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.

Figure 1

Individual study and weighted average ranks by bin (model 1). 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). 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

Individual study and weighted average ranks by bin (model 2) (see fig. 1 for explanation)