Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene

Purpose: We had previously performed a genome-wide linkage scan for bipolar affective disorder in an Ashkenazi Jewish sample, a population likely to have reduced genetic heterogeneity. This study is a second stage follow-up focusing on regions that showed positive linkage scores in our previous scan but were not fine-mapped at that time. Methods: We genotyped an additional 145 highly polymorphic microsatellites and conducted linkage analyses using standard laboratory and analytical methods. Results: We saw an improvement of the evidence for linkage in most regions, with the most notable change on chromosome 12p13.1-p12.3, where the evidence of linkage is now suggestive. This region harbors the gene encoding the ionotropic glutamate receptor subunit 2B ( GRIN2B ), a gene that previously yielded evidence for association in a candidate gene study on 323 Ashkenazi Jewish bipolar case-parent trios. We find that the evidence for linkage is significantly correlated with the presence of the putative high-risk allele identified in our candidate gene study. Conclusions: Following up weaker signals can significantly improve linkage signals even after relatively small increases in information content. Our results on chromosome 12p support GRIN2B as a candidate gene for bipolar disorder that needs further investigation.