A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees

Abstract

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.

FIG. 1

Results of two-point linkage and association with BP-I in families and trios from Costa Rica and Colombia using densely spaced SNP markers. Distribution of microsatellite markers analyzed previously [Herzberg et al., 2006] and tested SNPs (black vertical bars) are shown with respect to localization of low LD regions (gray horizontal bars), which were covered with increased density of SNPs in 5q33 (A). Two-point linkage analysis in BP-I families from CVCR (circle), CO (square), and combined results (×) is shown in panel (B). Tests of association given linkage were done using frequencies estimated from the corresponding trio sample. The LOD score (Y-axis) is plotted against of the physical position in megabases (Mb) of the corresponding SNPs. For clarity, only LOD scores greater than 2 are shown. Panel (C) shows association in presence of linkage in CVCR families (cross), CO families (star), and combined results (×); and association in population trios from CVCR (diamond), CO (triangle), and in combined trio sample (square) as −log₁₀ P-value (Y-axis) plotted against physical position in Mb of the corresponding SNP. For clarity, only results with−log₁₀ P-value greater than 2 are plotted. Positions of the RefSeq genes in the investigated region are shown in panel (D). The most promising positional and functional candidate genes in the region are shown in boldface.

FIG. 2

Comparison of allele frequencies in the CR and CVCR population samples. Allele frequencies were estimated from parental data. Presented is the frequency of the “1” allele at each marker.