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Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

ABSTRACT: Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

SUBMITTER: Segurado R

PROVIDER: S-EPMC1180589 | biostudies-literature | 2003 Jul

REPOSITORIES: biostudies-literature

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Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Segurado Ricardo R Detera-Wadleigh Sevilla D SD Levinson Douglas F DF Lewis Cathryn M CM Gill Michael M Nurnberger John I JI Craddock Nick N DePaulo J Raymond JR Baron Miron M Gershon Elliot S ES Ekholm Jenny J Cichon Sven S Turecki Gustavo G Claes Stephan S Kelsoe John R JR Schofield Peter R PR Badenhop Renee F RF Morissette J J Coon Hilary H Blackwood Douglas D McInnes L Alison LA Foroud Tatiana T Edenberg Howard J HJ Reich Theodore T Rice John P JP Goate Alison A McInnis Melvin G MG McMahon Francis J FJ Badner Judith A JA Goldin Lynn R LR Bennett Phil P Willour Virginia L VL Zandi Peter P PP Liu Jianjun J Gilliam Conrad C Juo Suh-Hang SH Berrettini Wade H WH Yoshikawa Takeo T Peltonen Leena L Lönnqvist Jouko J Nöthen Markus M MM Schumacher Johannes J Windemuth Christine C Rietschel Marcella M Propping Peter P Maier Wolfgang W Alda Martin M Grof Paul P Rouleau Guy A GA Del-Favero Jurgen J Van Broeckhoven Christine C Mendlewicz Julien J Adolfsson Rolf R Spence M Anne MA Luebbert Hermann H Adams Linda J LJ Donald Jennifer A JA Mitchell Philip B PB Barden Nicholas N Shink Eric E Byerley William W Muir Walter W Visscher Peter M PM Macgregor Stuart S Gurling Hugh H Kalsi Gursharan G McQuillin Andrew A Escamilla Michael A MA Reus Victor I VI Leon Pedro P Freimer Nelson B NB Ewald Henrik H Kruse Torben A TA Mors Ole O Radhakrishna Uppala U Blouin Jean-Louis JL Antonarakis Stylianos E SE Akarsu Nurten N

American journal of human genetics 20030611 1

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample siz ...[more]

PMID: 12802785

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Project description:OBJECTIVE:Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. METHOD:The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders. RESULTS:The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder. CONCLUSIONS:This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

Dataset Information

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Publications

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

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