Family-based association study of Neuregulin 1 with psychotic bipolar disorder

The Neuregulin 1 gene (NRG1) has been associated with schizophrenia, and, to a lesser extent, with bipolar disorder (BP). We investigated the association of NRG1 with BP in a large family sample, and then performed analyses according to the presence of psychotic features or mood-incongruent psychotic features. We genotyped 116 tagSNPs and four Icelandic "core" SNPs in 1,199 subjects from 314 nuclear families. Of 515 BP offspring, 341 had psychotic features, and 103 had mood-incongruent psychotic features. In single-marker and sliding window haplotype analyses using FBAT, there was little association using the standard BP or mood-incongruent psychotic BP phenotypes, but stronger signals were seen in the psychotic BP phenotype. The most significant associations with psychotic BP were in haplotypes within the 5' "core" region. The strongest global P-value was across three SNPs: NRG241930-NRG243177-rs7819063 (P = 0.0016), with an undertransmitted haplotype showing an individual P = 0.0007. The most significant individual haplotype was an undertransmitted two-allele subset of the above (NRG243177-rs7819063, P = 0.0004). Additional associations with psychotic BP were found across six SNPs in a 270 kb central region of the gene. The most 3' of these, rs7005606 (P = 0.0029), is located approximately 4 kb from the type I NRG1 isoform promoter. In sum, our study suggests that NRG1 may be specifically associated with the psychotic subset of BP; however, our results should be interpreted cautiously since they do not meet correction for multiple testing and await independent replication.