小柯机器人

美国马萨诸塞州综合医院Benjamin M. Neale、Duncan S. Palmer等研究人员合作通过躁郁症的外显子测序发现，AKAP11是与精神分裂症共享的风险基因。相关论文于2022年4月11日在线发表在《自然—遗传学》杂志上。

研究人员报告了躁郁症外显子组（BipEx）合作分析的结果，该研究分析了13,933名躁郁症（BD）患者的全外显子组测序，与14,422名对照组匹配。研究人员发现，在两个主要的BD亚型中，BD患者的超罕见蛋白质截断变异体（PTV）在强演化约束的基因中过多。研究人员发现在最近的精神分裂症外显子组荟萃分析（SCHEMA；24,248例和97,322例对照）所涉及的基因中，以及在CHD8的结合靶点中富集了超罕见的PTV。

然而，BD的全基因组关联研究（GWAS）所涉及的基因并没有明显地富集于超罕见的PTV。将基因水平的结果与SCHEMA相结合，AKAP11成为一个明确的风险基因（比值比=7.06，P=2.83×10^-9）。在蛋白质水平上，AKAP-11与GSK3B相互作用，GSK3B是锂离子的假设目标，也是BD的一种主要治疗方法。

这些结果支持了BD的多基因性，证明了罕见的编码变异在BD病因学中重要风险因素的作用。

附：英文原文

Title: Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author: Palmer, Duncan S., Howrigan, Daniel P., Chapman, Sinad B., Adolfsson, Rolf, Bass, Nick, Blackwood, Douglas, Boks, Marco P. M., Chen, Chia-Yen, Churchhouse, Claire, Corvin, Aiden P., Craddock, Nicholas, Curtis, David, Di Florio, Arianna, Dickerson, Faith, Freimer, Nelson B., Goes, Fernando S., Jia, Xiaoming, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S., Landn, Mikael, Locke, Adam E., McIntosh, Andrew M., McQuillin, Andrew, Morris, Derek W., ODonovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pedersen, Nancy L., Posthuma, Danielle, Reif, Andreas, Risch, Neil, Schaefer, Catherine, Scott, Laura, Singh, Tarjinder, Smoller, Jordan W., Solomonson, Matthew, Clair, David St., Stahl, Eli A., Vreeker, Annabel, Walters, James T. R., Wang, Weiqing, Watts, Nicholas A., Yolken, Robert, Zandi, Peter P., Neale, Benjamin M.

Issue&Volume: 2022-04-11

Abstract: We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR)=7.06, P=2.83×109). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

DOI: 10.1038/s41588-022-01034-x

Source: https://www.nature.com/articles/s41588-022-01034-x

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