts for the previously described genotype effect on DBH plasma levels, with a novel role for liver as an important source of variability in DBH levels. In combination, rs161115 and rs1108580 contribute to strongly reduced mRNA expression in the liver, reducing transcription in a tissue selective manner. In mice, Dbh mRNA levels in the liver correlated with cardiovascular risk phenotypes. Using a PheWAS (phenome-wide association study) analysis, the minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes including angina pectoris. Testing the combined effects of rs1611115 and rs1108580 indicated robust protection against myocardial infarction in three clinical cohorts. These results demonstrate profound effects of common DBH variants on expression in sympathetically innervated organs, modulating clinical phenotypes responsive to peripheral sympathetic tone. In a pathway parallel to DBH, catechol-O-methyltransferase (COMT) converts dopamine to an inactive metabolite. Almost half of the African-American samples tested demonstrate a significant mRNA fold change, while only one Caucasian sample demonstrates AEI, indicating the presence of a regulatory variant which has not yet been described. Extensive sequencing of regions predicted to harbor this regulatory variant, up to 500 kb from the gene, did not reveal a variant associated with these instances of AEI. There is a factor, acting predominantly in African-Americans, regulating allelic expression and I have ruled out hundreds of SNPs as being the cause. Alpha-synuclein (SNCA) is involved in dopamine regulation, and implicated in degeneration of dopaminergic neurons. Allelic mRNA analysis indicates the presence of a regulatory variant. I have found an association with rs17016074, likely affecting, or marking differential 3'UTR usage. This approach has revealed the presence of frequent regulatory variants in all three genes studied. Functional SNPs contributing to dysregulation of dopamine can be tested for association with clinical phenotypes using large publicly available genome-wide association datasets.
Wolfgang Sadee (Advisor)
Thomas Boyd (Committee Member)
Howard Gu (Committee Member)
Amanda Toland (Committee Member)
164 p.
Biomedical Research; Genetics
Dopamine beta-hydroxylase; DBH; allelic expression imbalance; myocardial infarction; mRNA expression; genetics; human; alpha-synuclein; SNCA; COMT

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Citations

  • Barrie, E. S. (2014). Genetic Factors Regulating Expression of Dopaminergic Genes [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1406388433

    APA Style (7th edition)

  • Barrie, Elizabeth. Genetic Factors Regulating Expression of Dopaminergic Genes. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1406388433.

    MLA Style (8th edition)

  • Barrie, Elizabeth. "Genetic Factors Regulating Expression of Dopaminergic Genes." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1406388433

    Chicago Manual of Style (17th edition)

osu1406388433
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This open access ETD is published by The Ohio State University and OhioLINK.