Institute for Genomic Medicine, Columbia University Medical Center, New York, USA.
The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Aug 30;94:109659. doi: 10.1016/j.pnpbp.2019.109659. Epub 2019 May 30.
Tardive dyskinesia (TD) is an adverse movement disorder induced by chronic treatment with antipsychotics drugs. The contribution of common genetic variants to TD susceptibility has been investigated in recent years, but with limited success. The aim of the current study was to investigate the potential contribution of rare variants to TD vulnerability. In order to identify TD risk genes, we performed whole-exome sequencing (WES) and gene-based collapsing analysis focusing on rare (allele frequency < 1%) and putatively deleterious variants (qualifying variants). 82 Jewish schizophrenia patients chronically treated with antipsychotics were included and classified as having severe TD or lack of any abnormal movements based on a rigorous definition of the TD phenotype. First, we performed a case-control, exome-wide collapsing analysis comparing 39 schizophrenia patients with severe TD to 3118 unrelated population controls. Then, we checked the potential top candidate genes among 43 patients without any TD manifestations. All the genes that were found to harbor one or more qualifying variants in patients without any TD features were excluded from the final list of candidate genes. Only one gene, regulating synaptic membrane exocytosis 2 (RIMS2), showed significant enrichment of qualifying variants in TD patients compared with unrelated population controls after correcting for multiple testing (Fisher's exact test p = 5.32E-08, logistic regression p = 2.50E-08). Enrichment was caused by a single variant (rs567070433) due to a frameshift in an alternative transcript of RIMS2. None of the TD negative patients had qualifying variants in this gene. In a validation cohort of 140 schizophrenia patients assessed for TD, the variant was also not detected in any individual. Some potentially suggestive TD genes were detected in the TD cohort and warrant follow-up in future studies. No significant enrichment in previously reported TD candidate genes was identified. To the best of our knowledge, this is the first WES study of TD, demonstrating the potential role of rare loss-of-function variant enrichment in this pharmacogenetic phenotype.
迟发性运动障碍（TD）是一种由抗精神病药物慢性治疗引起的不良运动障碍。近年来，人们研究了常见遗传变异对 TD 易感性的贡献，但取得的成果有限。本研究旨在研究罕见变异对 TD 易感性的潜在贡献。为了确定 TD 风险基因，我们进行了全外显子组测序（WES）和基于基因的合并分析，重点关注罕见（等位基因频率 < 1%）和潜在有害变异（合格变异）。我们纳入了 82 名接受抗精神病药物慢性治疗的犹太精神分裂症患者，并根据 TD 表型的严格定义，将其分为患有严重 TD 或无任何异常运动的患者。首先，我们进行了病例对照、外显子组范围的合并分析，将 39 名患有严重 TD 的精神分裂症患者与 3118 名无关的人群对照进行了比较。然后，我们检查了 43 名无 TD 表现的患者中潜在的候选基因。在无任何 TD 特征的患者中发现一个或多个合格变异的所有基因都被排除在候选基因的最终列表之外。只有一个基因，即调节突触膜胞吐作用 2（RIMS2），在经过多重检验校正后，与无关人群对照相比，TD 患者中合格变异的富集有显著意义（Fisher 精确检验 p=5.32E-08，逻辑回归 p=2.50E-08）。富集是由 RIMS2 的一个替代转录本中的单个变异（rs567070433）引起的，该变异导致移码。在这个基因中，没有一个 TD 阴性患者有合格的变异。在对 140 名精神分裂症患者进行 TD 评估的验证队列中，也没有在任何个体中检测到该变异。在 TD 队列中检测到了一些潜在的提示性 TD 基因，这需要在未来的研究中进一步研究。未发现先前报道的 TD 候选基因有显著富集。据我们所知，这是首例针对 TD 的 WES 研究，证明了罕见失功能变异富集在这种药物遗传学表型中的潜在作用。
