DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder

被引：108

作者：

Hennah, W. ^{[1
]}

Thomson, P. ^{[1
]}

McQuillin, A. ^{[3
]}

Bass, N. ^{[3
]}

Loukola, A. ^{[2
,4
]}

Anjorin, A. ^{[3
]}

Blackwood, D. ^{[5
]}

Curtis, D. ^{[6
,7
]}

Deary, I. J. ^{[8
]}

Harris, S. E. ^{[8
]}

Isometsa, E. T. ^{[9
,10
]}

Lawrence, J. ^{[3
]}

Lonnqvist, J. ^{[9
,10
]}

Muir, W. ^{[5
]}

Palotie, A. ^{[4
]}

Partonen, T. ^{[9
]}

Paunio, T. ^{[2
,10
]}

Pylkko, E. ^{[2
]}

Robinson, M. ^{[3
]}

Soronen, P. ^{[2
]}

Suominen, K. ^{[11
]}

Suvisaari, J. ^{[9
]}

Thirumalai, S. ^{[3
]}

St Clair, D. ^{[12
]}

Gurling, H. ^{[3
]}

Peltonen, L. ^{[2
,13
,14
]}

Porteous, D. ^{[1
]}

机构：

[1] Univ Edinburgh, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland

[2] Natl Publ Hlth Inst, Dept Mol Med, Helsinki, Finland

[3] UCL, Mol Psychiat Lab, Dept Mental Hlth Sci, Windeyer Inst Med Sci, London, England

[4] Univ Helsinki, Finnish Genome Ctr, Helsinki, Finland

[5] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland

[6] Univ London, Queen Mary Coll, London, England

[7] Royal London Hosp, City Mental Hlth Trust, London E1 1BB, England

[8] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[9] Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland

[10] Univ Helsinki, Cent Hosp, Dept Psychiat, Helsinki, Finland

[11] Univ Helsinki, Dept Psychiat, Jorvi Hosp, Cent Hosp, Espoo, Finland

[12] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland

[13] Univ Helsinki, Dept Med Genet, Helsinki, Finland

[14] MIT, Broad Inst, Boston, MA USA

来源：

MOLECULAR PSYCHIATRY | 2009年 / 14卷 / 09期

基金：

英国医学研究理事会; 芬兰科学院; 英国生物技术与生命科学研究理事会;

关键词：

DISC1; schizophrenia; bipolar disorder; association; heterogeneity; interplay; SUSCEPTIBILITY LOCUS; GENES; RISK; TRANSLOCATION; HAPLOTYPE; POLYMORPHISM; GENOTYPE; FAMILIES; MEMORY; 1Q42;

D O I：

10.1038/mp.2008.22

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. Molecular Psychiatry (2009) 14, 865-873; doi: 10.1038/mp.2008.22; published online 4 March 2008

引用

页码：865 / 873

页数：9

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