title: Genetic regulation of Nrxn1 [corrected] expression: an integrative cross-species analysis of schizophrenia candidate genes.
abstract: Neurexin 1 (NRXN1) is a large presynaptic transmembrane protein that has complex and variable patterns of expression in the brain. Sequence variants in NRXN1 are associated with differences in cognition, and with schizophrenia and autism. The murine Nrxn1 gene is also highly polymorphic and is associated with significant variation in expression that is under strong genetic control. Here, we use co-expression analysis, high coverage genomic sequence, and expression quantitative trait locus (eQTL) mapping to study the regulation of this gene in the brain. We profiled a family of 72 isogenic progeny strains of a cross between C57BL/6J and DBA/2J (the BXD family) using exon arrays and massively parallel RNA sequencing. Expression of most Nrxn1 exons have high genetic correlation (r>0.6) because of the segregation of a common trans eQTL on chromosome (Chr) 8 and a common cis eQTL on Chr 17. These two loci are also linked to murine phenotypes relevant to schizophrenia and to a novel human schizophrenia candidate gene with high neuronal expression (Pleckstrin and Sec7 domain containing 3). In both human and mice, NRXN1 is co-expressed with numerous synaptic and cell signaling genes, and known schizophrenia candidates. Cross-species co-expression and protein interaction network analyses identified glycogen synthase kinase 3 beta (GSK3B) as one of the most consistent and conserved covariates of NRXN1. By using the Molecular Genetics of Schizophrenia data set, we were able to test and confirm that markers in NRXN1 and GSK3B have epistatic interactions in human populations that can jointly modulate risk of schizophrenia.
authors: Department of Anatomy and Neurobiology, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, TN 38163, USA. kmozhui@uthsc.edu
authors: K
authors: K
authors: Mozhui
authors: X
authors: X
authors: Wang
authors: J
authors: J
authors: Chen
authors: M K
authors: MK
authors: Mulligan
authors: Z
authors: Z
authors: Li
authors: J
authors: J
authors: Ingles
authors: X
authors: X
authors: Chen
authors: L
authors: L
authors: Lu
authors: R W
authors: RW
authors: Williams
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D025941:Protein Interaction Mapping / Q000379:methods; D040641:Quantitative Trait Loci; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3