RESUMEN
It is general acknowledged that genes play a vital role in the etiology of attention deficit/hyperactivity disorder (ADHD). The relationship between the genes involved in catecholamine (dopamine, noradrenaline)/serotonin transmissions and ADHD has been widely described in medical literature. A pathway-based study was conducted in this study to test the association of gene-gene interaction and the cumulative effect of genetic polymorphisms within the dopamine, norepinephrine, and serotonin neurotransmitter pathways with ADHD susceptibility. A case-control study was conducted among Chinese children, and 168 ADHD patients and 233 controls were recruited using a combination diagnosis according to the DSM-IV ADHD rating scale. Classification and regression tree (CART) analysis was conducted to explore the gene-gene interaction, and logistic regression modal was applied to estimate the polygenic risk of the potential multiple genetic variants. The results of CART analyses indicated that the children carrying the combination of ADRA2A rs553668GG/GA and SLC6A4 rs6354 GG/GT genotypes displayed a 6.15-fold increased risk of ADHD, compared to those with the combination of ADRA2A rs553668 AA and ANKK1 rs1800497 AA genotypes. The unfavorable alleles of ADRA2A rs553668 G, DRD2 rs1124491 G and SLC6A4 rs6354 G showed cumulative effects on ADHD, and the OR for ADHD may increase by 1.42 times when the number of unfavorable allele number increased by one. Those findings reveal the importance of the gene-gene interactions and polygenic effects of many common variants to ADHD susceptibility, even the effect of each variant is very small.