An association study of the neuregulin 1 gene, bipolar affective disorder and psychosis

As evidence of partial aetiological overlap between bipolar affective disorder and schizophrenia is accumulating, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. As the neuregulin 1 (NRG1) gene has been associated with schizophrenia, we set out to investigate whether it is also associated with bipolar affective disorder, using a sample from Scotland, UK.

We tested four single nucleotide polymorphisms (SNPs), SNP8NRG221533 (rs35753505), SNP8NRG241930, SNP8NRG243177 (rs6994992) and SNPNRG222662 (rs4623364) for allelic and haplotypic association with bipolar disorder and the presence of psychotic or mood-incongruent psychotic features.

We found nominal allele-wise significant association (P = 0.02) for SNP8NRG221533, with the T allele being overrepresented in cases. This is the opposite allelic association to the original association study where the C allele was associated with schizophrenia. Allele-wise significance increased when we tested for association with the subgroups of bipolar disorder with psychotic features (chi2 = 8.53; P = 0.003; odds ratio = 1.49) and, more specifically, with mood-incongruent psychotic features (chi2 = 7.13; P = 0.008; odds ratio = 1.57). Furthermore, both these subphenotypes were significantly associated with the SNP8NRG221533(T)-SNP8NRG241930(G) haplotype (chi2 = 11.94, global P = 0.027 and chi2 = 11.88, global P = 0.019, respectively) and with the SNP8NRG221533(T)-SNP8NRG222662(C)-SNP8NRG241930(G) haplotype (chi2 = 19.98, global P = 0.009) in case of the broader subphenotype of psychotic bipolar.

This study supports the hypothesis that NRG1 may play a role in the development of bipolar disorder, especially in psychotic subtypes, albeit with different alleles to previous association reports in schizophrenia and bipolar disorder.