Genome-Wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes

Erin N. Smith, Daniel L. Koller, Corrie Panganiban, Szabolcs Szelinger, Peng Zhang, Judith A. Badner, Thomas B. Barrett, Wade H. Berrettini, Cinnamon S. Bloss, William Byerley, William Coryell, Howard J. Edenberg, Tatiana Foroud, Elliot S. Gershon, Tiffany A. Greenwood, Yiran Guo, Maria Hipolito, Brendan J. Keating, William B. Lawson, Chunyu LiuPamela B. Mahon, Melvin G. McInnis, Francis J. McMahon, Rebecca McKinney, Sarah S. Murray, Caroline M. Nievergelt, John I. Nurnberger, Evaristus A. Nwulia, James B. Potash, John Rice, Thomas G. Schulze, William A. Scheftner, Paul D. Shilling, Peter P. Zandi, Sebastian Zöllner, David W. Craig, Nicholas J. Schork, John R. Kelsoe

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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.

Original languageEnglish (US)
Article numbere1002134
JournalPLoS Genetics
Volume7
Issue number6
DOIs
StatePublished - Jun 1 2011

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Smith, E. N., Koller, D. L., Panganiban, C., Szelinger, S., Zhang, P., Badner, J. A., Barrett, T. B., Berrettini, W. H., Bloss, C. S., Byerley, W., Coryell, W., Edenberg, H. J., Foroud, T., Gershon, E. S., Greenwood, T. A., Guo, Y., Hipolito, M., Keating, B. J., Lawson, W. B., ... Kelsoe, J. R. (2011). Genome-Wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes. PLoS Genetics, 7(6), [e1002134]. https://doi.org/10.1371/journal.pgen.1002134