MTHFR 677C → T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val → Met

摘要: Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment has been associated with abnormal dopamine signaling the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val → Met polymorphism (rs4680), affects availability of signaling, consistently stratifies activation during working performance. However, low-dopamine COMT allele does not confer increased for schizophrenia, and effects on are specific to disorder. In setting other variants influencing genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C T (rs1801133), overall executive patients, influence through mechanisms upstream We found that hypofunctional 677T variant was decreased load-dependent insular cortices 79 but 75 demographically matched healthy controls. Further, significant MTHFR × interactions were observed, differed by diagnostic group: Reduced alleles 677C/C 158Met/Met These findings consistent epistatic polymorphisms suggest exacerbates deficiency. also importance weighing within context genotype.