Association between genetic polymorphisms in circadian cycle genes (PER2, PER3, and HCRTR2) and Attention Deficit Hyperactivity Disorder (ADHD).

Attention Deficit/Hyperactivity Disorder (ADHD) remains a neurodevelopmental condition with an incompletely understood etiology, despite evident genetic influences. Disruptions in the circadian cycle and sleep disturbances have been implicated in ADHD. This case-control study aimed to examine the presence of genetic polymorphisms in circadian cycle genes among ADHD patients. Using TaqMan real-time PCR, eight SNPs within circadian cycle genes were analyzed in a sample of 161 Brazilian children and adolescents, comprising 94 ADHD cases and 67 controls. A significant proportion of individuals with ADHD were male (77.6%) and born preterm (18.7%). The most common ADHD subtype was the combined type (60.6%), and Oppositional Defiant Disorder (ODD) was the most frequently observed comorbidity (37.2%). Associations were observed between ADHD and polymorphisms in the PER3 (Period Circadian Clock 3) gene. The C allele of rs228729 (PER3) was associated with an increased risk for the disorder, both in allelic (OR = 2.51 (1.59 - 3.98) and genotypic frequencies (CC homozygote: OR = 8.51 (2.88 - 25.12); TC heterozygote: OR = 4.45 (1.60 - 12.39)). The T allele of rs228727 (PER3) showed an increased predisposition to ADHD OR = 2.69 (1.65 - 4.38); TT homozygote: (OR = 27.50 (3.48 - 216.80)). Haplotype analysis revealed higher frequencies of the C/T (rs228729 and rs228727) in ADHD cases (nominal p = 0.007). No association was detected between the polymorphisms rs934945 (PER2) or rs6927478 (HCRTR2), nor for other PER3 variants (rs707467, rs228644, rs10462020, and rs228697). These findings support an association between PER3 polymorphisms and ADHD; however, given the exploratory nature of this study, further analyses in larger and independent cohorts are required.