Sex‐specific association of the reelin gene with bipolar disorder

Abstract

The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genomewide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR = 1.47, P = 5.9 × 10 -4 ); this withstood empirical correction for testing of multiple markers (empirical P = 0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR Female = 1.79, P = 8.9 × 10 -5 vs. OR Male = 1.12, P = 0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support.

Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

“…It is tempting to speculate that PC loss in rl/+ mice is due to apoptosis, and that estradiol inhibits cell death by increasing reelin expression. Recent genetic studies have highlighted a link between variants of the reelin gene and risk of psychosis in women (Shifman et al, 2008;Goes et al, 2009). In conclusion, there is accumulating evidence that an interaction between altered reelin function and altered estrogen/ androgen balance could be an important pathophysiological mechanism in ASD, as well as other psychoses.…”

Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

“…Reelin (RELN) is a susceptibility gene for SCZ with genetic evidence from a GWAS using DNA pooling strategy [15] and several hypothesis-driven association studies across diverse populations [16][17][18][19], and variants in RELN have been reported to confer risk for BPD as well [20]. Recent studies have also demonstrated a reduction in RELN messenger RNA (mRNA) and protein expression in postmortem brain tissues of patients with SCZ and BPD [21,22], and other analyses indicated epigenetic aberrations of RELN in psychiatric disorders [23].…”

A new single-nucleotide mutation (rs362719) of the reelin (RELN) gene associated with schizophrenia in female Chinese Han

“…In a recent report, rs362719 was found to be associated with a susceptibility to bipolar disorder in women but still may not be replicated (Goes et al, 2010). Since schizophrenia and bipolar disorder are closely related psychiatric disorders, it is encouraging to see a similar effect of rs362719 as regards the predisposition to schizophrenia.…”

“…Despite the efforts to identify the cause of schizophrenia, it remains elusive as regards the definitive causes of the disorder. Another research has identified another variant (rs362719) of RELN gene, which has been found to increase the susceptibility to bipolar disorder patients in women (Goes et al, 2010). Based on the hypothesis that the overlap gene shares a similar background in both schizophrenia and bipolar disorder, we conducted a case-control study of this SNP locus (rs362719) to test the possible association with the schizophrenia in various Chinese populations.…”