Journal of Human Genetics最新文献_第3页

Efficient HLA imputation from sequential SNPs data by transformer 通过转换器从序列 SNPs 数据中高效推算 HLA。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-08-02 DOI: 10.1038/s10038-024-01278-x

Kaho Tanaka, Kosuke Kato, Naoki Nonaka, Jun Seita

{"title":"Efficient HLA imputation from sequential SNPs data by transformer","authors":"Kaho Tanaka, Kosuke Kato, Naoki Nonaka, Jun Seita","doi":"10.1038/s10038-024-01278-x","DOIUrl":"10.1038/s10038-024-01278-x","url":null,"abstract":"Human leukocyte antigen (HLA) genes are associated with a variety of diseases, yet the direct typing of HLA alleles is both time-consuming and costly. Consequently, various imputation methods leveraging sequential single nucleotide polymorphisms (SNPs) data have been proposed, employing either statistical or deep learning models, such as the convolutional neural network (CNN)-based model, DEEP*HLA. However, these methods exhibit limited imputation efficiency for infrequent alleles and necessitate a large size of reference dataset. In this context, we have developed a Transformer-based model to HLA allele imputation, named “HLA Reliable IMpuatioN by Transformer (HLARIMNT)” designed to exploit the sequential nature of SNPs data. We evaluated HLARIMNT’s performance using two distinct reference panels; Pan-Asian reference panel (n = 530) and Type 1 Diabetes genetics Consortium (T1DGC) reference panel (n = 5225), alongside a combined panel (n = 1060). HLARIMNT demonstrated superior accuracy to DEEP*HLA across several indices, particularly for infrequent alleles. Furthermore, we explored the impact of varying training data sizes on imputation accuracy, finding that HLARIMNT consistently outperformed across all data size. These findings suggest that Transformer-based models can efficiently impute not only HLA types but potentially other gene types from sequential SNPs data.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01278-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome analysis through image processing with deep learning models 利用深度学习模型通过图像处理进行基因组分析。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-31 DOI: 10.1038/s10038-024-01275-0

Yao-zhong Zhang, Seiya Imoto

引用次数: 0

An application supporting diagnosis for rare genetic diseases – UR-DBMS and Syndrome Finder – 支持罕见遗传病诊断的应用程序--UR-DBMS 和 Syndrome Finder。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-31 DOI: 10.1038/s10038-024-01277-y

Kenji Naritomi

引用次数: 0

A homozygous nonsense variant in the alternatively spliced VLDLR exon 4 causes a neurodevelopmental disorder without features of VLDLR cerebellar hypoplasia. 交替剪接的 VLDLR 第 4 外显子中的一个同卵无义变体会导致一种神经发育障碍，但没有 VLDLR 小脑发育不全的特征。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-31 DOI: 10.1038/s10038-024-01279-w

Tess Holling, Ibrahim M Abdelrazek, Ghada M Elhady, Marwa Abd Elmaksoud, Seung Woo Ryu, Ebtesam Abdalla, Kerstin Kutsche

{"title":"A homozygous nonsense variant in the alternatively spliced VLDLR exon 4 causes a neurodevelopmental disorder without features of VLDLR cerebellar hypoplasia.","authors":"Tess Holling, Ibrahim M Abdelrazek, Ghada M Elhady, Marwa Abd Elmaksoud, Seung Woo Ryu, Ebtesam Abdalla, Kerstin Kutsche","doi":"10.1038/s10038-024-01279-w","DOIUrl":"https://doi.org/10.1038/s10038-024-01279-w","url":null,"abstract":"VLDLR cerebellar hypoplasia is characterized by intellectual disability, non-progressive cerebellar ataxia, and seizures. The characteristic MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified cortical gyration, and a small brain stem. Biallelic VLDLR pathogenic variants cause loss-of-function of the encoded very low-density lipoprotein receptor. VLDLR exons 4 and 16 are alternatively spliced, resulting in the expression of four transcript variants, including two exon 4-lacking mRNAs expressed in the human brain. Previously reported VLDLR pathogenic variants affect all four transcript variants. Here we report on two sisters with facial dysmorphism, microcephaly, intellectual disability, and normal brain imaging. Exome sequencing in one patient identified the homozygous VLDLR nonsense variant c.376C>T; p.(Gln126*) in exon 4; her similarly affected sister also carried the homozygous variant and parents were heterozygous carriers. VLDLR transcript analysis identified mRNAs with and without exon 4 in patient fibroblasts, while exon 4-containing VLDLR mRNAs were predominantly detected in control fibroblasts. We found significantly reduced VLDLR mRNA levels in patient compared to control cells, likely caused by nonsense-mediated mRNA decay of exon 4-containing VLDLR transcripts. Expression of neuronal VLDLR isoforms produced from exon 4-lacking transcripts may have protected both patients from developing the cerebellar hypoplasia phenotype.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-19 DOI: 10.1038/s10038-024-01276-z

Lihua Jiang, Yilong Wang, Weiqin Zhang, Xin Zhang, Feng Gao, Zhefeng Yuan

引用次数: 0

Association study of GBA1 variants with MSA based on comprehensive sequence analysis -Pitfalls in short-read sequence analysis depending on the human reference genome. 基于综合序列分析的 GBA1 变异与 MSA 的关联研究--取决于人类参考基因组的短读序列分析的陷阱。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-18 DOI: 10.1038/s10038-024-01266-1

Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Masaki Tanaka, Junko Nomoto, Hiroyuki Ishiura, Yosuke Omae, Yosuke Kawai, Katsushi Tokunaga, Tatsushi Toda, Shoji Tsuji

{"title":"Association study of GBA1 variants with MSA based on comprehensive sequence analysis -Pitfalls in short-read sequence analysis depending on the human reference genome.","authors":"Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Masaki Tanaka, Junko Nomoto, Hiroyuki Ishiura, Yosuke Omae, Yosuke Kawai, Katsushi Tokunaga, Tatsushi Toda, Shoji Tsuji","doi":"10.1038/s10038-024-01266-1","DOIUrl":"10.1038/s10038-024-01266-1","url":null,"abstract":"Multiple 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. 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. 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). 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 2.85 (95% CI; 1.05 - 7.76, p = 0.0400).","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts 利用 LAMPLINK 和日本队列鉴定类风湿关节炎的表观 SNP 组合。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-16 DOI: 10.1038/s10038-024-01269-y

Mio Shibata, Aika Terada, Takahisa Kawaguchi, Yoichiro Kamatani, Daigo Okada, Kazuhisa Nagashima, Koichiro Ohmura, Fumihiko Matsuda, Shuji Kawaguchi, Jun Sese, Ryo Yamada

{"title":"Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts","authors":"Mio Shibata, Aika Terada, Takahisa Kawaguchi, Yoichiro Kamatani, Daigo Okada, Kazuhisa Nagashima, Koichiro Ohmura, Fumihiko Matsuda, Shuji Kawaguchi, Jun Sese, Ryo Yamada","doi":"10.1038/s10038-024-01269-y","DOIUrl":"10.1038/s10038-024-01269-y","url":null,"abstract":"Genome-wide association studies have enabled the identification of important genetic factors in many trait studies. However, only a fraction of the heritability can be explained by known genetic factors, even in the most common diseases. Genetic loci combinations, or epistatic contributions expressed by combinations of single nucleotide polymorphisms (SNPs), have been argued to be one of the critical factors explaining some of the missing heritability, especially in oligogenic/polygenic diseases. Rheumatoid arthritis (RA) is a complex disease with more than 100 reported SNP associations, as well as various HLA haplotypes and amino acids; however, many associations between RA and inter-chromosomal SNP combinations are unknown. To discover novel associations of epistatic interactions with high odds ratios in RA, we applied the LAMPLINK method, a systematic enumerative procedure for identifying high-order SNP combinations, to a Japanese RA cohort (discovery cohort; 4024 patients with RA and 7731 controls). We validated the identified associations in a different Japanese cohort (validation cohort; 810 RA patients and 6303 controls). In this study, we identified 90 significant genetic associations in the discovery cohort. Among these, 74 (82.2%) associations were replicated in the validation cohort, and eight combinations were inter-chromosomal, all of which comprised rs7765379 or rs35265698 located in the HLA region. These two SNPs exhibited strong correlations with valine at amino acid position 11 in HLA-DRB1 (HLA-DRB1-11-Val). Finally, we discovered that rs9624 showed an association with RA through an epistatic interaction with HLA-DRB1-11-Val. Overall, LAMPLINK showed high reliability for identifying epistatic genetic contributions hidden in complex traits.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heterozygous mutations in the straitjacket region of the latency-associated peptide domain of TGFB2 cause Camurati-Engelmann disease type II. TGFB2 的潜伏相关肽域的紧身衣区的杂合突变导致卡姆拉蒂-恩格尔曼病 II 型。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-16 DOI: 10.1038/s10038-024-01274-1

Zheng Wang, Mitsuhiro Kometani, Leonid Zeitlin, Yael Wilnai, Akira Kinoshita, Koh-Ichiro Yoshiura, Hiroko Ninomiya, Takeshi Imamura, Long Guo, Jingyi Xue, Li Yan, Hirofumi Ohashi, Yann Pretemer, Shunsuke Kawai, Masaaki Shiina, Kazuhiro Ogata, Daniel H Cohn, Naomichi Matsumoto, Gen Nishimura, Junya Toguchida, Noriko Miyake, Shiro Ikegawa

{"title":"Heterozygous mutations in the straitjacket region of the latency-associated peptide domain of TGFB2 cause Camurati-Engelmann disease type II.","authors":"Zheng Wang, Mitsuhiro Kometani, Leonid Zeitlin, Yael Wilnai, Akira Kinoshita, Koh-Ichiro Yoshiura, Hiroko Ninomiya, Takeshi Imamura, Long Guo, Jingyi Xue, Li Yan, Hirofumi Ohashi, Yann Pretemer, Shunsuke Kawai, Masaaki Shiina, Kazuhiro Ogata, Daniel H Cohn, Naomichi Matsumoto, Gen Nishimura, Junya Toguchida, Noriko Miyake, Shiro Ikegawa","doi":"10.1038/s10038-024-01274-1","DOIUrl":"https://doi.org/10.1038/s10038-024-01274-1","url":null,"abstract":"Camurati-Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-β2. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-β2 inactivation. An activity assay confirmed a significant increase in TGF-β2/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-β2 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of a missense variant in COG5 in a Tunisian patient with COG5-CDG syndrome and insights into the effect of non-synonymous variants on COG5 protein. 突尼斯 COG5-CDG 综合征患者 COG5 中一个错义变体的特征以及非同义变体对 COG5 蛋白质影响的见解。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-11 DOI: 10.1038/s10038-024-01273-2

Boudour Khabou, Umar Bin Mohamad Sahari, Abir Ben Issa, Wafa Bouchaala, Emmanuelle Szenker-Ravi, Alvin Yu Jin Ng, Carine Bonnard, Hamdi Mbarek, Islam Zeyaul, Faiza Fakhfakh, Fatma Kammoun, Bruno Reversade, Chahnez Charfi Triki

{"title":"Characterization of a missense variant in COG5 in a Tunisian patient with COG5-CDG syndrome and insights into the effect of non-synonymous variants on COG5 protein.","authors":"Boudour Khabou, Umar Bin Mohamad Sahari, Abir Ben Issa, Wafa Bouchaala, Emmanuelle Szenker-Ravi, Alvin Yu Jin Ng, Carine Bonnard, Hamdi Mbarek, Islam Zeyaul, Faiza Fakhfakh, Fatma Kammoun, Bruno Reversade, Chahnez Charfi Triki","doi":"10.1038/s10038-024-01273-2","DOIUrl":"https://doi.org/10.1038/s10038-024-01273-2","url":null,"abstract":"The clinical diagnosis of patients with multisystem involvement including a pronounced neurologic damage is challenging. High-throughput sequencing methods remains crucial to provide an accurate diagnosis. In this study, we reported a Tunisian patient manifesting hypotonia and global developmental delay with visual and skin abnormalities. Exome sequencing was conducted followed by segregation analysis and, subsequently additional investigations. In silico analysis of non-synonymous variants (nsSNPs) described in COG5 in conserved positions was made. Results revealed a homozygous missense variant c.298 C > T (p.Leu100Phe) in the COG5 inherited from both parents. This variant altered both protein solubility and stability, in addition to a putative disruption of the COG5-COG7 interaction. This disruption has been confirmed using patient-derived cells in vitro in a COG5 co-immuno-precipitation, where interaction with binding partner COG7 was abrogated. Hence, we established the COG5-CDG diagnosis. Clinically, the patient shared common features with the already described cases with the report of the ichtyosis as a new manifestation. Conversely, the CADD scoring revealed 19 putatively pathogenic nsSNPs (Minor Allele Frequency MAF < 0.001, CADD > 30), 11 of which had a significant impact on the solubility and/or stability of COG5. These properties seem to be disrupted by six of the seven missense COG5-CDG variants. In conclusion, our study expands the genetic and phenotypic spectrum of COG5-CDG disease and highlight the utility of the next generation sequencing as a powerful tool in accurate diagnosis. Our results shed light on a likely molecular mechanism underlying the pathogenic effect of missense COG5 variants, which is the alteration of COG5 stability and solubility.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genomic variants associated with age at diagnosis of childhood-onset type 1 diabetes. 与儿童发病型 1 型糖尿病确诊年龄相关的基因组变异。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-07-10 DOI: 10.1038/s10038-024-01272-3

Pierre Bougnères, Sophie Le Fur, Yoichiro Kamatani, Thanh-Nga Mai, Marie-Pierre Belot, Kevin Perge, XiaoJian Shao, Mark Lathrop, Alain-Jacques Valleron

{"title":"Genomic variants associated with age at diagnosis of childhood-onset type 1 diabetes.","authors":"Pierre Bougnères, Sophie Le Fur, Yoichiro Kamatani, Thanh-Nga Mai, Marie-Pierre Belot, Kevin Perge, XiaoJian Shao, Mark Lathrop, Alain-Jacques Valleron","doi":"10.1038/s10038-024-01272-3","DOIUrl":"10.1038/s10038-024-01272-3","url":null,"abstract":"Age at diagnosis (AAD) of Type 1 diabetes (T1D) is determined by the age at onset of the autoimmune attack and by the rate of beta cell destruction that follows. Twin studies found that T1D AAD is strongly influenced by genetics, notably in young children. In young UK, Finnish, Sardinian patients AAD-associated genomic variants were previously identified, which may vary across populations and with time. In 1956 children of European ancestry born in mainland France in 1980-2008 who declared T1D before 15 years, we tested 94 T1D-associated SNPs for their association with AAD using nonparametric Kruskal-Wallis test. While high-risk HLA genotypes were not found to be associated with AAD, fourteen SNPs located in 12 non-HLA loci showed a strong association (2.9 × 10-12 -3 after FDR correction). Four of these loci have been associated with AAD in previous cohorts (GSDMB, IL2, TNFAIP3, IL1), supporting a partially shared genetic influence on AAD of T1D in the studied European populations. In contrast, the association of 8 new loci CLEC16A, TYK2, ERBB3, CCR7, FCRL3, DNAH2, FGF3/4, and HPSE2 with AAD is novel. The 12 protein-coding genes located within these loci are involved in major immune pathways or in predisposition to other autoimmune diseases, which suggests a prominent role for these genes in the early immune mechanisms of beta cell destruction.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0