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.
"Integration of the genomic information of these mouse loci with known linkage regions for psychiatric disorders may subsequently reveal homologous genes. In this way, a recent study found homology between a quantitative trait locus (QTL) for mouse avoidance behavior and an often identified linkage region for bipolar disorders (Avramopoulos et al., 2004; McInnis et al., 2003; Zandi et al., 2007). By integrating genetic data from the mouse and from a large human GWAS on this mood disorder, novel candidate genes with potential translational value for this complex mood disorder were discovered (de Mooij-van Malsen et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Current approaches to dissect the molecular neurobiology of complex neuropsychiatric disorders such as schizophrenia and major depression have been rightly criticized for failing to provide benefits to patients. Improving the translational potential of our efforts will require the development and refinement of better disease models that consider a wide variety of contributing factors, such as genetic variation, gene-by-environment interactions, endophenotype or intermediate phenotype assessment, cross species analysis, sex differences, and developmental stages. During a targeted expert meeting of the European College of Neuropsychopharmacology (ECNP) in Istanbul, we addressed the opportunities and pitfalls of current translational animal models of psychiatric disorders and agreed on a series of core guidelines and recommendations that we believe will help guiding further research in this area.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2011; 21(7):532-44. DOI:10.1016/j.euroneuro.2010.12.001 · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous linkage studies have identified chromosome 8q24 as a promising positional candidate region to search for bipolar disorder (BP) susceptibility genes. We, therefore, sought to identify BP susceptibility genes on chromosome 8q24 using a family-based association study of a dense panel of SNPs selected to tag the known common variation across the region of interest. A total of 1,458 SNPs across 16 Mb of 8q24 were examined in 3,512 subjects, 1,954 of whom were affected with BP, from 737 multiplex families. Single-locus tests were carried out with FBAT and Geno-PDT, and multi-locus test were carried out with HBAT and multi-locus Geno-PDT. None of the SNPs were associated with BP in the single-locus tests at a level that exceeded our threshold for study-wide significance (P < 3.00 x 10(-5)). However, there was consistent evidence at our threshold for the suggestive level (P < 7.00 x 10(-4)) from both the single locus and multi-locus tests of associations with SNPs in the genes ADCY8, ST3GAL1, and NSE2. Multi-locus analyses suggested joint effects between ADCY8 and ST3GAL1 (P = 3.00 x 10(-4)), with at least one copy of the "high risk" allele required at both genes for association with BP, consistent with a jointly dominant-dominant model of action. These findings with ADCY8 and ST3GAL1 warrant further investigation in order to confirm the observed associations and their functional significance for BP susceptibility.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2008; 147B(5):612-8. DOI:10.1002/ajmg.b.30651 · 3.42 Impact Factor
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