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1.
N Engl J Med ; 385(20): 1868-1880, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34758253

RESUMO

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).


Assuntos
Genoma Humano , Doenças Raras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Características da Família , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Doenças Raras/diagnóstico , Sensibilidade e Especificidade , Medicina Estatal , Reino Unido , Sequenciamento Completo do Genoma , Adulto Jovem
2.
Acta Chim Slov ; 68(2): 268-278, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34738119

RESUMO

Despite being around for more than 40 years, DNA sequencing is regarded as young technology in clinical medicine. As sequencing is becoming cheaper, faster and more accurate, it is rapidly being incorporated into clinical laboratories. In 2003, the completion of the first human genome opened the door to personalized medicine. Ever since it has been expected for genomics to widely impact clinical care and public health. However, many years can pass for genomic discoveries to reflect back and benefit the patients. DNA sequencing represents a less biased approach to diagnostics. It is not only a diagnostic tool, but can also influence clinical management and therapy. As new technologies rapidly emerge it is important for researchers and health professionals to have basic knowledge about the capabilities and drawbacks of the existing sequencing methods, and their use in clinical setting and research. This review provides an overview of nucleic acid sequencing technologies from historical perspective and later focuses on clinical utilization of sequencing. Some of the most promising areas are presented with selected examples from Slovenian researchers.


Assuntos
COVID-19 , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Medicina de Precisão , Análise de Sequência de DNA
3.
BMC Genomics ; 22(1): 789, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732136

RESUMO

BACKGROUND: Transposable elements (TE) comprise nearly half of the human genome and their insertions have profound effects to human genetic diversification and as well as disease. Despite their abovementioned significance, there is no consensus on the TE subfamilies that remain active in the human genome. In this study, we therefore developed a novel statistical test for recently mobile subfamilies (RMSs), based on patterns of overlap with > 100,000 polymorphic indels. RESULTS: Our analysis produced a catalogue of 20 high-confidence RMSs, which excludes many false positives in public databases. Intriguingly though, it includes HERV-K, an LTR subfamily previously thought to be extinct. The RMS catalogue is strongly enriched for contributions to germline genetic disorders (P = 1.1e-10), and thus constitutes a valuable resource for diagnosing disorders of unknown aetiology using targeted TE-insertion screens. Remarkably, RMSs are also highly enriched for somatic insertions in diverse cancers (P = 2.8e-17), thus indicating strong correlations between germline and somatic TE mobility. Using CRISPR/Cas9 deletion, we show that an RMS-derived polymorphic TE insertion increased the expression of RPL17, a gene associated with lower survival in liver cancer. More broadly, polymorphic TE insertions from RMSs were enriched near genes with allele-specific expression, suggesting widespread effects on gene regulation. CONCLUSIONS: By using a novel statistical test we have defined a catalogue of 20 recently mobile transposable element subfamilies. We illustrate the gene regulatory potential of RMS-derived polymorphic TE insertions, using CRISPR/Cas9 deletion in vitro on a specific candidate, as well as by genome wide analysis of allele-specific expression. Our study presents novel insights into TE mobility and regulatory potential and provides a key resource for human disease genetics and population history studies.


Assuntos
Elementos de DNA Transponíveis , Retrovirus Endógenos , Elementos de DNA Transponíveis/genética , Regulação da Expressão Gênica , Genoma Humano , Humanos
4.
BMC Genomics ; 22(1): 666, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34719381

RESUMO

BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Genoma , Genoma Humano , Genômica , Genótipo , Humanos , Sequenciamento Completo do Genoma
5.
Front Immunol ; 12: 756288, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777369

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has caused many deaths worldwide. To date, the mechanism of viral immune escape remains unclear, which is a great obstacle to developing effective clinical treatment. RNA processing mechanisms, including alternative polyadenylation (APA) and alternative splicing (AS), are crucial in the regulation of most human genes in many types of infectious diseases. Because the role of APA and AS in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown, we performed de novo identification of dynamic APA sites using a public dataset of human peripheral blood mononuclear cell (PBMC) RNA-Seq data in COVID-19 patients. We found that genes with APA were enriched in innate immunity -related gene ontology categories such as neutrophil activation, regulation of the MAPK cascade and cytokine production, response to interferon-gamma and the innate immune response. We also reported genome-wide AS events and enriched viral transcription-related categories upon SARS-CoV-2 infection. Interestingly, we found that APA events may give better predictions than AS in COVID-19 patients, suggesting that APA could act as a potential therapeutic target and novel biomarker in those patients. Our study is the first to annotate genes with APA and AS in COVID-19 patients and highlights the roles of APA variation in SARS-CoV-2 infection.


Assuntos
COVID-19/genética , Poliadenilação , SARS-CoV-2 , Processamento Alternativo , COVID-19/imunologia , Feminino , Genoma Humano , Humanos , Imunidade Inata , Leucócitos Mononucleares , Masculino , RNA Mensageiro , Transcriptoma
6.
BMC Genomics ; 22(1): 712, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600465

RESUMO

BACKGROUND: The current and future applications of genomic data may raise ethical and privacy concerns. Processing and storing of this data introduce a risk of abuse by potential offenders since the human genome contains sensitive personal information. For this reason, we have developed a privacy-preserving method, named Varlock providing secure storage of sequenced genomic data. We used a public set of population allele frequencies to mask the personal alleles detected in genomic reads. Each personal allele described by the public set is masked by a randomly selected population allele with respect to its frequency. Masked alleles are preserved in an encrypted confidential file that can be shared in whole or in part using public-key cryptography. RESULTS: Our method masked the personal variants and introduced new variants detected in a personal masked genome. Alternative alleles with lower population frequency were masked and introduced more often. We performed a joint PCA analysis of personal and masked VCFs, showing that the VCFs between the two groups cannot be trivially mapped. Moreover, the method is reversible and personal alleles in specific genomic regions can be unmasked on demand. CONCLUSION: Our method masks personal alleles within genomic reads while preserving valuable non-sensitive properties of sequenced DNA fragments for further research. Personal alleles in the desired genomic regions may be restored and shared with patients, clinics, and researchers. We suggest that the method can provide an additional security layer for storing and sharing of the raw aligned reads.


Assuntos
Genômica , Privacidade , Alelos , Frequência do Gene , Genoma Humano , Humanos
7.
Sci Rep ; 11(1): 20833, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675242

RESUMO

Several single-cell RNA sequencing (scRNA-seq) studies analyzing immune response to COVID-19 infection have been recently published. Most of these studies have small sample sizes, which limits the conclusions that can be made with high confidence. By re-analyzing these data in a standardized manner, we validated 8 of the 20 published results across multiple datasets. In particular, we found a consistent decrease in T-cells with increasing COVID-19 infection severity, upregulation of type I Interferon signal pathways, presence of expanded B-cell clones in COVID-19 patients but no consistent trend in T-cell clonal expansion. Overall, our results show that the conclusions drawn from scRNA-seq data analysis of small cohorts of COVID-19 patients need to be treated with some caution.


Assuntos
Biomarcadores/metabolismo , COVID-19/imunologia , COVID-19/metabolismo , RNA Citoplasmático Pequeno , Análise de Célula Única , Líquido da Lavagem Broncoalveolar , Biologia Computacional , Bases de Dados Factuais , Perfilação da Expressão Gênica/métodos , Genoma Humano , Genoma Viral , Humanos , Imunidade , Leucócitos Mononucleares/citologia , RNA-Seq , Reprodutibilidade dos Testes , SARS-CoV-2 , Análise de Sequência de RNA/métodos , Transdução de Sinais , Regulação para Cima
8.
Nat Commun ; 12(1): 5942, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642312

RESUMO

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15-30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4-9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.


Assuntos
Grupos Étnicos/genética , Genoma Humano , Migração Humana/história , Índios Norte-Americanos/genética , Filogenia , Dinâmica Populacional/estatística & dados numéricos , Grupos Étnicos/classificação , Variação Genética , Genômica/métodos , História Antiga , Humanos , Índios Norte-Americanos/classificação , México , Filogeografia
9.
Nat Commun ; 12(1): 5929, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642339

RESUMO

Arab populations are largely understudied, notably their genetic structure and history. Here we present an in-depth analysis of 6,218 whole genomes from Qatar, revealing extensive diversity as well as genetic ancestries representing the main founding Arab genealogical lineages of Qahtanite (Peninsular Arabs) and Adnanite (General Arabs and West Eurasian Arabs). We find that Peninsular Arabs are the closest relatives of ancient hunter-gatherers and Neolithic farmers from the Levant, and that founder Arab populations experienced multiple splitting events 12-20 kya, consistent with the aridification of Arabia and farming in the Levant, giving rise to settler and nomadic communities. In terms of recent genetic flow, we show that these ancestries contributed significantly to European, South Asian as well as South American populations, likely as a result of Islamic expansion over the past 1400 years. Notably, we characterize a large cohort of men with the ChrY J1a2b haplogroup (n = 1,491), identifying 29 unique sub-haplogroups. Finally, we leverage genotype novelty to build a reference panel of 12,432 haplotypes, demonstrating improved genotype imputation for both rare and common alleles in Arabs and the wider Middle East.


Assuntos
Cromossomos Humanos Y , Genoma Humano , Haplótipos , Migração Humana/história , Filogenia , África , Alelos , Árabes/genética , Ásia , DNA Mitocondrial/genética , Conjuntos de Dados como Assunto , Europa (Continente) , Feminino , Fluxo Gênico , Frequência do Gene , História do Século XXI , História Antiga , História Medieval , Humanos , Masculino , Filogeografia , Catar , Análise de Sequência de DNA , Sequenciamento Completo do Genoma
10.
BMC Genomics ; 22(1): 718, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34610795

RESUMO

BACKGROUND: Overlapping genes share same genomic regions in parallel (sense) or anti-parallel (anti-sense) orientations. These gene pairs seem to occur in all domains of life and are best known from viruses. However, the advantage and biological significance of overlapping genes is still unclear. Expressed sequence tags (ESTs) analysis enabled us to uncover an overlapping gene pair in the human genome. RESULTS: By using in silico analysis of previous experimental documentations, we reveal a new form of overlapping genes in the human genome, in which two genes found on opposite strands (Pou5f1 and Tcf19), share two exons and one intron enclosed, at the same positions, between OCT4B3 and TCF19-D splice variants. CONCLUSIONS: This new form of overlapping gene expands our previous perception of splicing events and may shed more light on the complexity of gene regulation in higher organisms. Additional such genes might be detected by ESTs analysis also of other organisms.


Assuntos
Processamento Alternativo , Genoma Humano , Fator 3 de Transcrição de Octâmero/genética , Fatores de Transcrição/genética , Éxons/genética , Genômica , Humanos , Íntrons/genética
13.
Nutrients ; 13(10)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34684344

RESUMO

Previous studies have suggested that vitamin D (VD) was associated with psychiatric diseases, but efforts to elucidate the functional relevance of VD with depression and anxiety from genetic perspective have been limited. Based on the UK Biobank cohort, we first calculated polygenic risk score (PRS) for VD from genome-wide association study (GWAS) data of VD. Linear and logistic regression analysis were conducted to evaluate the associations of VD traits with depression and anxiety traits, respectively. Then, using individual genotype and phenotype data from the UK Biobank, genome-wide environment interaction studies (GWEIS) were performed to identify the potential effects of gene × VD interactions on the risks of depression and anxiety traits. In the UK Biobank cohort, we observed significant associations of blood VD level with depression and anxiety traits, as well as significant associations of VD PRS and depression and anxiety traits. GWEIS identified multiple candidate loci, such as rs114086183 (p = 4.11 × 10-8, LRRTM4) for self-reported depression status and rs149760119 (p = 3.88 × 10-8, GNB5) for self-reported anxiety status. Our study results suggested that VD was negatively associated with depression and anxiety. GWEIS identified multiple candidate genes interacting with VD, providing novel clues for understanding the biological mechanism potential associations between VD and psychiatric disorders.


Assuntos
Ansiedade/sangue , Ansiedade/genética , Depressão/sangue , Depressão/genética , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Vitamina D/sangue , Ansiedade/epidemiologia , Bancos de Espécimes Biológicos , Depressão/epidemiologia , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Regressão , Fatores de Risco
14.
Nutrients ; 13(10)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34684477

RESUMO

It is unclear whether genetic interactions are involved in the association between vegetable intake and reduced body mass index (BMI) or obesity. We conducted a comprehensive search for single nucleotide polymorphisms (SNPs) which are associated with the interaction between vegetable intake frequency and BMI or obesity. We performed a genome-wide association analysis to evaluate the genetic interactions between self-reported intake of vegetables such as carrot, broccoli, spinach, other green vegetables (green pepper and green beans), pumpkin, and cabbage with BMI and obesity, which is defined as a BMI ≥ 25.0 kg/m2 in the Japanese population (n = 12,225). The mean BMI and prevalence of obesity was 23.9 ± 3.4 kg/m2 and 32.3% in men and 22.1 ± 3.8 kg/m2 and 17.3% in in women, respectively. A significant interaction was observed between rs4445711 and frequency of carrot intake on BMI (p = 4.5 × 10-8). This interaction was slightly attenuated after adjustment for age, sex, alcohol intake, smoking, physical activity and the frequency of total vegetable intake (p = 2.1 × 10-7). A significant interaction was also observed between rs4445711 and frequency of carrot intake on obesity (p = 2.5 × 10-8). No significant interactions that were the same as the interaction between frequency of carrot intake and rs4445711 were observed between the intake frequency of broccoli, spinach, other green vegetables, pumpkin or cabbage and BMI or obesity. The frequency of carrot consumption is implicated in reducing BMI by the intermediary of rs4445711. This novel genetic association may provide new clues to clarify the association between vegetable intake and BMI or obesity.


Assuntos
Índice de Massa Corporal , Daucus carota , Comportamento Alimentar , Obesidade/epidemiologia , Obesidade/genética , Feminino , Frequência do Gene/genética , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
15.
BMC Genomics ; 22(1): 730, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625021

RESUMO

BACKGROUND: Differential expression (DE) analysis of RNA-seq data typically depends on gene annotations. Different sets of gene annotations are available for the human genome and are continually updated-a process complicated with the development and application of high-throughput sequencing technologies. However, the impact of the complexity of gene annotations on DE analysis remains unclear. RESULTS: Using "mappability", a metric of the complexity of gene annotation, we compared three distinct human gene annotations, GENCODE, RefSeq, and NONCODE, and evaluated how mappability affected DE analysis. We found that mappability was significantly different among the human gene annotations. We also found that increasing mappability improved the performance of DE analysis, and the impact of mappability mainly evident in the quantification step and propagated downstream of DE analysis systematically. CONCLUSIONS: We assessed how the complexity of gene annotations affects DE analysis using mappability. Our findings indicate that the growth and complexity of gene annotations negatively impact the performance of DE analysis, suggesting that an approach that excludes unnecessary gene models from gene annotations improves the performance of DE analysis.


Assuntos
Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Anotação de Sequência Molecular , RNA-Seq , Sequenciamento Completo do Exoma
17.
Nat Commun ; 12(1): 6147, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686674

RESUMO

Joint fine-mapping that leverages information between quantitative traits could improve accuracy and resolution over single-trait fine-mapping. Using summary statistics, flashfm (flexible and shared information fine-mapping) fine-maps signals for multiple traits, allowing for missing trait measurements and use of related individuals. In a Bayesian framework, prior model probabilities are formulated to favour model combinations that share causal variants to capitalise on information between traits. Simulation studies demonstrate that both approaches produce broadly equivalent results when traits have no shared causal variants. When traits share at least one causal variant, flashfm reduces the number of potential causal variants by 30% compared with single-trait fine-mapping. In a Ugandan cohort with 33 cardiometabolic traits, flashfm gave a 20% reduction in the total number of potential causal variants from single-trait fine-mapping. Here we show flashfm is computationally efficient and can easily be deployed across publicly available summary statistics for signals in up to six traits.


Assuntos
Mapeamento Cromossômico/métodos , Estudo de Associação Genômica Ampla/métodos , Teorema de Bayes , Simulação por Computador , Genoma Humano , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
18.
Nat Genet ; 53(10): 1456-1468, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594038

RESUMO

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated with cell-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption and is altered during the environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identified an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.


Assuntos
Neoplasias Encefálicas/genética , Plasticidade Celular/genética , Epigênese Genética , Glioma/genética , Análise de Célula Única , Estresse Fisiológico/genética , Evolução Clonal , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Genoma Humano , Humanos , Mutação/genética , Filogenia , Regiões Promotoras Genéticas/genética , Microambiente Tumoral/genética
19.
Nat Genet ; 53(10): 1434-1442, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594041

RESUMO

Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.


Assuntos
DNA Polimerase III/genética , DNA Polimerase II/genética , Mutação em Linhagem Germinativa/genética , Adolescente , Adulto , Idoso , Desenvolvimento Embrionário/genética , Genoma Humano/genética , Humanos , Neoplasias Intestinais/patologia , Intestinos/patologia , Pessoa de Meia-Idade , Mutagênese/genética , Filogenia , Células-Tronco/patologia , Adulto Jovem
20.
Nat Genet ; 53(10): 1425-1433, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34611362

RESUMO

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.


Assuntos
Herança Multifatorial/genética , Homeostase do Telômero/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Locos de Características Quantitativas
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