Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

Cathryn M. Lewis, Douglas F. Levinson, Lesley H. Wise, Lynn E. DeLisi, Richard E. Straub, Iiris Hovatta, Nigel M. Williams, Sibylle G. Schwab, Ann E. Pulver, Stephen V. Faraone, Linda M. Brzustowicz, Charles A. Kaufmann, David L. Garver, Hugh M.D. Gurling, Eva Lindholm, Hilary Coon, Hans W. Moises, William Byerley, Sarah H. Shaw, Andrea Mesen, Robin Sherrington, F. Anthony O’Neill, Dermot Walsh, Kenneth S. Kendler, Jesper Ekelund, Tiina Paunio, Jouko Lönnqvist, Leena Peltonen, Michael C. O’Donovan, Michael J. Owen, Dieter B. Wildenauer, Wolfgang Maier, Gerald Nestadt, Jean-Louis Blouin, Stylianos E. Antonarakis, Bryan J. Mowry, Jeremy M. Silverman, Raymond R. Crowe, C. Robert Cloninger, Ming T. Tsuang, Dolores Malaspina, Jill M. Harkavy-Friedman, Dragan M. Svrakic, Anne S. Bassett, Jennifer Holcomb, Gursharan Kalsi, Andrew McQuillin, Jon Brynjolfson, Thordur Sigmundsson, Hannes Petursson, Elena Jazin, Tomas Zoëga, Tomas Helgason

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.