Association analysis of noncoding variants in neuroligins 3 and 4X genes with autism spectrum disorder in an Italian cohort

Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and4X have been studied as good positional and functional candidate genes for autism spectrum disorderpathogenesis, although contradictory results have been reported. Here, we performed a case-controlstudy to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes andautism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The resultswere first compared with data from 379 European healthy controls (1000 Genomes Project) and thenwith those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP)array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multipleloci approach. According to both the European and the Italian control groups, a 6-marker haplotypeon NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T))was associated with autism (odd ratio = 3.58, p-value = 2.58 ? 10-6 for the European controls; oddsratio = 2.42, p-value = 6.33 ? 10-3 for the Italian controls). Furthermore, several haplotype blocksat 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar associationwith autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated toautism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence