AbstractMultiple system atrophy (MSA) is a neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar ataxia. To elucidate variants associated with MSA, we have been conducting short-read-based whole-genome sequence analysis. In the process of the association studies, we initially focused on GBA1, a previously proposed susceptibility gene for MSA, to evaluate whether GBA1 variants can be efficiently identified despite its extraordinarily high homology with its pseudogene, GBA1LP.

摘要多系统萎缩（MSA）是一种神经退行性疾病，其特征是自主神经衰竭，帕金森病和小脑共济失调的各种组合。为了阐明与MSA相关的变体，我们一直在进行基于短读的全基因组序列分析。在关联研究的过程中，我们最初将重点放在GBA1（一种先前提出的MSA易感基因）上，以评估尽管GBA1与其假基因GBA1LP具有极高的同源性，但是否可以有效鉴定GBA1变体。

To accomplish this, we conducted a short-read whole-genome sequence analysis with alignment to GRCh38 as well as Sanger sequence analysis and compared the results. We identified five variants with inconsistencies between the two pipelines, of which three variants (p.L483P, p.A495P–p.V499V, p.L483_M489delinsW) were the results of misalignment due to minor alleles in GBA1P1 registered in GRCh38.

为此，我们进行了短读全基因组序列分析，并与GRCh38进行了比对，以及Sanger序列分析，并比较了结果。我们确定了两个管道之间不一致的五个变体，其中三个变体（p.L483P，p.A495P–p.V499V，p.L483\U M489delinsW）是由于在GRCh38中注册的GBA1P1中的次要等位基因导致的错位结果。

The miscalling events in these variants were resolved by alignment to GRCh37 as the reference genome, where the major alleles are registered. In addition, a structural variant was not properly identified either by short-read or by Sanger sequence analyses. Having accomplished correct variant calling, we identified three variants pathogenic for Gaucher disease (p.S310G, p.L483P, and p.L483_M489delinsW).

通过将GRCh37作为参考基因组进行比对，可以解决这些变体中的错误事件，其中主要等位基因被注册。此外，通过短读或Sanger序列分析均未正确识别结构变体。完成正确的变体调用后，我们确定了三种对高雪氏病致病的变体（p.S310G，p.L483P和p.L483\U M489delinsW）。

Of these variants, the allele frequency of p.L483P (0.003) in the MSA cases was higher than that (0.0011) in controls. The meta-analysis incorporating a previous report demonstrated a significant association of p.L483P with MSA with an odds ratio of 2.92 (95% CI; 1.08 – 7.90, p = 0.0353)..

在这些变体中，MSA病例中p.L483P的等位基因频率（0.003）高于对照组（0.0011）。纳入先前报告的荟萃分析表明，p.L483P与MSA显着相关，优势比为2.92（95%CI；1.08-7.90，p=0.0353）。。

IntroductionGBA1 (HGNC:4177) is the gene encoding a lysosomal enzyme, glucocerebrosidase, located on chromosome 1q21. GBA1 consists of 11 exons spanning 7.6 kb, and a highly homologous pseudogene (GBA1LP, HGNC:4178) is located approximately 16 kb apart from the functional GBA1 gene [1,2,3]. Unequal pairing with rearrangement between GBA1 and GBA1LP is a frequent cause leading to the generation of gene–pseudogene rearrangements, many of which are causative variants for Gaucher disease.

简介GBA1（HGNC:4177）是编码溶酶体酶葡萄糖脑苷脂酶的基因，位于染色体1q21上。GBA1由11个外显子组成，跨度为7.6kb，一个高度同源的假基因（GBA1LP，HGNC:4178）位于距功能性GBA1基因约16kb的位置[1,2,3]。GBA1和GBA1LP之间重排的不平等配对是导致基因-假基因重排产生的常见原因，其中许多是高雪氏病的致病变异。

Of these rearrangements, nonreciprocal recombination (gene conversion) events are the most frequent, in which a portion of the functional gene sequence is replaced by the corresponding part of the pseudogene [1, 2, 4].Biallelic pathogenic variants of GBA1 cause deficient glucocerebrosidase activities leading to the development of Gaucher disease [4].

在这些重排中，非互易重组（基因转换）事件是最常见的，其中功能基因序列的一部分被假基因的相应部分取代[1，2，4]。。

Starting from the observation that family members of patients with Gaucher disease have a considerably high prevalence of Parkinson disease (PD) [5], numerous studies have consistently shown that deleterious variants of GBA1 are strong risk factors for the development of PD [6,7,8,9]. Furthermore, we have reported that GBA1 variants pathogenic for Gaucher disease are also significantly, albeit with a small odds ratio, associated with an increased risk of developing multiple system atrophy (MSA), which is also a neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar ataxia along with the accumulation of α-synuclein within oligodendroglia [10].

从观察到高雪氏病患者的家庭成员帕金森病（PD）的患病率相当高开始，许多研究一致表明，GBA1的有害变异是PD发展的强烈危险因素[6,7,8,9]。。

Other studies, however, have not demonstrated the associations of GBA1 variants with MSA, possibly owing to their small sample sizes [11,12,13].Given the remarkable progress of short-read sequencing technologies employing next-generation sequenc.

然而，其他研究尚未证明GBA1变体与MSA的关联，可能是由于其样本量较小[11，12，13]。鉴于采用下一代sequenc的短读测序技术取得了显着进展。

Case 4: c.115+1G>A was called by short-read sequence analysis, while p.H313del was called by Sanger sequence analysisWhen the read depth data of the short-read sequence analysis were analyzed, we noticed that the read depths in the part of the GBA1 region were increased to about 1.5, whereas those in the GBA1LP region were decreased to about 0.5, raising the possibility that the copy numbers of GBA1 and GBA1LP regions are three and one, respectively (Fig. 3A).

案例4：短读序列分析调用c.115+1 g A，而桑格序列分析调用p.H313del当分析短读序列分析的读取深度数据时，我们注意到GBA1区域部分的读取深度增加到约1.5，而GBA1LP区域的读取深度减少到约0.5，这增加了GBA1和GBA1LP区域的拷贝数分别为3和1的可能性（图3A）。

Of note, long-read sequence analysis revealed that the long-reads 1 and 2 indeed contained a chimeric structure containing the GBA1LP–MTX1 and the GBA1 regions. The long-reads 3 and 4 contained a chimeric structure containing the GBA1LP–MTX1 and the GBA1–MTX1LP regions (Fig. 3B). Based on these results, we concluded that a gene conversion event occurred in the GBA1LP–MTX1 region due to the extraordinarily high homology between the GBA1–MTX1LP and GBA1LP–MTX1 regions.

值得注意的是，长读序列分析表明，长读序列1和2确实包含包含GBA1LP–MTX1和GBA1区域的嵌合结构。长读数3和4包含一个包含GBA1LP–MTX1和GBA1–MTX1LP区域的嵌合结构（图3B）。。

The region spanning the intron 2 of GBA1LP and the intron 5 of MTX1 (NC_00001.11:g.155213012_155218391 indicated by a box in Fig. 3B) was replaced by the region spanning the intron 2 of GBA1 and the intron 5 of MTX1LP (NC_00001.11:g.155233640_155240628). Of note, there is a deletion of CAC in this region (NC_00001.11:g.155237401_155237403del).

跨越GBA1LP内含子2和MTX1内含子5的区域（NC\U 00001.11:g.155213012\U 155218391由图3B中的框表示）被跨越GBA1内含子2和MTX1LP内含子5的区域所取代（NC\U 00001.11:g.155233640\U 155240628）。值得注意的是，该区域删除了CAC（NC\U 00001.11:g.155237401\U 155237403del）。

Taken together with these observations, the complex structural variant is described as　NC_00001.11:g.155213012_155218391delins[NC_00001.11:g.155233640_155237400; NC_00001.11:g.155237404_155240628] according to the guidelines of the Human Genome Variation Society (https://www.hgvs.org/content/guidelines).

结合这些观察结果，根据人类基因组变异学会的指南，复杂的结构变异被描述为NC\U 00001.11:g.155213012\u 155218391delins[NC\U 00001.11:g.155233640\u 155237400；NC\U 00001.11:g.155237404\u 155240628](https://www.hgvs.org/content/guidelines)。

Consistent with the above interpretation, one of the paired-end reads spanning the breakpoint between GBA1 (upstream) and GBA1LP (downstream) contained GBA1-specific sequences derived from GBA1. On the other han.

与上述解释一致，跨越GBA1（上游）和GBA1LP（下游）之间断点的配对末端读数之一包含源自GBA1的GBA1特异性序列。另一个汉人。

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Download referencesAcknowledgementsWe thank Mio Takeyama, Keiko Hirayama, and Zhenghong Wu for their support in laboratory experiments. This work was supported in part by KAKENHI (19H03425 and 22H02823) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants (16kk0205001h0001, 17kk0205001h0002, 18kk0205001h0003, 20ek0109491h0001, 21ek0109491h0002, 22ek0109491h0003, and 23ek0109673h0001) from the Japan Agency for Medical Research and Development (AMED) to ST.

下载参考文献致谢我们感谢Mio Takeyama，Keiko Hirayama和Zhenghong Wu在实验室实验中的支持。这项工作得到了日本教育、文化、体育、科学和技术部的KAKENHI（19H03425和22H02823）的部分支持，以及日本医学研究与发展机构（AMED）向ST.的赠款（16KK020501H0001、17KK020501H0002、18KKK020501H0003、20ek0109491h0001、21ek0109491h0002、22ek0109491h0003和23ek0109673h0001）。

This work was supported in part by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan to ST and grants (21ek0109573h0001, 22ek0109573h0002, and 23ek0109573h0003) from the AMED to JM.FundingOpen Access funding provided by The University of Tokyo.Author informationAuthors and AffiliationsDepartment of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, JapanKenta Orimo, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda & Shoji TsujiDepartment of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, JapanJun MitsuiInstitute of Medical Genomics, International University of Health and Welfare, 4-3, Kozunomori, Narita-shi, Chiba, 286-8686, JapanMasaki Tanaka, Junko Nomoto & Shoji TsujiDepartment of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, JapanHiroyuki IshiuraGenome Medical Science Project, National Center for Global Health and Medicine, 1-21-1,.

这项工作部分得到了中枢神经系统退行性疾病研究委员会、罕见和难治性疾病政策规划和评估研究、健康、劳动和福利科学研究资助、日本厚生劳动省对ST的资助，以及AMED向JM提供的赠款（21ek0109573h0001、22ek0109573h0002和23ek0109573h0003）。东京大学提供了开放获取资金。作者信息作者和附属机构东京大学医学研究生院神经病学系，东京文kyo ku Hongo 7-3-1，113-8655，日本Orimo，Takashi Matsukawa，Hiroyuki Ishura，Tatsushi Toda＆Shoji Tsuji东京大学医学研究生院精准医学神经病学系，东京文kyo ku Hongo 7-3-1，113-8655，日本三井医学基因组学研究所，国际卫生福利大学，4-3，日本千叶成田市小野村，286-8686冈山大学医学、牙科和药物科学研究生院神经病学系，2-5-1，Shikata cho，Kita ku，冈山，700-8558，JapanHiroyuki IshiuraGenome医学项目，国家全球健康与医学中心，1-21-1，。

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PubMed Google ScholarConsortiaNCBN Controls WGS ConsortiumHatsue Ishibashi-Ueda, Tsutomu Tomita, Michio Noguchi, Ayako Takahashi, Yu-ichi Goto, Sumiko Yoshida, Kotaro Hattori, Ryo Matsumura, Aritoshi Iida, Yutaka Maruoka, Hiroyuki Gatanaga, Akihiko Shimomura, Masaya Sugiyama, Satoshi Suzuki, Kengo Miyo, Yoichi Matsubara, Akihiro Umezawa, Kenichiro Hata, Tadashi Kaname, Kouichi Ozaki, Haruhiko Tokuda, Hiroshi Watanabe, Shumpei Niida, Eisei Noiri, Koji Kitajima, Yosuke Omae, Reiko Miyahara, Hideyuki Shimanuki, Yosuke Kawai & Katsushi TokunagaContributionsKO and ST designed and conceptualized the study, analyzed the data; wrote the draft of the manuscript.

PubMed Google ScholarConsortiaNCBN控制着WGS财团Hatsue Ishibashi Ueda、Tsutomu Tomita、Michio Noguchi、Ayako Takahashi、Yu-ichi Goto、Sumiko Yoshida、Kotaro Hattori、Ryo Matsumura、Aritoshi Iida、Yutaka Maruoka、Hiroyuki Gatanaga、Akihiko Shimomura、Masaya Sugiyama、Satoshi Suzuki、Kengo Miyo、Yoichi Matsubara、Akihiro Umezawa、Kenichiro Hata、Tadashi Kaname、Kouichi Ozaki、Haruhi Iko Tokuda，Hiroshi Watanabe，Shumpei Niida，Eisei Noiri，Koji Kitajima，Yosuke Omae，Reiko Miyahara，Hideyuki Shimanuki，Yosuke Kawai＆Katsushi TokunagaContributionsKO和ST设计并概念化了这项研究，分析了数据；写了手稿的草稿。

JM designed and conceptualized the study; wrote the draft of the manuscript. MT, JN, YO, YK, and KT contributed to the whole-genome sequence analysis. TM, HI and TT wrote the draft of the manuscript. NCBN Controls WGS Consortium contributed to the collection of the control samples.Corresponding authorCorrespondence to.

JM设计并概念化了这项研究；写了手稿的草稿。MT，JN，YO，YK和KT有助于全基因组序列分析。TM，HI和TT撰写了手稿的草稿。NCBN Controls WGS Consortium为对照样品的收集做出了贡献。对应作者对应。

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Competing interests

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The authors declare no competing interests.

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This study was approved by the Institutional Review Board of the University of Tokyo.

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Reprints and permissionsAbout this articleCite this articleOrimo, K., Mitsui, J., Matsukawa, T. et al. Association study of GBA1 variants with MSA based on comprehensive sequence analysis -Pitfalls in short-read sequence analysis depending on the human reference genome-.

转载和许可本文引用本文Orimo，K.，Mitsui，J.，Matsukawa，T。等人。基于综合序列分析的GBA1变体与MSA的关联研究-取决于人类参考基因组的短读序列分析中的缺陷。

J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01266-1Download citationReceived: 29 April 2024Revised: 22 May 2024Accepted: 07 June 2024Published: 18 July 2024DOI: https://doi.org/10.1038/s10038-024-01266-1Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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疾病遗传学下一代测序