Genetic Variation in ADHD-Related Risk Genes in an Indigenous Population of the Amazon

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable neurodevelopmental disorder; however, its genetic architecture remains poorly explored in Indigenous populations. This study aimed to analyze and characterize genetic variation in 11 genes (ADGRL3, CDH8, DCC, DUSP6, FOXP1, FOXP2, MEF2C, PCDH7, SEMA6D, SORCS3, and ST3GAL3) previously implicated in ADHD, in an indigenous sample, comparing them with reference populations from the 1000 Genomes Project. Exome data from 64 individuals representing 12 Indigenous groups from the Brazilian Amazon were analyzed. Among the identified, 99 met the inclusion criteria. Four previously unreported variants in the developed reference datasets were identified in ADGRL3, DCC, and FOXP2. Significant differences in allele frequencies were observed for 56 variants compared with continental populations. Multidimensional scaling analysis indicated genetic differentiation of the Indigenous group in relation to other populations. This study highlights the distinct genetic profile of Amazonian Indigenous populations, likely shaped by demographic and evolutionary processes such as genetic drift and founder effects. The identification of exclusive variants and marked allele frequency differences reinforces the importance of including historically underrepresented populations in genomic studies related to ADHD and neurodevelopment, contributing to a broader understanding of human genetic diversity.