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.

Figure 1

Ranks by study and average ranks. The following are shown: within-study ranks (R_study) grouped as shown in the legend; the average rank (R_avg) for each bin across studies (low values are best), weighted proportional to for each study; and the overall place of each bin in ascending order of average ranks (the lowest/best average rank is first place). Average ranks with significant P_AvgRnk values are highlighted above the columns (black for P_AvgRnk<.01, gray for P_AvgRnk<.05). Exact P_AvgRnk values are shown in table 2. Tied ranks sometimes resulted in uneven numbers of bins in some groupings, particularly for lower ranks when there were many zero or negative scores. Marshfield (“Mfd”) locations are shown for the marker at the distal boundary of each bin. Bin boundaries were selected at ∼30 cM spacing on the Généthon map; mean bin width is 29.1 cM on the Marshfield map. Peds = number of pedigrees; Aff = number of genotyped affected cases. See table 1 for the references associated with each study.

Figure 2

Average ranks (R_avg) for 20 SCZ genome scans. Shown are the average ranks for each bin, comparing the results for the unweighted (◊) and weighted (⧫) analyses. P_AvgRnk thresholds are shown. See table 2 for exact P_AvgRnk and P_ord values for the most significant bins.

Figure 3

SCZ average ranks versus random distribution. The blackened diamonds (⧫) denote the weighted average ranks (R_avg) for the bins with the best (i.e., lowest) 19 ranks in the SCZ GSMA, sorted in order of R_avg. Bin numbers are labeled in boldface type for bins with P_AvgRnk and P_ord<.05 and labeled in normal type for bins with only P_ord<.05. The gray data points indicate the mean R_avg for each ordered bin (first place, second place, etc.) in 5,000 randomly permuted replicates, and the vertical gray bars represent 2 SDs above and below these means. The figure illustrates how, for this cluster of 19 bins, average ranks are significantly lower than expected from the random distribution. See table 2 for exact P values and cytogenetic locations of the best 19 bins.