Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population
2011 (English)In: Bipolar Disorders, ISSN 1398-5647, E-ISSN 1399-5618, Vol. 13, no 7-8, 614-623 p.Article in journal (Refereed) Published
Objectives: Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD. Methods: Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population. Results: Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10–15%) susceptibility haplotype covering the entire coding region and 3? untranslated region (UTR) of NR3C1. Conclusions: This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.
Place, publisher, year, edition, pages
John Wiley & Sons, 2011. Vol. 13, no 7-8, 614-623 p.
bipolar disorder, glucocorticoid receptor, HPA axis, isolated population, NR3C1
Research subject Psychology
IdentifiersURN: urn:nbn:se:su:diva-70450DOI: 10.1111/j.1399-5618.2011.00960.xISI: 000297053300004OAI: oai:DiVA.org:su-70450DiVA: diva2:481321
This work was funded in part by the University of Antwerp, the Fund for Scientific Research-Flanders (FWO-F), the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT), the Swedish Research Council (2006–4472 and 2009–5269), the Medical Faculty, Umeå University, and the County Councils of Västerbotten and Norrbotten, Sweden. None of the funding agencies had any further role in the study design, in collection, analysis, or interpretation of the data, in writing of the report, or in the decision to submit the paper for publication. SC holds a Ph.D. fellowship from IWT and SC is a senior Clinical Investigator of FWO-F.
The authors are grateful to the patients and their relatives for their cooperation and participation in this research study. We acknowledge the contribution of the personnel of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be) for the genetic analyses. Research nurse Eva Lundberg is acknowledged for her help and expertise in clinically evaluating the bipolar disorder patient sample.2012-01-202012-01-202012-02-01Bibliographically approved