Human Genetics最新文献

{"title":"Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder.","authors":"Aiko Iwata-Otsubo, Cara M Skraban, Atsunori Yoshimura, Toyonori Sakata, Cesar Augusto P Alves, Sarah K Fiordaliso, Yukiko Kuroda, Jaime Vengoechea, Angela Grochowsky, Paige Ernste, Lauren Lulis, Addie Nesbitt, Ahmad Abou Tayoun, Christopher Gray, Meghan C Towne, Kelly Radtke, Elizabeth A Normand, Lindsay Rhodes, Christoph Seiler, Katsuhiko Shirahige, Kosuke Izumi","doi":"10.1007/s00439-024-02656-3","DOIUrl":"10.1007/s00439-024-02656-3","url":null,"abstract":"<p><p>General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"437-453"},"PeriodicalIF":5.3,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140193641","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}

{"title":"The association between DNA methylation and human height and a prospective model of DNA methylation-based height prediction.","authors":"Zhonghua Wang, Guangping Fu, Guanju Ma, Chunyan Wang, Qian Wang, Chaolong Lu, Lihong Fu, Xiaojing Zhang, Bin Cong, Shujin Li","doi":"10.1007/s00439-024-02659-0","DOIUrl":"10.1007/s00439-024-02659-0","url":null,"abstract":"<p><p>As a vital anthropometric characteristic, human height information not only helps to understand overall developmental status and genetic risk factors, but is also important for forensic DNA phenotyping. We utilized linear regression analysis to test the association between each CpG probe and the height phenotype. Next, we designed a methylation sequencing panel targeting 959 CpGs and subsequent height inference models were constructed for the Chinese population. A total of 11,730 height-associated sites were identified. By employing KPCA and deep neural networks, a prediction model was developed, of which the cross-validation RMSE, MAE and R² were 5.62 cm, 4.45 cm and 0.64, respectively. Genetic factors could explain 39.4% of the methylation level variance of sites used in the height inference models. Collectively, we demonstrated an association between height and DNA methylation status through an EWAS analysis. Targeted methylation sequencing of only 959 CpGs combined with deep learning techniques could provide a model to estimate human height with higher accuracy than SNP-based prediction models.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"401-421"},"PeriodicalIF":3.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174495","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}

{"title":"The relationship between extreme inter-individual variation in macrophage gene expression and genetic susceptibility to inflammatory bowel disease.","authors":"Claire L O'Brien, Kim M Summers, Natalia M Martin, Dylan Carter-Cusack, Yuanhao Yang, Rasel Barua, Ojas V A Dixit, David A Hume, Paul Pavli","doi":"10.1007/s00439-024-02642-9","DOIUrl":"10.1007/s00439-024-02642-9","url":null,"abstract":"<p><p>The differentiation of resident intestinal macrophages from blood monocytes depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). Analysis of genome-wide association studies (GWAS) indicates that dysregulation of macrophage differentiation and response to microorganisms contributes to susceptibility to chronic inflammatory bowel disease (IBD). Here, we analyzed transcriptomic variation in monocyte-derived macrophages (MDM) from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. Transcriptional network analysis of the data revealed no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the temporal response to lipopolysaccharide (LPS). However, the basal or LPS-inducible expression of individual genes varied independently by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) in macrophages was associated with HLA genotype. Correlation analysis indicated the downstream impacts of variation in the immediate early response to LPS. For example, variation in early expression of IL1B was significantly associated with local SNV genotype and with subsequent peak expression of target genes including IL23A, CXCL1, CXCL3, CXCL8 and NLRP3. Similarly, variation in early IFNB1 expression was correlated with subsequent expression of IFN target genes. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu is associated with genetic susceptibility to IBD.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"233-261"},"PeriodicalIF":5.3,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989844","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}

{"title":"PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss.","authors":"Shelby E Redfield, Pedro De-la-Torre, Mina Zamani, Hanjun Wang, Hina Khan, Tyler Morris, Gholamreza Shariati, Majid Karimi, Margaret A Kenna, Go Hun Seo, Hongen Xu, Wei Lu, Sadaf Naz, Hamid Galehdari, Artur A Indzhykulian, A Eliot Shearer, Barbara Vona","doi":"10.1007/s00439-024-02649-2","DOIUrl":"10.1007/s00439-024-02649-2","url":null,"abstract":"<p><p>Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild-moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild-moderate hearing loss may identify further affected families.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"311-329"},"PeriodicalIF":3.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065149","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}

{"title":"Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.","authors":"Daniel Brooks, Elizabeth Burke, Sukyeong Lee, Tanya N Eble, Melanie O'Leary, Ikeoluwa Osei-Owusu, Heidi L Rehm, Shweta U Dhar, Lisa Emrick, David Bick, Michelle Nehrebecky, Ellen Macnamara, Dídac Casas-Alba, Judith Armstrong, Carolina Prat, Antonio F Martínez-Monseny, Francesc Palau, Pengfei Liu, David Adams, Seema Lalani, Jill A Rosenfeld, Lindsay C Burrage","doi":"10.1007/s00439-024-02657-2","DOIUrl":"10.1007/s00439-024-02657-2","url":null,"abstract":"<p><p>Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"279-291"},"PeriodicalIF":3.8,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11191325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049313","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}

{"title":"Clinical and genetic architecture of a large cohort with auditory neuropathy.","authors":"Hongyang Wang, Liping Guan, Xiaonan Wu, Jing Guan, Jin Li, Nan Li, Kaili Wu, Ya Gao, Dan Bing, Jianguo Zhang, Lan Lan, Tao Shi, Danyang Li, Wenjia Wang, Linyi Xie, Fen Xiong, Wei Shi, Lijian Zhao, Dayong Wang, Ye Yin, Qiuju Wang","doi":"10.1007/s00439-024-02652-7","DOIUrl":"10.1007/s00439-024-02652-7","url":null,"abstract":"<p><p>Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"293-309"},"PeriodicalIF":5.3,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11043192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059190","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}

{"title":"Screening copy number variations in 35 unsolved inherited retinal disease families.","authors":"Xiaozhen Liu, Hehua Dai, Genlin Li, Ruixuan Jia, Xiang Meng, Shicheng Yu, Liping Yang, Jing Hong","doi":"10.1007/s00439-023-02631-4","DOIUrl":"10.1007/s00439-023-02631-4","url":null,"abstract":"<p><p>The purpose of this study was to screen Copy Number Variations (CNVs) in 35 unsolved Inherited Retinal Dystrophy (IRD) families. Initially, next generation sequencing, including a specific Hereditary Eye Disease Enrichment Panel or Whole exome sequencing, was employed to screen (likely) pathogenic Single-nucleotide Variants (SNVs) and small Insertions and Deletions (indels) for these cases. All available SNVs and indels were further validated and co-segregation analyses were performed in available family members by Sanger sequencing. If not, after excluding deep intronic variants, Multiplex ligation-dependent probe amplification (MLPA), quantitative fluorescence PCR (QF-PCR) and Sanger sequencing were employed to screen CNVs. We determined that 18 probands who had heterozygous SNVs/indels or whose parents were not consanguineous but had homozygous SNVs/indels in autosomal recessive IRDs genes had CNVs in another allele of these genes, 11 families had disease-causing hemizygous CNVs in X-linked IRD genes, 6 families had (likely) pathogenic heterozygous CNVs in PRPF31 gene. Of 35 families, 33 different CNVs in 16 IRD-associated genes were detected, with PRPF31, EYS and USH2A the most common disease-causing gene in CNVs. Twenty-six and 7 of them were deletion and duplication CNVs, respectively. Among them, 14 CNVs were first reported in this study. Our research indicates that CNVs contribute a lot to IRDs, and screening of CNVs substantially increases the diagnostic rate of IRD. Our results emphasize that MLPA and QF-PCR are ideal methods to validate CNVs, and the novel CNVs reported herein expand the mutational spectrums of IRDs.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"197-210"},"PeriodicalIF":5.3,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10881639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570247","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}

{"title":"The pivotal role of long non-coding RNAs as potential biomarkers and modulators of chemoresistance in ovarian cancer (OC).","authors":"Shika Hanif Malgundkar, Yahya Tamimi","doi":"10.1007/s00439-023-02635-0","DOIUrl":"10.1007/s00439-023-02635-0","url":null,"abstract":"<p><p>Ovarian cancer (OC) is a fatal gynecological disease that is often diagnosed at later stages due to its asymptomatic nature and the absence of efficient early-stage biomarkers. Previous studies have identified genes with abnormal expression in OC that couldn't be explained by methylation or mutation, indicating alternative mechanisms of gene regulation. Recent advances in human transcriptome studies have led to research on non-coding RNAs (ncRNAs) as regulators of cancer gene expression. Long non-coding RNAs (lncRNAs), a class of ncRNAs with a length greater than 200 nucleotides, have been identified as crucial regulators of physiological processes and human diseases, including cancer. Dysregulated lncRNA expression has also been found to play a crucial role in ovarian carcinogenesis, indicating their potential as novel and non-invasive biomarkers for improving OC management. However, despite the discovery of several thousand lncRNAs, only one has been approved for clinical use as a biomarker in cancer, highlighting the importance of further research in this field. In addition to their potential as biomarkers, lncRNAs have been implicated in modulating chemoresistance, a major problem in OC. Several studies have identified altered lncRNA expression upon drug treatment, further emphasizing their potential to modulate chemoresistance. In this review, we highlight the characteristics of lncRNAs, their function, and their potential to serve as tumor markers in OC. We also discuss a few databases providing detailed information on lncRNAs in various cancer types. Despite the promising potential of lncRNAs, further research is necessary to fully understand their role in cancer and develop effective strategies to combat this devastating disease.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"107-124"},"PeriodicalIF":5.3,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139563724","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}

{"title":"Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder.","authors":"Ashraf Yahia, Danyang Li, Sanna Lejerkrans, Shyam Rajagopalan, Nelli Kalnak, Kristiina Tammimies","doi":"10.1007/s00439-023-02636-z","DOIUrl":"10.1007/s00439-023-02636-z","url":null,"abstract":"<p><p>Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"169-183"},"PeriodicalIF":5.3,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10881898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650616","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}

{"title":"Mitochondrial genetic variation and risk of chronic kidney disease and acute kidney injury in UK Biobank participants.","authors":"Vasantha Jotwani, Stephanie Y Yang, Heather Thiessen-Philbrook, Chirag R Parikh, Ronit Katz, Gregory J Tranah, Joachim H Ix, Steve Cummings, Sushrut S Waikar, Michael G Shlipak, Mark J Sarnak, Samir M Parikh, Dan E Arking","doi":"10.1007/s00439-023-02615-4","DOIUrl":"10.1007/s00439-023-02615-4","url":null,"abstract":"<p><p>Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFR_Cr-CysC, N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m². MtDNA haplotype was significantly associated with eGFR (p = 2.8E-12), but not with prevalent ESKD (p = 5.9E-2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E-10). When compared to the reference haplotype, mtDNA haplotypes I (β = 0.402, standard error (SE) = 0.111; p = 2.7E-4), IV (β = 0.430, SE = 0.073; p = 4.2E-9), and V (β = 0.233, SE = 0.050; p = 2.7E-6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"151-157"},"PeriodicalIF":5.3,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10881785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722357","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}