Email updates

Keep up to date with the latest news and content from BMC Medical Genetics and BioMed Central.

Open Access Highly Accessed Research article

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1

Wei Xu1, Sarah Cohen-Woods2, Qian Chen3, Abdul Noor4, Jo Knight45, Georgina Hosang2, Sagar V Parikh57, Vincenzo De Luca7, Federica Tozzi128, Pierandrea Muglia1289, Julia Forte128, Andrew McQuillin10, Pingzhao Hu11, Hugh MD Gurling10, James L Kennedy45, Peter McGuffin2, Anne Farmer2, John Strauss57 and John B Vincent456*

Author Affiliations

1 Dalla Lana School of Public Health, University of Toronto, Toronto, Canada

2 MRC SGDP Centre, King’s College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

3 Cancer Care Ontario, Toronto, Canada

4 Neurogenetics Section, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), R-32, 250 College Street, Toronto, ON M5T 1R8, Canada

5 Department of Psychiatry, University of Toronto, Toronto, Canada

6 The Institute of Medical Science, University of Toronto, Toronto, Canada

7 Centre for Addiction and Mental Health (CAMH), Toronto, Canada

8 GSK Research & Development, Medical Genetics, Clinical Pharmacology and Discovery Medicine, Via Fleming 4, Verona, Italy

9 Exploratory Medicine & Early Development, NeuroSearch, Copenhagen, Denmark

10 Molecular Psychiatry Laboratory, Mental Health Sciences Unit, Faculty of Brain Sciences, University College London, London, UK

11 The Centre for Applied Genomics, The Hospital for Sick Children Research Institute, Toronto, Canada

12 GSK Research & Development, Medical Genetics, Clinical Pharmacology and Discovery Medicine, Greenford Road, Greenford, Middlesex UB6 OHE, UK

For all author emails, please log on.

BMC Medical Genetics 2014, 15:2  doi:10.1186/1471-2350-15-2

Published: 4 January 2014

Abstract

Background

Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).

Methods

Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.

Results

Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.

Conclusions

The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.

Keywords:
Case/control; Trio; Transmission disequilibrium test; Pathway analysis