Abstract
We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10−3 from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10−4) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10−9, odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10−8, OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Craddock N, Jones I . Genetics of bipolar disorder. J Med Genet 1999; 36: 585–594.
Craddock N, Sklar P . Genetics of bipolar disorder: successful start to a long journey. Trends Genet 2009; 25: 99–105.
Ferreira MA, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058.
Cichon S, Mühleisen TW, Degenhardt FA, Mattheisen M, Miró X, Strohmaier J et al. Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. Am J Hum Genet 2011; 88: 372–381.
Psychiatric GWAS Consortium Bipolar Disorder Working Group. Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S et al. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43: 977–983.
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–678.
Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 2011; 43: 1193–1201.
Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R et al. SCAN. Schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiatry 1990; 47: 589–593.
McGuffin P, Farmer A, Harvey I . A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch Gen Psychiatry 1991; 48: 764–770.
Craddock M, Asherson P, Owen MJ, Williams J, McGuffin P, Farmer AE . Concurrent validity of the OPCRIT diagnostic system. Comparison of OPCRIT diagnoses with consensus best-estimate lifetime diagnoses. Br J Psychiatry 1996; 169: 58–63.
Spitzer RL, Endicott J, Robins E . Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 1978; 35: 773–782.
Craddock N, Jones I, Kirov G, Jones L . The Bipolar Affective Disorder Dimension Scale (BADDS)-a dimensional scale for rating lifetime psychopathology in bipolar spectrum disorders. BMC Psychiatry 2004; 4: 19–28.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Giannoulatou E, Yau C, Colella S, Ragoussis J, Holmes CC . GenoSNP: a variational Bayes within-sample SNP genotyping algorithm that does not require a reference population. Bioinformatics 2008; 24: 2209–2214.
Cross-Disorder Phenotype Group of the Psychiatric GWAS Consortium. Craddock N, Kendler K, Neale M, Nurnberger J, Purcell S et al. Dissecting the phenotype in genome-wide association studies of psychiatric illness. Br J Psychiatry 2009; 195: 97–99.
Acknowledgements
We are indebted to all individuals who have participated in, or helped with, our research. We particularly thank those involved with Bipolar UK—the Bipolar Organization and the Bipolar Disorder Research Network (BDRN). Sample collection and analysis was supported by the Wellcome Trust (grant 078901) and a grant from the Stanley Medical Research Institute via the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. Genotyping was supported by the Wellcome Trust under WTCCC. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/0 as well as the UK Blood Services collection of Common Controls (UKBS-CC collection), funded by the Wellcome Trust grant 076113/C/04/Z and by NIHR programme grant to NHSBT (RP-PG-0310-1002).
Author information
Authors and Affiliations
Consortia
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
Rights and permissions
About this article
Cite this article
Green, E., Hamshere, M., Forty, L. et al. Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case–control sample. Mol Psychiatry 18, 1302–1307 (2013). https://doi.org/10.1038/mp.2012.142
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2012.142
Keywords
This article is cited by
-
Bipolar disorder-iPSC derived neural progenitor cells exhibit dysregulation of store-operated Ca2+ entry and accelerated differentiation
Molecular Psychiatry (2023)
-
Genetic and functional analyses implicate microRNA 499A in bipolar disorder development
Translational Psychiatry (2022)
-
Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study
Molecular Psychiatry (2021)
-
Genetic variants in the bipolar disorder risk locus SYNE1 that affect CPG2 expression and protein function
Molecular Psychiatry (2021)
-
Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain
Molecular Psychiatry (2020)