Human molecular genetics最新文献_第10页

Correction to: Psychosocial adversity and socioeconomic position during childhood and epigenetic age: analysis of two prospective cohort studies. 更正：童年时期的社会心理逆境和社会经济地位与表观遗传年龄：对两项前瞻性队列研究的分析。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae118

引用次数: 0

Joint models reveal genetic architecture of pubertal stage transitions and their association with BMI in admixed Chilean population. 联合模型揭示了智利混血人口青春期阶段转换的遗传结构及其与体重指数的关系。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae098

Lucas Vicuña, Esteban Barrientos, Valeria Leiva-Yamaguchi, Danilo Alvares, Veronica Mericq, Anita Pereira, Susana Eyheramendy

{"title":"Joint models reveal genetic architecture of pubertal stage transitions and their association with BMI in admixed Chilean population.","authors":"Lucas Vicuña, Esteban Barrientos, Valeria Leiva-Yamaguchi, Danilo Alvares, Veronica Mericq, Anita Pereira, Susana Eyheramendy","doi":"10.1093/hmg/ddae098","DOIUrl":"10.1093/hmg/ddae098","url":null,"abstract":"Early or late pubertal onset can lead to disease in adulthood, including cancer, obesity, type 2 diabetes, metabolic disorders, bone fractures, and psychopathologies. Thus, knowing the age at which puberty is attained is crucial as it can serve as a risk factor for future diseases. Pubertal development is divided into five stages of sexual maturation in boys and girls according to the standardized Tanner scale. We performed genome-wide association studies (GWAS) on the \"Growth and Obesity Chilean Cohort Study\" cohort composed of admixed children with mainly European and Native American ancestry. Using joint models that integrate time-to-event data with longitudinal trajectories of body mass index (BMI), we identified genetic variants associated with phenotypic transitions between pairs of Tanner stages. We identified $42$ novel significant associations, most of them in boys. The GWAS on Tanner $3rightarrow 4$ transition in boys captured an association peak around the growth-related genes LARS2 and LIMD1 genes, the former of which causes ovarian dysfunction when mutated. The associated variants are expression and splicing Quantitative Trait Loci regulating gene expression and alternative splicing in multiple tissues. Further, higher individual Native American genetic ancestry proportions predicted a significantly earlier puberty onset in boys but not in girls. Finally, the joint models identified a longitudinal BMI parameter significantly associated with several Tanner stages' transitions, confirming the association of BMI with pubertal timing.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1660-1670"},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Plasma proteometabolome in lung cancer: exploring biomarkers through bidirectional Mendelian randomization and colocalization analysis. 肺癌血浆蛋白代谢组：通过双向孟德尔随机化和共定位分析探索生物标记物。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae110

Bo Dong, Mengyao Wang, Kaixiu Li, Zuwei Li, Lunxu Liu, Shensi Shen

{"title":"Plasma proteometabolome in lung cancer: exploring biomarkers through bidirectional Mendelian randomization and colocalization analysis.","authors":"Bo Dong, Mengyao Wang, Kaixiu Li, Zuwei Li, Lunxu Liu, Shensi Shen","doi":"10.1093/hmg/ddae110","DOIUrl":"10.1093/hmg/ddae110","url":null,"abstract":"Unlike other cancers with widespread screening (breast, colorectal, cervical, prostate, and skin), lung nodule biopsies for positive screenings have higher morbidity with clinical complications. Development of non-invasive diagnostic biomarkers could thereby significantly enhance lung cancer management for at-risk patients. Here, we leverage Mendelian Randomization (MR) to investigate the plasma proteome and metabolome for potential biomarkers relevant to lung cancer. Utilizing bidirectional MR and co-localization analyses, we identify novel associations, highlighting inverse relationships between plasma proteins SFTPB and KDELC2 in lung adenocarcinoma (LUAD) and positive associations of TCL1A with lung squamous cell carcinoma (LUSC) and CNTN1 with small cell lung cancer (SCLC). Additionally, our work reveals significant negative correlations between metabolites such as theobromine and paraxanthine, along with paraxanthine-related ratios, in both LUAD and LUSC. Conversely, positive correlations are found in caffeine/paraxanthine and arachidonate (20:4n6)/paraxanthine ratios with these cancer types. Through single-cell sequencing data of normal lung tissue, we further explore the role of lung tissue-specific protein SFTPB in carcinogenesis. These findings offer new insights into lung cancer etiology, potentially guiding the development of diagnostic biomarkers and therapeutic approaches.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1688-1696"},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing. 通过三重全基因组测序探索系统性硬化症病因的复杂性。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae105

Hongzheng Dai, Shamika Ketkar, Taotao Tan, Elizabeth G Atkinson, Lindsay Burrage, Kim C Worley, Brian Christopher, Marka A Lyons, Shervin Assassi, Maureen D Mayes, Brendan Lee

{"title":"Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing.","authors":"Hongzheng Dai, Shamika Ketkar, Taotao Tan, Elizabeth G Atkinson, Lindsay Burrage, Kim C Worley, Brian Christopher, Marka A Lyons, Shervin Assassi, Maureen D Mayes, Brendan Lee","doi":"10.1093/hmg/ddae105","DOIUrl":"10.1093/hmg/ddae105","url":null,"abstract":"Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing (WGS) in 101 indexed family trios, supplemented with transcriptome sequencing on cultured fibroblast cells of four patients and five family controls where available. Single nucleotide variants (SNVs) and copy number variants (CNVs) were examined, with emphasis on de novo variants. We also performed enrichment test for rare variants in candidate genes previously proposed in association with systemic sclerosis. We identified 42 exonic and 34 ncRNA de novo SNV changes in 101 trios, from a total of over 6000 de novo variants genome wide. We observed higher than expected de novo variants in PRKXP1 gene. We also observed such phenomenon along with increased expression in patient group in NEK7 gene. Additionally, we also observed significant enrichment of rare variants in candidate genes in the patient cohort, further supporting the complexity/multi-factorial etiology of systemic sclerosis. Our findings identify new candidate genes including PRKXP1 and NEK7 for future studies in SSc. We observed rare variant enrichment in candidate genes previously proposed in association with SSc, which suggest more efforts should be pursued to further investigate possible pathogenetic mechanisms associated with those candidate genes.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1643-1647"},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Neurodevelopmental disorder-associated CYFIP2 regulates membraneless organelles and eIF2α phosphorylation via protein interactors and actin cytoskeleton. 神经发育障碍相关的CYFIP2通过蛋白相互作用体和肌动蛋白细胞骨架调节无膜细胞器和eIF2α磷酸化。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae107

Yinhua Zhang, Hyae Rim Kang, Yukyung Jun, Hyojin Kang, Geul Bang, Ruiying Ma, Sungjin Ju, Da Eun Yoon, Yoonhee Kim, Kyoungmi Kim, Jin Young Kim, Kihoon Han

{"title":"Neurodevelopmental disorder-associated CYFIP2 regulates membraneless organelles and eIF2α phosphorylation via protein interactors and actin cytoskeleton.","authors":"Yinhua Zhang, Hyae Rim Kang, Yukyung Jun, Hyojin Kang, Geul Bang, Ruiying Ma, Sungjin Ju, Da Eun Yoon, Yoonhee Kim, Kyoungmi Kim, Jin Young Kim, Kihoon Han","doi":"10.1093/hmg/ddae107","DOIUrl":"10.1093/hmg/ddae107","url":null,"abstract":"De novo variants in the Cytoplasmic FMR1-interacting protein 2 (CYFIP2) have been repeatedly associated with neurodevelopmental disorders and epilepsy, underscoring its critical role in brain development and function. While CYFIP2's role in regulating actin polymerization as part of the WAVE regulatory complex (WRC) is well-established, its additional molecular functions remain relatively unexplored. In this study, we performed unbiased quantitative proteomic analysis, revealing 278 differentially expressed proteins (DEPs) in the forebrain of Cyfip2 knock-out embryonic mice compared to wild-type mice. Unexpectedly, these DEPs, in conjunction with previously identified CYFIP2 brain interactors, included not only other WRC components but also numerous proteins associated with membraneless organelles (MLOs) involved in mRNA processing and translation within cells, including the nucleolus, stress granules, and processing bodies. Additionally, single-cell transcriptomic analysis of the Cyfip2 knock-out forebrain revealed gene expression changes linked to cellular stress responses and MLOs. We also observed morphological changes in MLOs in Cyfip2 knock-out brains and CYFIP2 knock-down cells under basal and stress conditions. Lastly, we demonstrated that CYFIP2 knock-down in cells, potentially through WRC-dependent actin regulation, suppressed the phosphorylation levels of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), thereby enhancing protein synthesis. These results suggest a physical and functional connection between CYFIP2 and various MLO proteins and also extend CYFIP2's role within the WRC from actin regulation to influencing eIF2α phosphorylation and protein synthesis. With these dual functions, CYFIP2 may fine-tune the balance between MLO formation/dynamics and protein synthesis, a crucial aspect of proper mRNA processing and translation.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1671-1687"},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Sequence-to-expression approach to identify etiological non-coding DNA variations in P53 and cMYC-driven diseases. 从序列到表达的方法识别 P53 和 cMYC 驱动型疾病中的病因非编码 DNA 变异。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae109

Katherine Kin, Shounak Bhogale, Lisha Zhu, Derrick Thomas, Jessica Bertol, W Jim Zheng, Saurabh Sinha, Walid D Fakhouri

{"title":"Sequence-to-expression approach to identify etiological non-coding DNA variations in P53 and cMYC-driven diseases.","authors":"Katherine Kin, Shounak Bhogale, Lisha Zhu, Derrick Thomas, Jessica Bertol, W Jim Zheng, Saurabh Sinha, Walid D Fakhouri","doi":"10.1093/hmg/ddae109","DOIUrl":"10.1093/hmg/ddae109","url":null,"abstract":"Disease risk prediction based on genomic sequence and transcriptional profile can improve disease screening and prevention. Despite identifying many disease-associated DNA variants, distinguishing deleterious non-coding DNA variations remains poor for most common diseases. In this study, we designed in vitro experiments to uncover the significance of occupancy and competitive binding between P53 and cMYC on common target genes. Analyzing publicly available ChIP-seq data for P53 and cMYC in embryonic stem cells showed that ~344-366 regions are co-occupied, and on average, two cis-overlapping motifs (CisOMs) per region were identified, suggesting that co-occupancy is evolutionarily conserved. Using U2OS and Raji cells untreated and treated with doxorubicin to increase P53 protein level while potentially reducing cMYC level, ChIP-seq analysis illustrated that around 16 to 922 genomic regions were co-occupied by P53 and cMYC, and substitutions of cMYC signals by P53 were detected post doxorubicin treatment. Around 187 expressed genes near co-occupied regions were altered at mRNA level according to RNA-seq data analysis. We utilized a computational motif-matching approach to illustrate that changes in predicted P53 binding affinity in CisOMs of co-occupied elements significantly correlate with alterations in reporter gene expression. We performed a similar analysis using SNPs mapped in CisOMs for P53 and cMYC from ChIP-seq data, and expression of target genes from GTEx portal. We found significant correlation between change in cMYC-motif binding affinity in CisOMs and altered expression. Our study brings us closer to developing a generally applicable approach to filter etiological non-coding variations associated with common diseases.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1697-1710"},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Correction to: The C-terminal extension of dyskerin is a dyskeratosis congenita mutational hotspot that modulates interaction with telomerase RNA and subcellular localization. 更正为Dyskerin的C端延伸部分是先天性角化障碍的突变热点，可调节与端粒酶RNA的相互作用和亚细胞定位。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae126

引用次数: 0

Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels 在 MECP2 重复综合征人 iPSC 衍生神经元中模拟反义寡核苷酸疗法，揭示与 MeCP2 水平相关的基因表达程序

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-15 DOI: 10.1093/hmg/ddae135

Sameer S Bajikar, Yehezkel Sztainberg, Alexander J Trostle, Harini P Tirumala, Ying-Wooi Wan, Caroline L Harrop, Jesse D Bengtsson, Claudia M B Carvalho, Davut Pehlivan, Bernhard Suter, Jeffrey L Neul, Zhandong Liu, Paymaan Jafar-Nejad, Frank Rigo, Huda Y Zoghbi

{"title":"Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels","authors":"Sameer S Bajikar, Yehezkel Sztainberg, Alexander J Trostle, Harini P Tirumala, Ying-Wooi Wan, Caroline L Harrop, Jesse D Bengtsson, Claudia M B Carvalho, Davut Pehlivan, Bernhard Suter, Jeffrey L Neul, Zhandong Liu, Paymaan Jafar-Nejad, Frank Rigo, Huda Y Zoghbi","doi":"10.1093/hmg/ddae135","DOIUrl":"https://doi.org/10.1093/hmg/ddae135","url":null,"abstract":"Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human neurons from multiple MDS patient-derived induced pluripotent cells (iPSCs) to evaluate the benefit of using an ASO against MECP2 in a MDS human neuronal context. Importantly, we identified a signature of genes that is partially and qualitatively modulated upon ASO treatment, pinpointed genes sensitive to MeCP2 function, and altered in a model of Rett syndrome, a neurological disorder caused by loss of MeCP2 function. Furthermore, the signature contained genes that are aberrantly altered in unaffected control human neurons upon MeCP2 depletion, revealing gene expression programs qualitatively sensitive to MeCP2 levels in human neurons. Lastly, ASO treatment led to a partial rescue of abnormal neuronal morphology in MDS neurons. All together, these data demonstrate that ASOs targeting MECP2 benefit human MDS neurons. Moreover, our study establishes a paradigm by which to evaluate the contribution of individual genes within a CNV to pathogenesis and to assess their potential as a therapeutic target.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"6 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease TTN 单倍变体导致骨骼肌疾病的病理机制

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-15 DOI: 10.1093/hmg/ddae136

Jochen Gohlke, Johan Lindqvist, Zaynab Hourani, Sarah Heintzman, Paola Tonino, Bakri Elsheikh, Ana Morales, Matteo Vatta, Arthur Burghes, Henk Granzier, Jennifer Roggenbuck

{"title":"Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease","authors":"Jochen Gohlke, Johan Lindqvist, Zaynab Hourani, Sarah Heintzman, Paola Tonino, Bakri Elsheikh, Ana Morales, Matteo Vatta, Arthur Burghes, Henk Granzier, Jennifer Roggenbuck","doi":"10.1093/hmg/ddae136","DOIUrl":"https://doi.org/10.1093/hmg/ddae136","url":null,"abstract":"Pathogenic variants in the titin gene (TTN) are known to cause a wide range of cardiac and musculoskeletal disorders, with skeletal myopathy mostly attributed to biallelic variants. We identified monoallelic truncating variants (TTNtv), splice site or internal deletions in TTN in probands with mild, progressive axial and proximal weakness, with dilated cardiomyopathy frequently developing with age. These variants segregated in an autosomal dominant pattern in 7 out of 8 studied families. We investigated the impact of these variants on mRNA, protein levels, and skeletal muscle structure and function. Results reveal that nonsense-mediated decay likely prevents accumulation of harmful truncated protein in skeletal muscle in patients with TTNtvs. Splice variants and an out-of-frame deletion induce aberrant exon skipping, while an in-frame deletion produces shortened titin with intact N- and C-termini, resulting in disrupted sarcomeric structure. All variant types were associated with genome-wide changes in splicing patterns, which represent a hallmark of disease progression. Lastly, RNA-seq studies revealed that GDF11, a member of the TGF-β superfamily, is upregulated in diseased tissue, indicating that it might be a useful therapeutic target in skeletal muscle titinopathies.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"19 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Deciphering single-cell gene expression variability and its role in drug response 解密单细胞基因表达变异及其在药物反应中的作用

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-15 DOI: 10.1093/hmg/ddae138

Sizhe Liu, Liang Chen

引用次数: 0