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

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

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