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Neurexins are cell adhesion molecules that help to specify and stabilize synapses and provide receptors for neuroligins, neurexophilins, dystroglycans and α-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.

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