Journal article
Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes
PLoS genetics, Vol.7(6), e1002134
06/30/2011
DOI: 10.1371/journal.pgen.1002134
PMCID: PMC3128104
PMID: 21738484
Abstract
Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10
−7
). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.
Bipolar disorder (BD) is a highly heritable disease that has been difficult to characterize genetically. We have genotyped 1,190 BD cases and 401 controls to find regions of the genome associated with BD. After combining these data with previously existing genotyped samples, we did not find any genome-wide significant associations. However, when we used an additional study to prioritize loci for replication and meta-analysis purposes, we found that we were more likely to see an association in our sample with variants for which we had the highest power. We quantified this effect using logistic regression and saw a strong association between power to detect an effect based on an initial study's results and replication P-value in a second study (P = 1.5×10
−7
), supporting the presence of shared genetic risk factors across the studies. Moreover, this association was stronger when we restricted analysis to SNPs near coding regions, and it was further enriched when SNPs had the same direction of effect in both studies. This result supports the presence of genetic factors underlying BD near exons whose collective effect results in a detectable signal and provides a framework for assessing the potential for replication when combining results from multiple studies.
Details
- Title: Subtitle
- Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes
- Creators
- Erin N Smith - Scripps ClinicDaniel L Koller - Indiana University IndianapolisCorrie Panganiban - Translational Genomics Research InstituteSzabolcs Szelinger - Translational Genomics Research InstitutePeng Zhang - University of MichiganJudith A Badner - University of ChicagoThomas B Barrett - Portland VA Medical CenterWade H Berrettini - University of PennsylvaniaCinnamon S Bloss - Scripps ClinicWilliam Byerley - University of California San Francisco Medical CenterWilliam Coryell - University of IowaHoward J Edenberg - Indiana University IndianapolisTatiana Foroud - Indiana University IndianapolisElliot S Gershon - University of ChicagoTiffany A Greenwood - University of California San DiegoYiran Guo - Children's Hospital of PhiladelphiaMaria Hipolito - Howard UniversityBrendan J Keating - University of PennsylvaniaWilliam B Lawson - Howard UniversityChunyu Liu - University of ChicagoPamela B Mahon - Johns Hopkins UniversityMelvin G McInnis - University of MichiganFrancis J McMahon - National Institute of Mental HealthRebecca McKinney - University of California San DiegoSarah S Murray - Scripps ClinicCaroline M Nievergelt - University of California San DiegoJohn I Nurnberger - Indiana University IndianapolisEvaristus A Nwulia - Howard UniversityJames B Potash - Johns Hopkins UniversityJohn Rice - Washington University in St. LouisThomas G Schulze - National Institutes of HealthWilliam A Scheftner - Rush UniversityPaul D Shilling - University of California San DiegoPeter P Zandi - Johns Hopkins UniversitySebastian Zöllner - University of MichiganDavid W Craig - Translational Genomics Research InstituteNicholas J Schork - Scripps ClinicJohn R Kelsoe - University of California San Diego
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.7(6), e1002134
- DOI
- 10.1371/journal.pgen.1002134
- PMID
- 21738484
- PMCID
- PMC3128104
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library of Science; San Francisco, USA
- Alternative title
- BD GWAS Suggests Enrichment near Genes
- Language
- English
- Date published
- 06/30/2011
- Academic Unit
- Psychiatry
- Record Identifier
- 9984003422302771
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