DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder

Abstract

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P = 0.00020; corrected P = 0.016; odds ratio = 2.73 ± 95% confidence interval (CI) 1. 42-5.27) and at rs821577 in the London cohort (uncorrected P = 0.00070; corrected P = 0.040; odds ratio = 1.64±95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio = 1.27 ± 95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P = 0.0058; corrected P = 0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P = 0.00050; corrected P = 0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

“…Independent linkage/ association studies now implicate DISC1 in schizophrenia, severe affective disorders and autistic spectrum disorders of diverse populations (Devon et al, 2001;Ekelund et al, 2001;Hennah et al, 2005Hennah et al, , 2008Sachs et al, 2005;Zhang et al, 2005;Chen et al, 2007;Kilpinen et al, 2008). However, robust evidence for functional variants is still lacking, and genetic heterogeneity is likely.…”

Variation in DISC1 is associated with anxiety, depression and emotional stability in elderly women

“…These risk alleles have previously been associated with schizophrenia, bipolar disorder, and social and physical anhedonia, mainly in females. 1,7 Reports suggest that heritability of neuroticism, anxiety and depression is higher in females than in males, and that the genes involved differ between men and women. [8][9][10] We tested SNPs and models specifically chosen on the basis of earlier evidence, and hence do not believe that stringent multiple testing corrections are appropriate, but these results need to be replicated in other suitable cohorts before variation in DISC1 is fully accepted as contributing to normal variation in neuroticism and mood.…”

“…1 We investigated the association between these SNPs and the personality trait emotional stability/neuroticism (a potential endophenotype for mental illness), and anxiety and depression in two relatively healthy older Scottish cohorts (Lothian Birth Cohort of 1921 (LBC1921), 2 n = 360; and Lothian Birth Cohort of 1936 (LBC1936), 3 n = 1065).…”

“…It is therefore not surprising that MAO-A and B gene polymorphisms and altered expression are implicated in a variety of neurological disorders. [1][2][3][4][5] Moreover, the demonstration that MAO inhibitors, such as iproniazid, were effective antidepressant agents was pivotal in Schildkraut's 6 formulation of the catecholamine hypothesis of affective disorders. Here, we report for the first time the identification of a novel flavin adenine dinucleotide (FAD)-dependent protein, renalase, in various regions of the CNS.…”

“…5 Mood was assessed at a mean age of B79 years (LBC1921) or B70 years (LBC1936) using scores on the Hospital Anxiety and Depression scale (HADS). 6 LBC1921 was genotyped on a Sequenom platform (Sequenom, San Diego, CA, USA) 1 and LBC1936 using TaqMan (Applied Biosystems, Pleasonton, CA, USA) at 1 ) for each SNP or combination of SNPs and sex as fixed factors. As previous studies have shown that variance in DISC1 has stronger effects in females than in males, 1 the models were also run analysing males and females separately.…”