Meta-analysis of 32 genome-wide linkage studies of schizophrenia

Abstract

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Figure 1

Genomewide results for primary analysis (weighted, 30 cM bins) for ALL studies (red) and EUR studies (blue). The two upper dashed lines represent empirical thresholds for genomewide significant (theoretical P_SR = 0.00037) and suggestive (theoretical P_SR= 0.0077) evidence for linkage for a single bin for ALL studies; and the lower dashed line represents the threshold for aggregate significance for ALL studies (theoretical P_SR = 0.046 in 10 or more bins). The thresholds for EUR studies were slightly less stringent (P_SR values of 0.00044, 0.0078 and 0.0475 (in 10 or more bins) respectively), but the Figure shows all EUR bins within the region for their correct threshold of significance.

Figure 2

Ranks by study and summed ranks. Shown for each study is the within-study rank of each bin. ‘1’ against a red background indicates bins with ranks of 116-120 (the bin containing the most significant linkage score in a study is ranked 120); 2 indicates ranks 111-115; 3—ranks 101-110; 4—ranks 81-100; 5—ranks 61-80; 6—ranks 41-60; 7—ranks 21-40; and 8—ranks 1-20 (cells with 7 and 8 have a white background). Shown at the top of each part of the figure are the bin number, the weighted summed rank for each bin across studies (i.e., weighted for each sample by the square root of the N of genotyped affected individuals), and the rank-ordered position of that bin in the ALL analysis (i.e., 1 is the best position, see details in Table 2). Purple background indicates bins with empirical suggestive evidence for linkage in the ALL analysis; 10 bins shaded in purple, yellow or blue met the threshold for aggregate genome-wide evidence for linkage (10 bins with nominal P < 0.046); and bin 8.2 (shaded blue) also met empirical suggestive evidence for linkage in the EUR analysis. Shown at the bottom is the distal boundary of each bin in Rutgers cM and in Mb (build 36). Note that tied ranks can result in uneven numbers of bins in a grouping, particularly for lower ranks when there are many zero or negative scores. See Table 1 for the references associated with each study.