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.