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Rare variants in neuronal excitability genes influence risk for bipolar disorder

2015; National Academy of Sciences; Volume: 112; Issue: 11 Linguagem: Inglês

10.1073/pnas.1424958112

1091-6490

Seth A. Ament, Szabolcs Szelinger, Gustavo Glusman, J. R. Ashworth, Liping Hou, Nirmala Akula, Tatyana Shekhtman, Judith A. Badner, Mary E. Brunkow, Denise E. Mauldin, Anna-Barbara Stittrich, Katherine Rouleau, Sevilla D. Detera‐Wadleigh, John I. Nürnberger, Howard J. Edenberg, Elliot S. Gershon, Nicholas J. Schork, Nathan D. Price, Richard Gelinas, Leroy Hood, David W. Craig, Francis J. McMahon, John R. Kelsoe, Jared C. Roach, John R. Kelsoe, Tiffany A. Greenwood, Caroline M. Nievergelt, Paul D. Shilling, Tatyana Shekhtman, Jared C. Roach, Seth A. Ament, Leroy Hood, John I. Nürnberger, Howard J. Edenberg, Tatiana Foroud, Daniel L. Koller, Elliot S. Gershon, Judith A. Badner, Chunyu Liu, William A. Scheftner, William Lawson, William Coryell, James B. Potash, John P. Rice, William Byerley, Francis J. McMahon, Liping Hou, Wade H. Berrettini, Peter P. Zandi, Melvin G. McInnis, David W. Craig, Szabolcs Szelinger, Thomas G. Schulze, Nicholas J. Schork, Danjuma Quarless,

Genomics and Rare Diseases

Significance Bipolar disorder (BD) is a common, severe, and recurrent psychiatric disorder with no known cure and substantial morbidity and mortality. Heritable causes contribute up to 80% of the lifetime risk for BD. Common genetic variation explains ∼25% of this heritable risk. Rare genetic variants may explain additional risk. We identified contributions of rare variants to BD by sequencing the genomes of 200 individuals from 41 families with BD. The two main findings of this study were as follows: rare risk variants for BD were enriched in genes and pathways that regulate diverse aspects of neuronal excitability; and most of these risk variants were noncoding with predicted regulatory functions. These results highlight specific hypotheses for future research and potential therapeutic targets.