SNP fine mapping of chromosome 8q24 in bipolar disorder.

We previously reported linkage to chromosome 8q24 in bipolar disorder (BP) with a LOD of 3.32. We fine mapped the locus with SNPs and tested for association with BP in families with evidence of linkage to the region. We genotyped 249 informative SNPs over 3.4 Mb in an initial sample of 155 nuclear families (352 affected offsprings), and followed up the best findings by genotyping six of the most significantly associated SNPs in a replication sample of 103 nuclear families (231 affected offsprings). We used FBAT and GIST for association tests. Two clusters of SNPs emerged with the strongest evidence of association. The first consisted of three SNPs, approximately 3 kb 5' from the gene ST3GAL1. These SNPs were associated with BP in the initial sample by FBAT (best P = 0.001) and GIST (best P = 0.05) and associated in the replication sample by FBAT (best P = 0.04). The second cluster consisted of four SNPs (one of which was not genotyped in the replication sample), approximately 480 kb 5' of ST3GAL1 in a relative gene desert. These SNPs were associated with BP in the initial sample by FBAT (best P = 0.007) and GIST (best P = 0.03), and marginally associated in the replication sample by FBAT (best P = 0.07) and GIST (P = 0.04). ST3GAL1 belongs to a family of glycosyltransferase proteins, several members of which are highly expressed in the brain and involved in neurogenesis. Several other interesting candidate genes are also located nearby. The congruence of findings across methods and samples suggests further investigation is warranted in these two targeted regions.