LAUSR

Background ADHD is a common neuropsychiatric disorder, it is highly heritable and polygenic, with a great number of combinations of variants, each with small effects, involved in its underlying molecular processes. However, the identification of the specific genetic factors associated to ADHD is still a great challenge, and genome-wide significant findings are just starting to appear. On the other hand, gene-set and pathway based methods using GWAS data are helping to elucidate ADHD's pathophysiological mechanisms, having already implicated processes related to the development of the central nervous system in its underpinnings, particularly, axon guidance and neurite outgrowth. In this sense, there is evidence suggesting that one of the mechanisms by which methylphenidate, can improve symptomatology and overall quality of life in patients is by affecting neuronal differentiation. Thus, we attempted to verify, through a gene-set analysis, if a biological hypothesis suggesting the involvement of genes related to neuronal differentiation in the central nervous system can play a role in ADHD susceptibility in adults. Methods PsychChip genotype data for >5 M high-quality SNPs was obtained after QC and imputation procedures for 407 adults with ADHD (53.1% males, mean age of 33.6 years) and 463 unrelated controls (47.9% males, mean age of 29.4 years) of European ancestry. Annotation from human genome build 37 (hg19) with a flanking region of 2 kb upstream and 1 kb downstream was considered for each gene. Competitive gene-set analysis was conducted using MAGMA software, with a multi=mean model for gene-based analyses. Sex, age, and the 10 first principal components were included as covariates in this step. Gene-set analysis was performed with gene set enrichment for GWAS using data from Gene Ontology (GO). A GO annotated gene-set representing 156 genes known to be involved in central nervous system neuron differentiation (GO: 0021953) specific pathways was selected to be tested in a case-control association study. Results No single marker or gene analyzed reached genome-wide significance. In the gene-set analysis, we found evidence that the group of genes represented by the GO: 0021953 set was significantly associated with ADHD susceptibility in adults (p=0.037), when compared to the other genes in the genome. Within this gene-set, the top hit genes were GIGYF2 (p=0.003), ABT1 (p=0.007), LHX4 (p=0.019), OLIG2 (p=0.033), PAFAH1B1 (p=0.036). Discussion Our results provide insight into the genetics of ADHD and preliminary evidence suggesting that a molecular pathway involved in nervous system development and essential to neuronal differentiation could be informative and contribute to the disorder's susceptibility. The use of biologically meaningful gene-sets, such as the regulatory mechanism involved in neuronal differentiation, containing genes previously associated with neuropsychiatric disorders, can help to understand the specific molecular pathways associated with ADHD. Interestingly, neurite outgrowth, a process previously implicated in ADHD susceptibility is closely related to neuron differentiation since it marks the beginning of the neuronal maturation stage and subsequent neuronal growth and function. The overall evidence, and the results presented here suggesting that neuronal differentiation could be related to ADHD susceptibility, support alterations of neuronal connectivity, synapse formation and synaptic plasticity in the mechanisms playing a role in ADHD.