Genetic regulation of Nrnx1 expression

An integrative cross-species analysis of schizophrenia candidate genes

Khyobeni Mozhui, X. Wang, J. Chen, Megan Mulligan, Z. Li, J. Ingles, X. Chen, Lu Lu, Robert Williams

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere25
JournalTranslational psychiatry
Volume1
DOIs
StatePublished - Jul 26 2011

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Genetic Association Studies
Schizophrenia
Quantitative Trait Loci
Genes
Exons
RNA Sequence Analysis
Protein Interaction Maps
High-Throughput Nucleotide Sequencing
Chromosomes, Human, Pair 8
Chromosomes, Human, Pair 17
Brain
Autistic Disorder
Cognition
Molecular Biology
Phenotype
Population
Proteins

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Genetic regulation of Nrnx1 expression : An integrative cross-species analysis of schizophrenia candidate genes. / Mozhui, Khyobeni; Wang, X.; Chen, J.; Mulligan, Megan; Li, Z.; Ingles, J.; Chen, X.; Lu, Lu; Williams, Robert.

In: Translational psychiatry, Vol. 1, e25, 26.07.2011.

Research output: Contribution to journalArticle

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