Polymorphisms of sepiapterin reductase gene alter promoter activity and may influence risk of bipolar disorder

Abstract

OBJECTIVES: In a previous investigation, we observed altered expression of sepiapterin reductase (SPR) in cultured neural cells chronically exposed to paroxetine. SPR is an enzyme, which catalyzes the final step in the synthesis of tetrahydrobiopterin (BH4). BH4 is an essential cofactor for synthesis of many neurotransmitters including serotonin. Given the pivotal role of SPR in neurotransmitter production, we sought to test the hypothesis that SPR would influence susceptibility to mood disorders and patient response to antidepressants. METHODS: We tested for association of SPR promoter polymorphisms with antidepressant response in a well-characterized triad cohort of mood disorders. We evaluated the functional effect of these variants using the Dual-Luciferase Reporter Gene Assay System in two independent cell lines. RESULTS: Two promoter single nucleotide polymorphisms (rs1876487 and rs2421095) in SPR were identified that occurred in three distinct haplotypes. We found a statistically significant association of haplotype pair 2,3 with bipolar I disorder [odds ratio: 5.47; 95% confidence interval: (1.68-17.88); P<0.005] and the personality measure self-transcendence (P=>0.020). Moreover, we found preliminary evidence that individuals with haplotype pair 2,3 responded better to the treatment with selective serotonin reuptake inhibitors. Reporter gene assays revealed a 1.4-fold to 1.6-fold decrease in the transcription rate of the two less common haplotypes (2 and 3) compared with haplotype 1, in the two cell lines investigated. CONCLUSION: This reduced transcription rate for SPR promoter haplotypes 2 and 3 may impact on BH4-mediated neurotransmitter production, thus suggesting a biological process through which SPR gene variants might influence antidepressant response and susceptibility to bipolar disorder. Copyright © 2009 Lippincott Williams and Wilkins.