GENE-SET ANALYSIS OF SEROTONERGIC SYNAPSE GENES IN ADULTHOOD ADHD

Attention-Deficit Hyperactivity Disorder (ADHD) is highly heritable and has been associated with several genes in different reports. The serotonergic genes are among the most consistently associated with ADHD and related phenotypes, according to meta-analyses. Therefore, the aim of this study was to investigate associations between serotonergic pathway genes and ADHD susceptibility and treatment, through gene-set approach. The gene-set analysis increases statistical power, when compared to genome-wide association studies, making it a better approach for samples limited in size. Therefore, the aim of this study was to investigate associations between serotonergic pathway genes and ADHD susceptibility and treatment, through gene-set approach. The sample comprised 407 subjects with ADHD and 463 controls (negatively screened for ADHD). Individuals were diagnosed according to the DSM-IV criteria at the adult division of the ADHD Outpatient Clinic from Hospital de Clínicas de Porto Alegre (ProDAH-A HCPA). All subjects were unrelated Brazilian adults of European descent. For 189 patients with ADHD, the treatment response to immediate-release methylphenidate (at least 30 days) was assessed. The outcome measure was the variation in ADHD severity scores according to SNAP-IV. Genome-wide genotypes were assessed using the Psych Chip array or imputed based on the standard Ricopili pipeline. The final data retained 5,842,763 SNPs across the genome. The gene locations for build 37 (hg19) were used for SNP annotation to genes. Gene-based analyses were performed in MAGMA, using the multi=all model, which has higher sensitivity to different genetic architecture variation. Serotonergic gene-set was selected based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) serotonergic synapse pathway. The gene-set comprised 103 genes, including serotonin transporter, receptors and other related genes. The competitive gene-set analysis for ADHD susceptibility was not significant (P-value=0.11). Since the serotonergic system is widely associated with mood disorders, especially in women, the same analysis was performed, including gender and mood disorder as covariates, revealing a P-value=0.28. Furthermore, the gene-set analyses concerning treatment response revealed no significant result. Two analyses were performed, without any covariates (P-value=0.24), and adjusting by other drugs use and total baseline SNAP score in the analysis (P-value=0.28). These findings suggest that the gene-set investigated for the serotonergic system does not fulfill the expectation of explaining more of the ADHD susceptibility and treatment response as compared with the whole genome. However, it should be pointed out that even for the gene-set approach our sample size is limited, and the same analysis should be repeated in larger samples.