Differential Effect of Folate Metabolic System Genetic Variants on Attention Deficit Hyperactivity Disorder Severity

Background: Adequate folate level is vital for the synthesis of neurotransmitters, and hence, folate deficiency was related to neurobehavioral disorders like depression, Autism spectrum disorders, and Attention Deficit Hyperactivity Disorder (ADHD). Genetic variants involved in folate metabolism were also reported to affect ADHD traits. We have analyzed the contribution of FOLR1 rs2071010, FOLR2 rs2298444, TCN2 rs1801198, and SHMT1 rs1979277 in the etiology of Indian ADHD probands. Methods: Ethnically matched controls (N = 286) and unrelated nuclear families with ADHD probands (N = 221) were recruited following the Diagnostic and Statistical Manual for Mental Disorders (DSM). Traits were assessed using the Conners' Parent Rating Scale-Revised, DSM, and Parental Account of Children's Symptoms criteria. Genetic variants were analyzed by PCR-based methods/TaqMan assay. Genetic association analyses were performed using the UNPHASED. Linkage disequilibrium was calculated using Haploview. Quantitative Trait Analysis was performed to identify the association between genetic variants and trait scores. Results: Parental bias in the transmission of rs1979277 "C" to the ADHD probands was detected. Maternally biased transmission of rs2298444 "G" was also observed. LD between rs2071010-rs2298444 was strong in the control population. Trait scores of the male ADHD probands were higher in the presence of rs2298444 "A" while the behavioral problem was less in the presence of rs1801198 "CC". In the male probands, studied sites exhibited stronger independent effects, while in the female probands, additive effects between rs2298444-rs1801198 and rs2298444-rs1979277 were observed. Conclusion: We infer that ADHD severity is differentially influenced by genetic variants regulating folate metabolism.