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10个基因中的罕见编码变体赋予精神分裂症的巨大风险
2022-04-16 14:21

美国麻省总医院Mark J. Daly等研究人员合作发现,10个基因中的罕见编码变体赋予精神分裂症的巨大风险。2022年4月8日,《自然》杂志在线发表了这项成果。

通过对24,248个精神分裂症病例和97,322个对照组的全外显子进行荟萃分析,研究人员发现10个基因的超罕见编码变异(URV)可赋予精神分裂症的巨大风险(几率为3-50,P<2.14×10-6),32个基因的假发现率<5%。这些基因在中枢神经系统神经元中的表达量最大,具有多种分子功能,包括突触的形成、结构和功能。NMDA(N-甲基-D-天门冬氨酸)受体亚单位GRIN2A和AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)受体亚单位GRIA3的关联,为谷氨酸系统的功能障碍作为精神分裂症发病机制的一个机制假说提供了支持。研究人员观察到精神分裂症、自闭症谱系障碍、癫痫和严重神经发育障碍之间的罕见变异风险有重叠之处,尽管在一些共享基因中牵涉到不同的突变类型。然而,研究人员描述的大多数基因并不牵涉到神经发育。
 
结果证明,从精神分裂症的常见变异体分析中优先考虑的基因在罕见变异体风险中是富集的,从而表明常见和罕见的遗传风险因素至少部分地汇聚于相同的潜在致病生物过程。即使排除了明显相关的基因,精神分裂症病例仍然携带大量的URV,这表明更多的风险基因有待于用这种方法发现。
 
据悉,罕见的编码变异可提供基因功能和疾病发病机制之间最直接的联系。
 
附:英文原文
 
Title: Rare coding variants in ten genes confer substantial risk for schizophrenia

Author: Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D., Bass, Nicholas, Bigdeli, Tim B., Breen, Gerome, Bromet, Evelyn J., Buckley, Peter F., Bunney, William E., Bybjerg-Grauholm, Jonas, Byerley, William F., Chapman, Sinad B., Chen, Wei J., Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M., DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A., Eskelinen, Saana, Fanous, Ayman H., Faraone, Stephen V., Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B., Gage, Diane, Gagliano Taliun, Sarah A., Ganna, Andrea, Genovese, Giulio, Glahn, David C., Grove, Jakob, Hall, Mei-Hua, Hmlinen, Eija, Heyne, Henrike O., Holi, Matti, Hougaard, David M., Howrigan, Daniel P., Huang, Hailiang, Hwu, Hai-Gwo, Kahn, Ren S., Kang, Hyun Min, Karczewski, Konrad J., Kirov, George, Knowles, James A., Lee, Francis S., Lehrer, Douglas S., Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R., McCarroll, Steven A., McIntosh, Andrew M., Medeiros, Helena, Milani, Lili, Morley, Christopher P., Morris, Derek W., Mortensen, Preben Bo, Myers, Richard M., Nordentoft, Merete, OBrien, Niamh L., Olivares, Ana Maria

Issue&Volume: 2022-04-08

Abstract: Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P<2.14×106) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

DOI: 10.1038/s41586-022-04556-w

Source: https://www.nature.com/articles/s41586-022-04556-w

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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