Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain - PubMed (original) (raw)

Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain

Wee-Tin Kao et al. Proc Natl Acad Sci U S A. 2010.

Abstract

Structural and polymorphic variations in Neuregulin 3 (NRG3), 10q22-23 are associated with a broad spectrum of neurodevelopmental disorders including developmental delay, cognitive impairment, autism, and schizophrenia. NRG3 is a member of the neuregulin family of EGF proteins and a ligand for the ErbB4 receptor tyrosine kinase that plays pleotropic roles in neurodevelopment. Several genes in the NRG-ErbB signaling pathway including NRG1 and ErbB4 have been implicated in genetic predisposition to schizophrenia. Previous fine mapping of the 10q22-23 locus in schizophrenia identified genome-wide significant association between delusion severity and polymorphisms in intron 1 of NRG3 (rs10883866, rs10748842, and rs6584400). The biological mechanisms remain unknown. We identified significant association of these SNPs with increased risk for schizophrenia in 350 families with an affected offspring and confirmed association to patient delusion and positive symptom severity. Molecular cloning and cDNA sequencing in human brain revealed that NRG3 undergoes complex splicing, giving rise to multiple structurally distinct isoforms. RNA expression profiling of these isoforms in the prefrontal cortex of 400 individuals revealed that NRG3 expression is developmentally regulated and pathologically increased in schizophrenia. Moreover, we show that rs10748842 lies within a DNA ultraconserved element and homedomain and strongly predicts brain expression of NRG3 isoforms that contain a unique developmentally regulated 5' exon (P = 1.097E(-12) to 1.445E(-15)). Our observations strengthen the evidence that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the human brain, and reveal a probable mechanistic basis for disease association.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Schematic overview of SNPs associated with schizophrenia in 356 families (P < 0.05). Heat map shows LD _r_2 values.

Fig. 2.

Fig. 2.

Organization of NRG3 transcripts cloned from adult human brain (whole brain and hippocampus). Exons are shown in the order in which they occur in the transcript. The length of each exon is not proportional to the number of amino acids encoded. The nomenclature describing each exon is listed in the box (Bottom). The top row is a compendium of all exon nomenclatures (reference). The numbering is consistent with RefSeq gene annotations for NRG3 [University of California, Santa Cruz, Genome Browser or NCBI36/hg18 and GRCh37 Assembly (hg19)]. Isoforms are numbered and subdivided into classes based on common exon inclusion. Class categories were used to design primer probe sets for QPCR. Numerical annotation refers to “transcript.” Sequence annotation features for functional domains are derived from the Protein Knowledgebase (

http://www.uniprot.org/uniprot/P56975

). Nucleotide sequences for NRG3 variants have been deposited in GenBank database under accession numbers HM068873–HM068885.

Fig. 3.

Fig. 3.

Quantitative expression of full-length NRG3 transcripts comprising leader exons E1 (class I) and E3 contiguous with E4 (class IV and DQ857894) is significantly increased in the DLPFC of patients with schizophrenia (n = 245 normal individuals and n = 113 with schizophrenia). Values are mean ± SEM.

Fig. 4.

Fig. 4.

Allele-associated differences in expression of NRG3 class II and III in the adult DLPFC (A and B) and fetal DLPFC (C and D) associated with rs10748842. A_–_D show increased expression of NRG3 transcripts in T/T individuals compared with C-carrier individuals. In A and B, n = 315; 223 T/T and 92 C-carriers. In C and D, n = 34 fetal DLPFC; 24 T/T individuals and 10 C-carriers. No diagnosis by genotype interactions were observed. Values are mean ± SEM.

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