DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder

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 harmon...

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Published in:	Molecular psychiatry Vol. 14; no. 9; pp. 865 - 873
Main Authors:	Hennah, W, Thomson, P, McQuillin, A, Bass, N, Loukola, A, Anjorin, A, Blackwood, D, Curtis, D, Deary, I J, Harris, S E, Isometsä, E T, Lawrence, J, Lönnqvist, J, Muir, W, Palotie, A, Partonen, T, Paunio, T, Pylkkö, E, Robinson, M, Soronen, P, Suominen, K, Suvisaari, J, Thirumalai, S, Clair, D St, Gurling, H, Peltonen, L, Porteous, D
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-09-2009 Nature Publishing Group
Subjects:	Alleles Autism Behavioral Sciences Biological Psychology Bipolar disorder Bipolar Disorder - genetics Case-Control Studies Cohort Studies Cytoskeletal proteins Disc1 protein Europe Female Gene Frequency Genetic aspects Genetic diversity Genetic Predisposition to Disease Genetics Genomes Genotype Hospitals Humans International Cooperation Male Medicine Medicine & Public Health Mental disorders Mental health Nerve Tissue Proteins - genetics Neuropsychological Tests Neurosciences Odds Ratio original-article Pharmacotherapy Physiological aspects Polymorphism Polymorphism, Single Nucleotide Psychiatric Status Rating Scales Psychiatry Public health Risk factors Schizophrenia Schizophrenia - genetics Sex Factors Single nucleotide polymorphisms Single-nucleotide polymorphism Europe United Kingdom England Scotland United Kingdom > UK Finland association bipolar disorder interplay schizophrenia DISC1 heterogeneity
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	1359-4184 1476-5578
DOI:	10.1038/mp.2008.22