Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms

Neurexins are cell adhesion molecules that help to specify and stabilize synapses and provide receptors for neuroligins, neurexophilins, dystroglycans and alpha-latrotoxins. We previously reported significant allele frequency differences for single nucleotide polymorphisms (SNPs) in the neurexin 3 (NRXN3) gene in each of two comparisons between individuals who were dependent on illegal substances and controls. We now report work clarifying details of NRXN3's gene structure and variants and documenting association of NRXN3 SNPs with alcohol dependence. We localize this association signal with the vicinity of the NRXN3 splicing site 5 (SS#5). A splicing site SNP, rs8019381, that is located 23 bp from the SS#5 exon 23 donor site displays association with P = 0.0007 (odds ratio = 2.46). Including or excluding exon 23 at SS#5 produces soluble or transmembrane NRXN3 isoforms. We thus examined expression of these NRXN3 isoforms in postmortem human cerebral cortical brain samples from individuals with varying rs8019381 genotypes. Two of the splice variants that encode transmembrane NRXN3 isoforms were expressed at significantly lower levels in individuals with the addiction-associated rs8019381 'T' allele than in CC homozygotes. Taken together with recent reports of NRXN3 association with nicotine dependence and linkage with opiate dependence, these data support roles for NRXN3 haplotypes that alter expression of specific NRXN3 isoforms in genetic vulnerabilities to dependence on a variety of addictive substances.