Análise de polimorfismos genéticos em genes do ciclo circadiano (PER2, PER3 e HCRTR2) e de vias inflamatórias (IL-6, TNF e NRXN3) em pacientes brasileiros com TDAH

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that typically begins in childhood and results in impairments in personal, social or academic functioning. It is characterized by extremes of inattention and/or hyperactivity and is often associated with other disorders. The etiology and pathophysiology remain largely elucidated, despite the evident influence of genetic factors, as demonstrated by high heritability in studies with twins and families. There is still no consensus on which genes could truly be determinants. Alterations in the circadian cycle and sleep disturbances are implicated in ADHD, as well as neuroinflammation, which has been indicated as a significant influence in the development of the disorder. In light of this, the primary aim of this study was to examine the existence of genetic polymorphisms in genes associated with the circadian cycle and inflammation among individuals with ADHD. Additionally, we aimed to establish correlations between our findings and clinical data, comorbidities, and the genomic ancestry of the participants. Significant associations were identified between polymorphisms in the PER3 gene and ADHD. The C allele (rs228729) demonstrated an increased risk for the disorder, evident in allelic frequency (OR=2.51 (1.59 - 3.98)) and genotypic frequencies (CC homozygote - OR=8.51 (2.88 - 25.12) and TC heterozygote - OR=4.45 (1.60 - 12.39)). Similarly, the association with the disorder was observed for the T allele (rs228727) (OR=2.69 (1.65 - 4.38)) (TT homozygote - OR=27.50 (3.48 - 216.80)). The region of PER3, which includes the variants rs228729 and rs228727 associated with ADHD, is co-inherited (D’=0.82), underscoring the correlation of this genomic region in PER3 with the disorder. No correlations were found between ADHD and the other genes investigated in this study, including other circadian cycle genes (PER2 and HCRTR2) and genes involved in inflammatory pathways (IL-6R, TNF and NRXN3). The findings suggest an association of the circadian cycle gene (PER3) and ADHD, but further analyses in larger and independent samples are recommended for a better understanding of this complex, multifactorial, and polygenic disorder.