英国卡迪夫大学Michael J. Owen和Michael C. O’Donovan合作发现，外显子组测序鉴定的从头突变表明精神分裂症中SLC6A1中存在罕见错义变体。相关论文在线发表在2020年1月13日的《自然—神经科学》上。

研究人员在613个精神分裂症三重症患者的新样本中分析了从头变异（DNV）的外显子组测序数据，并将其与已发表的数据相结合，得出总共3444个三重症患者。在这项新数据中，功能缺失（LoF）DNV在3,471个LoF不耐受基因中得到了富集，这支持了先前的发现。在完整数据集中，与神经发育障碍相关的基因（n = 159）显著丰富了LoF DNV。在这些神经发育障碍基因中，编码γ-氨基丁酸转运蛋白的SLC6A1与错义损伤的DNV相关。在可获得全基因组通用变异数据的1,122个三重症患者中，精神分裂症和双相情感障碍多基因风险明显 过度传播给先证者。在LoF不耐受或神经发育障碍基因中携带LoF或缺失DNV的先证者与非携带者相比，精神分裂症多基因风险的过度传播明显更少，这提供了第二条有力的证据，表明这些DNV增加了对精神分裂症的抵抗力。

据了解，精神分裂症是一种高度多基因疾病，其常见和罕见风险的等位基因对其均具有重要作用。

附：英文原文

Title: De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia

Author: Elliott Rees, Jun Han, Joanne Morgan, Noa Carrera, Valentina Escott-Price, Andrew J. Pocklington, Madeleine Duffield, Lynsey S. Hall, Sophie E. Legge, Antonio F. Pardias, Alexander L. Richards, Julian Roth, Tatyana Lezheiko, Nikolay Kondratyev, Vasilii Kaleda, Vera Golimbet, Mara Parellada, Javier Gonzlez-Peas, Celso Arango, Micha Gawlik, George Kirov, James T. R. Walters, Peter Holmans, Michael C. ODonovan, Michael J. Owen

Issue&Volume: 2020-01-13

Abstract: Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n=159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.

DOI: 10.1038/s41593-019-0565-2

Source: https://www.nature.com/articles/s41593-019-0565-2