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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.

ABSTRACT: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

SUBMITTER: Lewis CM

PROVIDER: S-EPMC1180588 | biostudies-literature | 2003 Jul

REPOSITORIES: biostudies-literature

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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.

Lewis Cathryn M CM Levinson Douglas F DF Wise Lesley H LH DeLisi Lynn E LE Straub Richard E RE Hovatta Iiris I Williams Nigel M NM Schwab Sibylle G SG Pulver Ann E AE Faraone Stephen V SV Brzustowicz Linda M LM Kaufmann Charles A CA Garver David L DL Gurling Hugh M D HM Lindholm Eva E Coon Hilary H Moises Hans W HW Byerley William W Shaw Sarah H SH Mesen Andrea A Sherrington Robin R O'Neill F Anthony FA Walsh Dermot D Kendler Kenneth S KS Ekelund Jesper J Paunio Tiina T Lönnqvist Jouko J Peltonen Leena L O'Donovan Michael C MC Owen Michael J MJ Wildenauer Dieter B DB Maier Wolfgang W Nestadt Gerald G Blouin Jean-Louis JL Antonarakis Stylianos E SE Mowry Bryan J BJ Silverman Jeremy M JM Crowe Raymond R RR Cloninger C Robert CR Tsuang Ming T MT Malaspina Dolores D Harkavy-Friedman Jill M JM Svrakic Dragan M DM Bassett Anne S AS Holcomb Jennifer J Kalsi Gursharan G McQuillin Andrew A Brynjolfson Jon J Sigmundsson Thordur T Petursson Hannes H Jazin Elena E Zoëga Tomas T Helgason Tomas T

American journal of human genetics 20030611 1

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studie ...[more]

PMID: 12802786

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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 II: Schizophrenia.

Publications

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.

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