Human Heredity最新文献

{"title":"The Diagnostic Value of miR-124a Expression in Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis.","authors":"Tianhao Wu, Yanlong Zhang, Aqin Peng, Xirui Wu","doi":"10.1159/000529171","DOIUrl":"10.1159/000529171","url":null,"abstract":"<p><strong>Introduction: </strong>Rheumatoid arthritis (RA), a chronic autoimmune disorder, is currently a severe health threat. Previous studies have documented the altered expression of various miRNAs in RA patients. This study determined the expression of miR-124a in RA patients and estimated its diagnostic value for RA.</p><p><strong>Methods: </strong>A total of 80 RA patients were enrolled as the study subjects, and 36 patients with osteoarthritis were included, with another 36 healthy people as the controls. miR-124a expression levels in peripheral blood plasma, peripheral blood mononuclear cells (PBMCs), and synovial fluid were measured using reverse transcription quantitative polymerase chain reaction, followed by Pearson correlation analysis. Additionally, the association between miR-124a and major clinical indicators was assessed, such as rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and disease activity score of 28 joints (DAS28). The diagnostic efficacy of miR-124a expression in plasma, PBMCs, and synovial fluid for RA was evaluated by the receiver operating characteristic curve, and the difference in the area under the curve (AUC) was analyzed.</p><p><strong>Results: </strong>miR-124a was downregulated in RA patients, and the expression levels of miR-124a in plasma, PBMCs, and synovial fluid showed a certain degree of positive correlation. miR-124a was inversely linked with RF, ESR, and DAS28. For the diagnosis of RA patients, the AUC of plasma miR-124a was 0.899 and the cut-off value was 0.800, with 68.75% sensitivity and 94.44% specificity; the AUC of miR-124a in PBMCs was 0.937 and the cut-off value was 0.805, with 82.50% sensitivity and 91.67% specificity; the AUC of miR-124a in plasma combined with PBMCs was 0.961, with a higher diagnostic value than independent plasma or PBMCs; the AUC of miR-124a in synovial fluid was 0.929 and the cut-off value was 0.835, with 80.00% sensitivity and 88.89% specificity.</p><p><strong>Conclusion: </strong>miR-124a expression is downregulated in the plasma, PBMCs, and synovial fluid of RA patients and has a high diagnostic value for RA.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":"58-67"},"PeriodicalIF":1.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9962987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduction of Missed Diagnosis of G6PD Deficiency in Heterozygous Females by G6PD/6PGD Ratio Assay Combined with Amplification Refractory Mutation System PCR.","authors":"Shiguo Chen, Jian Gao, Qunyan Wu, Xi Li, Sheng Lin, Jindi Su, Kaifeng Zheng, Zhaopeng Guo, Jilong Yao, Shan Duan","doi":"10.1159/000527806","DOIUrl":"10.1159/000527806","url":null,"abstract":"<p><strong>Objective: </strong>Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder that results in impaired enzyme activity. The G6PD/6PGD ratio assay was routinely used for G6PD deficiency screening in China, but there is an apparent defect of missed diagnosis in heterozygous females. The study aims to explore the means to improve its accuracy.</p><p><strong>Methods: </strong>A total of 4,161 Chinese females of childbearing age were collected in this retrospective study. All samples were first subjected to G6PD/6PGD ratio assay and then screened by amplification refractory mutation system PCR (ARMS-PCR) for six hotspot mutants in Chinese population (c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.392G>T, and c.871G>A). For the samples with G6PD/6PGD ratio<1.0 and no mutations were found by ARMS-PCR, next-generation sequencing (NGS) was performed. Sanger sequencing was finally used to verify all the variants.</p><p><strong>Results: </strong>The prevalence of G6PD deficiency in Shenzhen females of childbearing age was 7.31%. The proportion of the six hotspot mutations accounted for 98.03% of all 304 G6PD variants carriers. Taking the ARMS-PCR/NGS results as a reference, the missed diagnosis rate of the G6PD/6PGD ratio assay was 33.88%. Using ARMS-PCR to retest the samples with a G6PD/6PGD ratio between 1.00 and ∼1.10 or 1.00 and ∼1.15 could reduce the missed diagnosis rate from the original 33.88% to 18.09% or 12.05% separately.</p><p><strong>Conclusion: </strong>ARMS-PCR is an appropriate supplementary method for discovering most carriers missed by the G6PD/6PGD ratio assay.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":"1-7"},"PeriodicalIF":1.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9254952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Common Variant of ARRB2 Promoter Region Associated with the Prognosis of Heart Failure.","authors":"Hongqiang Ren, Yijun Liu, Zhen Tan, Guiquan Luo, Mei Zhang, Shuang Li, Tingwei Tang, Li Zhao","doi":"10.1159/000530827","DOIUrl":"10.1159/000530827","url":null,"abstract":"<p><strong>Introduction: </strong>The role of ARRB2 in cardiovascular disease has recently gained increasing attention. However, the association between ARRB2 polymorphisms and heart failure (HF) has not yet been investigated.</p><p><strong>Methods: </strong>A total of 2,386 hospitalized patients with chronic HF were enrolled as the first cohort and followed up for a mean period of 20.2 months. Meanwhile, ethnically and geographically matched 3,000 individuals without evidence of HF were included as healthy controls. We genotyped the common variant in ARRB2 gene to identify the association between variant and HF. A replicated independent cohort enrolling 837 patients with chronic HF was applied to validate the observed association. A series of function analyses were conducted to illuminate the underlying mechanism.</p><p><strong>Results: </strong>We identified a common variant rs75428611 associated with the prognosis of HF in two-stage population: adjusted p = 0.001, hazard ratio (HR) = 1.31 (1.11-1.54) in additive model and adjusted p = 0.001, HR = 1.39 (1.14-1.69) in dominant model in first-stage population; adjusted p = 0.04, HR = 1.41 (1.02-1.95) in additive model and adjusted p = 0.03, HR = 1.51 (1.03-2.20) in dominant model in replicated stage. However, rs75428611 did not significantly associate with the risk of HF. Functional analysis indicated that rs75428611-G allele increased the promoter activity and the mRNA expression level of ARRB2 by facilitating transcription factor SRF binding but not the A allele.</p><p><strong>Conclusions: </strong>Our findings demonstrated that rs75428611 in promoter of ARRB2 was associated with the risk of HF mortality. It is a promising potential treatment target for HF.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":"68-78"},"PeriodicalIF":1.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9351239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel PMVK Variant Associated with Familial Porokeratosis.","authors":"Wenjing Zhang, Xinmiao Nie, Lei Shi, Fengmin Shao, Lihua Cao","doi":"10.1159/000531120","DOIUrl":"10.1159/000531120","url":null,"abstract":"<p><strong>Background: </strong>Porokeratosis is a rare chronic progressive hypokeratotic skin disease, possibly related to the mevalonate pathway. Variations in four enzymes, including phosphomevalonate kinase (PMVK) may alter this pathway, ultimately leading to porokeratosis.</p><p><strong>Objectives: </strong>The aim of the study was to identify the causative gene variant of porokeratosis in a Chinese family and investigate its population frequency and pathogenicity.</p><p><strong>Method: </strong>In this study, Sanger sequencing was used to identify the gene variant causative of porokeratosis; its population frequency was investigated by polymerase chain reaction-restriction fragment length polymorphism in 4 patients and three normal individuals as well as in 100 normal unrelated controls; finally, the pathogenicity of the mutation and the associated structural changes were predicted.</p><p><strong>Results: </strong>We identified a novel heterozygous missense variant, c.207G&gt;T (p. Lys69Asn) in the PMVK gene. This variant was found in all patients but not in the normal individuals in this family or in the 100 controls. In silico analysis indicated that the variant was pathogenic; p.Lys69Asn changed the length of the α-helix and the hydrogen bond pattern compared with the wild-type protein.</p><p><strong>Conclusions: </strong>The novel variant c.207G&gt;T (p. Lys69Asn) in the PMVK gene was the causative variant in this porokeratosis family. This finding provides further evidence for the genetic basis of this disease.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":"50-57"},"PeriodicalIF":1.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9632284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Study of Disease-Causing Variants in PAH, QDPR, PTS, and PCD Genes in Iranian Patients with Hyperphenylalaninemia: A Systematic Review.","authors":"Mahmoud Ghanei, Seyedeh Helia Sadat Fatemi, Tayebeh Hamzehlouei","doi":"10.1159/000529037","DOIUrl":"10.1159/000529037","url":null,"abstract":"<p><strong>Background: </strong>Hyperphenylalaninemia (HPA) is an autosomal recessive disorder that results from a deficiency in the phenylalanine hydroxylase enzyme (PAH) or from a flaw in the genes that are responsible for the biosynthesis or regeneration of the cofactor tetrahydrobiopterin (BH4), including GCH1, SR, QDPR, PTS, and PCD. Identification of disease-causing variants in these genes can help physicians and clinical geneticists in differential diagnosis, appropriate prescription drugs, and saving time and cost. This study attempted to identify these genes' most prevalent disease-causing variants in Iranian HPA patients.</p><p><strong>Summary: </strong>This study was performed under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Before it started, the flow work and inclusion/exclusion criteria were published as a protocol in PROSPERO (CRD42021273705). We conducted a comprehensive search on December 10, 2022, on international online databases, including Web of Science, Scopus, EMBASE, Science Direct, PubMed/Medline, Google Scholar, SID, ISC, and Magiran search engine, to find pertinent publications. Some studies were chosen based on inclusion and exclusion criteria. Altogether, 1,243 Iranian patients from 13 articles were considered. In total, we identified 129 distinct disease-causing variants in PAH (20 novel variants), 29 in QDPR (17 novel variants), 15 in PTS (seven novel variants), and one novel variant in PCD. Twenty disease-causing variants for PAH, 18 for QDPR, and 8 for PTS are included in the genes' proposed genetic diagnostic panels. These panels include more than 75% of the documented disease-causing variants in the Iranian population.</p><p><strong>Key messages: </strong>The findings of this research illustrated the spectrum of disease-causing variants in the PAH, QDPR, PTS, and PCD genes identified in Iranian HPA patients. Common disease-causing variants of these genes may be chosen as a preliminary diagnostic panel for early diagnosis and lowering therapy costs.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":"8-17"},"PeriodicalIF":1.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10750328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10527867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel c.3636-4 A&gt;G Mutation in the CCDC88C Plays a Causative Role in Familial Spinocerebellar Ataxia.","authors":"Senmao Chai, Deyang Liu, Yajing Liu, Ming Sang","doi":"10.1159/000534692","DOIUrl":"10.1159/000534692","url":null,"abstract":"<p><strong>Introduction: </strong>Spinocerebellar ataxia (SCA) is an autosomal dominant genetic disease characterized by cerebellar neurological deficits. Specifically, its primary clinical manifestation is ataxia accompanied by peripheral nerve damage. A total of 48 causative genes of SCA have been identified. This study aimed to identify causative genes of autosomal dominant SCA in a four-generation Chinese kindred comprising eight affected individuals.</p><p><strong>Methods: </strong>Genomic DNA samples were extracted from the pedigree members, and genomic whole-exome sequencing was performed, followed by bidirectional Sanger sequencing, and minigene assays to identify mutation sites.</p><p><strong>Results: </strong>A novel pathogenic heterozygous mutation in the splice region of the coiled-coil domain containing the 88C (CCDC88C) gene (NM_001080414:c.3636-4 A&gt;G) was identified in four affected members. The minigene assay results indicated that this mutation leads to the insertion of CAG bases (c.3636-1_3636-3 insCAG).</p><p><strong>Conclusion: </strong>CCDC88C gene mutation leads to SCA40 (OMIM:616053), which is a rare subtype of SCA without symptoms during childhood. Our findings further demonstrated the role of the CCDC88C gene in SCA and indicated that the c.3636-4 A&gt;G (NM_001080414) variant of CCDC88C is causative for a later-onset phenotype of SCA40. Our findings enrich the mutation spectrum of CCDC88C gene and provide a theoretical basis for the genetic counseling of SCA40.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":"91-97"},"PeriodicalIF":1.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71412057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Violation of the constant genetic effect assumption can result in biased estimates for non-linear Mendelian randomization","authors":"S. Burgess","doi":"10.1101/2022.10.26.22280570","DOIUrl":"https://doi.org/10.1101/2022.10.26.22280570","url":null,"abstract":"Non-linear Mendelian randomization is an extension of conventional Mendelian randomization that performs separate instrumental variable analyses in strata of the study population with different average levels of the exposure. The approach estimates a localized average causal effect function, representing the average causal effect of the exposure on the outcome at different levels of the exposure. The commonly-used residual method for dividing the population into strata works under the assumption that the effect of the genetic instrument on the exposure is linear and constant in the study population. However, this assumption may not hold in practice. We use the recently developed doubly-ranked method to re-analyse various datasets previously analysed using the residual method. In particular, we consider a genetic score for 25-hydroxyvitamin D [25(OH)D] used in a recent non-linear Mendelian randomization analysis to assess the potential effect of vitamin D supplementation on all-cause mortality. We show that the effect of the genetic score on 25(OH)D concentrations varies strongly, with a five-fold difference in the estimated genetic association with the exposure in the lowest and highest decile groups. Evidence for a protective causal effect of vitamin D supplementation on all-cause mortality in low vitamin D individuals is evident for the residual method, but not for the doubly-ranked method. We show that the constant genetic effect assumption is more reasonable for some exposures, and less reasonable for others. If the doubly-ranked method indicates that this assumption is violated, then estimates from both the residual and doubly-ranked methods can be biased, although bias was smaller on average in the doubly-ranked method. Analysts should compare results from both methods, as well as considering transforming the exposure to reduce heterogeneity in the genetic effect on the exposure.","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"1 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41898686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a novel mutation in patients with type A insulin resistance syndrome.","authors":"Liling Zhao, Hongmei Dai, Qin Zhang, Wenmu Hu, Ping Jin","doi":"10.1159/000525223","DOIUrl":"10.1159/000525223","url":null,"abstract":"<p><strong>Introduction: </strong>Type A insulin resistance syndrome is a rare type of congenital insulin resistance often caused by heterozygous mutations in the insulin receptor gene (INSR). The aim of this study is to explore the clinical and genetic characteristics of three patients with type A insulin resistance syndrome from two Chinese families.</p><p><strong>Methods: </strong>The peripheral blood samples were collected from each family members. Whole-exome sequencing were performed on three patients.</p><p><strong>Results: </strong>Patient #1 was diagnosed with hyperinsulinemia at the age of 11 years and presented with hirsutism, acanthosis nigricans, and polycystic ovaries by 13 years. A heterozygous c.3470A > G mutation in the INSR gene was identified in patient #1. Patient #2 was a 13-year-old girl who presented with insulin resistance, polycystic ovary, and hyperandrogenemia. A novel c.3601C > G INSR mutation was identified in patient #2. Co-segregated analysis showed that the c.3601C > G mutation was also found in her father, who had hyperinsulinemia and diabetes mellitus, which was consistent with autosomal dominant inheritance. SIFT and PolyPhen-2 predicted that the c.3470A > G and c.3601C > G mutations in INSR had damaging effects.</p><p><strong>Conclusion: </strong>Our study expands the genotypic and phenotypic spectrum of type A insulin resistance syndrome. Awareness of the clinical features coupled with INSR gene screening is key to early detection and active intervention.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"87 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43136904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mitochondrial tRNAAsp T7561C, tRNAHis C12153T and A12172G mutations may be associated with essential hypertension in a Han Chinese pedigree.","authors":"Haiying Fu, Jinming Sun, Xiaoyan Xu","doi":"10.1159/000524163","DOIUrl":"10.1159/000524163","url":null,"abstract":"<p><strong>Objectives: </strong>Mutations in mitochondrial tRNA (mt-tRNA) are the important causes for maternally inherited hypertension, however, the pathophysiology of mt-tRNA mutations in clinical expression of hypertension remains poorly understood.</p><p><strong>Material and methods: </strong>In this study, we report the molecular features of a Han Chinese pedigree with maternally transmitted essential hypertension. The entire mitochondrial genomes are PCR amplified and sequenced, Moreover, phylogenetic analysis, haplogroup analysis, as well as pathogenicity scoring system are used to assess the potential roles for mtDNA mutations.</p><p><strong>Results: </strong>Strikingly, among ten matrilineal relatives, three of them suffer from variable degree of hypertension at different age at onset. Sequence analysis of the complete mitochondrial genomes suggests the presence of three possible pathogenic mtDNA mutations: tRNAAsp T7561C, tRNAHis C12153T and A12172G, together with a set of variants belonging to East Asian mitochondrial haplogroup M7a. Interestingly, the T7561C mutation occurs at position 44 in the variable region of tRNAAsp, while the C12153T and A12172G mutations are localized at extremely conserved nucleotides in the D-arm and anticodon stem of tRNAHis gene, respectively, which are critical for tRNA steady-state level and function.</p><p><strong>Conclusions: </strong>Mitochondrial T7561C, C12153T and A12172G mutations may lead to the failure in tRNAs metabolism, and cause mitochondrial dysfunction that is responsible for hypertension. However, the homoplasmy form of mt-tRNA mutations, incomplete penetrance of hypertension suggest that T7561C, C12153T and A12172G mutations are insufficient to produce the clinical phenotype, hence, other risk factors such as environmental factors, nuclear genes and epigenetic modifications may contribute to the phenotypic manifestation of maternally inherited hypertension in this Chinese pedigree.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":"87 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2022-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49367155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.","authors":"Rasha N Alotaibi, Brian J Howe, Lina M Moreno Uribe, Carla Sanchez, Frederic W B Deleyiannis, Carmencita Padilla, Fernando A Poletta, Ieda M Orioli, Carmen J Buxó, George L Wehby, Alexandre R Vieira, Jeffrey Murray, Consuelo Valencia-Ramírez, Claudia P Restrepo Muñeton, Ross E Long, John R Shaffer, Steven E Reis, Seth M Weinberg, Katherine Neiswanger, Daniel W McNeil, Mary L Marazita","doi":"10.1159/000522642","DOIUrl":"10.1159/000522642","url":null,"abstract":"<p><p>Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.</p>","PeriodicalId":13226,"journal":{"name":"Human Heredity","volume":" ","pages":""},"PeriodicalIF":1.1,"publicationDate":"2022-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9284765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}