title: Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort.
abstract: Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants inNLGN3andNLGN4Xgenes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with 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 multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype onNLGN4X(rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58,p-value = 2.58 × 10-6for the European controls; odds ratio = 2.42,p-value = 6.33 × 10-3for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms onNLGN4Xmay be associated to autism, suggesting the key role ofNLGN4Xin autism pathophysiology and in its male prevalence.
authors: Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy. landinimartina@gmail.com.
authors: Martina
authors: M
authors: Landini
authors: Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy. ivan.merelli@itb.cnr.it.
authors: Ivan
authors: I
authors: Merelli
authors: Scientific Institute, IRCSS Eugenio Medea, 23842 Bosisio Parini, Italy. mariaelisabetta.raggi@bp.lnf.it.
authors: M Elisabetta
authors: ME
authors: Raggi
authors: Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy. nadiagalluccio@gmail.com.
authors: Nadia
authors: N
authors: Galluccio
authors: Scientific Institute, IRCSS Eugenio Medea, 23842 Bosisio Parini, Italy. francesca.ciceri@bp.lnf.it.
authors: Francesca
authors: F
authors: Ciceri
authors: Scientific Institute, IRCSS Eugenio Medea, 23842 Bosisio Parini, Italy. arianna.bonfanti@bp.lnf.it.
authors: Arianna
authors: A
authors: Bonfanti
authors: Scientific Institute, IRCSS Eugenio Medea, 72100 Brindisi, Italy. serena.camposeo@libero.it.
authors: Serena
authors: S
authors: Camposeo
authors: Scientific Institute, IRCSS Eugenio Medea, 72100 Brindisi, Italy. angelo.massagli@gmail.com.
authors: Angelo
authors: A
authors: Massagli
authors: Scientific Institute, IRCSS Eugenio Medea, 23842 Bosisio Parini, Italy. laura.villa@bp.lnf.it.
authors: Laura
authors: L
authors: Villa
authors: Department of Health Sciences, University of Milan, 20142 Milan, Italy. erika.salvi@unimi.it.
authors: Erika
authors: E
authors: Salvi
authors: Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy. daniele.cusi@unimi.it.|Sanipedia srl, via Ariosto 21, 20091 Bresso, Italy. daniele.cusi@unimi.it.
authors: Daniele
authors: D
authors: Cusi
authors: Scientific Institute, IRCSS Eugenio Medea, 23842 Bosisio Parini, Italy. massimo.molteni@bp.lnf.it.
authors: Massimo
authors: M
authors: Molteni
authors: Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy. luciano.milanesi@itb.cnr.it.
authors: Luciano
authors: L
authors: Milanesi
authors: Scientific Institute, IRCSS Eugenio Medea, 23842 Bosisio Parini, Italy. amarabotti@unisa.it.|Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. amarabotti@unisa.it.
authors: Anna
authors: A
authors: Marabotti
authors: Institute of Biomedical Technologies, National Research Council, Via Fratelli Cervi 93, 20090 Segrate, Italy. alessandra.mezzelani@itb.cnr.it.
authors: Alessandra
authors: A
authors: Mezzelani
mesh_terms: D000483:Alleles; D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; C430845:NLGN4X protein, human; D009419:Nerve Tissue Proteins; C098004:neuroligin 3
keywords: SNPs; autism; genetics; haplotype analysis; neuroligins; noncoding regions