Initial association of NR2E1 with bipolar disorder and identification of candidate mutations in bipolar disorder, schizophrenia, and aggression through resequencing

Nuclear receptor 2E1 gene (NR2E1) resides within a 6q21-22 locus for bipolar disorder and schizophrenia. Mice deleted for Nr2e1 show altered neurogenesis, cortical and limbic abnormalities, aggression, hyperexcitability, and cognitive impairment. NR2E1 is therefore a positional and functional candidate for involvement in mental illness. We performed association analyses in 394 patients with bipolar disorder, 396 with schizophrenia, and 479 controls using six common markers and haplotypes. We also performed a comprehensive mutation screen of NR2E1, resequencing its entire coding region, complete 5′ and 3′ untranslated regions, consensus splice-sites, and evolutionarily conserved regions in 126 humans with bipolar disorder, schizophrenia, or aggressive disorders. NR2E1 was associated with bipolar disorder I and II [odds ratio (OR = 0.77, P = 0.013), bipolar disorder I (OR = 0.77, P = 0.015), bipolar disorder in females (OR = 0.72, P = 0.009), and with age at onset ≤25 years (OR = 0.67, P = 0.006)], all of which remained significant after correcting for multiple comparisons. We identified eight novel candidate mutations that were absent in 325 controls; four of these were predicted to alter known neural transcription factor binding sites. Analyses of NR2E1 mRNA in human brain revealed forebrain-specific transcription. The data presented support the hypothesis that genetic variation at NR2E1 may be associated with susceptibility to brain-behavior disorders.