RESUMO
Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data1,2. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank3. This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.
Assuntos
Bancos de Espécimes Biológicos , Bases de Dados Genéticas , Variação Genética , Genoma Humano , Genômica , Sequenciamento Completo do Genoma , África/etnologia , Ásia/etnologia , Estudos de Coortes , Sequência Conservada , Éxons/genética , Genoma Humano/genética , Haplótipos/genética , Humanos , Mutação INDEL , Irlanda/etnologia , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único/genética , Reino UnidoRESUMO
BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).
Assuntos
Doença , Genômica , Longevidade , Humanos , Alelos , Testes Genéticos , Variação Genética , Genótipo , Islândia/epidemiologia , Longevidade/genética , Doença/genética , Doenças Cardiovasculares/genética , Neoplasias/genéticaRESUMO
AIMS: Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications. METHODS AND RESULTS: This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders. CONCLUSION: The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Humanos , Estudo de Associação Genômica Ampla/métodos , Síncope/genética , Doenças Cardiovasculares/genética , Sistema Nervoso Autônomo , Análise da Randomização MendelianaRESUMO
The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics and to evolutionary studies. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35× genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32-0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45-1.57). The number of clustered mutations increases faster with the mother's age than with the father's, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19-0.33%) decrease in cytosine-phosphate-guanine to thymine-phosphate-guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28-0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.
Assuntos
Envelhecimento/genética , Mutação em Linhagem Germinativa/genética , Idade Materna , Mutagênese , Pais , Idade Paterna , Adolescente , Adulto , Idoso , Animais , Criança , Cromossomos Humanos Par 8/genética , Evolução Molecular , Feminino , Sequência Rica em GC , Genoma Humano/genética , Gorilla gorilla/genética , Humanos , Mutação INDEL , Islândia , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Pan troglodytes/genética , Polimorfismo de Nucleotídeo Único , Pongo/genética , Adulto JovemAssuntos
Doença de Alzheimer , Glicoproteínas de Membrana , Receptores Imunológicos , Idoso , Feminino , Humanos , Masculino , Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Clusterina/metabolismo , Predisposição Genética para Doença/genética , Homozigoto , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
MOTIVATION: Data analysis is requisite on reliable data. In genetics this includes verifying that the sample is not contaminated with another, a problem ubiquitous in biology. RESULTS: In human, and other diploid species, DNA contamination from the same species can be found by the presence of three haplotypes between polymorphic SNPs. read_haps is a tool that detects sample contamination from short read whole genome sequencing data. AVAILABILITYAND IMPLEMENTATION: github.com/DecodeGenetics/read_haps.
Assuntos
Diploide , Sequenciamento de Nucleotídeos em Larga Escala , Sequência de Bases , Haplótipos , Humanos , Análise de Sequência de DNA , Software , Sequenciamento Completo do GenomaRESUMO
SUMMARY: popSTR2 is an update and augmentation of our previous work 'popSTR: a population-based microsatellite genotyper'. To make genotyping sensitive to inter-sample differences, we supply a kernel to estimate sample-specific slippage rates. For clinical sequencing purposes, a panel of known pathogenic repeat expansions is provided along with a script that scans and flags for manual inspection markers indicative of a pathogenic expansion. Like its predecessor, popSTR2 allows for joint genotyping of samples at a population scale. We now provide a binning method that makes the microsatellite genotypes more amenable to analysis within standard association pipelines and can increase association power. AVAILABILITY AND IMPLEMENTATION: https://github.com/DecodeGenetics/popSTR. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Repetições de Microssatélites , Software , GenótipoRESUMO
To find sequence variants affecting prostate cancer (PCA) susceptibility in an unscreened Romanian population we use a genome-wide association study (GWAS). The study population included 990 unrelated pathologically confirmed PCA cases and 1034 male controls. DNA was genotyped using Illumina SNP arrays, and 24.295.558 variants were imputed using the 1000 Genomes data set. An association test was performed between the imputed markers and PCA. A systematic literature review for variants associated with PCA risk identified 115 unique variants that were tested in the Romanian sample set. Thirty of the previously reported SNPs replicated (P-value < 0.05), with the strongest associations observed at: 8q24.21, 11q13.3, 6q25.3, 5p15.33, 22q13.2, 17q12 and 3q13.2. The replicated variants showing the most significant association in Romania are rs1016343 at 8q24.21 (P = 2.2 × 10-4 ), rs7929962 at 11q13.3 (P = 2.7 × 10-4 ) and rs9364554 at 6q25.2 (P = 4.7 × 10-4 ). None of the variants tested in the Romanian GWAS reached genome-wide significance (P-value <5 × 10-8 ) but 807 markers had P-values <1 × 10-4 . Here, we report the results of the first GWAS of PCA performed in a Romanian population. Our study provides evidence that a substantial fraction of previously validated PCA variants associate with risk in this unscreened Romanian population.
Assuntos
Biomarcadores Tumorais/genética , Loci Gênicos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Antígeno Prostático Específico/genética , Neoplasias da Próstata/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Frequência do Gene , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Risco , RomêniaRESUMO
Two familial forms of colorectal cancer (CRC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP), are caused by rare mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the genes APC and MUTYH, respectively. No information is available on the presence of high-risk CRC mutations in the Romanian population. We performed whole-genome sequencing of 61 Romanian CRC cases with a family history of cancer and/or early onset of disease, focusing the analysis on candidate variants in the LS and FAP genes. The frequencies of all candidate variants were assessed in a cohort of 688 CRC cases and 4567 controls. Immunohistochemical (IHC) staining for MLH1, MSH2, MSH6, and PMS2 was performed on tumour tissue. We identified 11 candidate variants in 11 cases; six variants in MLH1, one in MSH6, one in PMS2, and three in APC. Combining information on the predicted impact of the variants on the proteins, IHC results and previous reports, we found three novel pathogenic variants (MLH1:p.Lys84ThrfsTer4, MLH1:p.Ala586CysfsTer7, PMS2:p.Arg211ThrfsTer38), and two novel variants that are unlikely to be pathogenic. Also, we confirmed three previously published pathogenic LS variants and suggest to reclassify a previously reported variant of uncertain significance to pathogenic (MLH1:c.1559-1G>C).
Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Predisposição Genética para Doença , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , DNA Glicosilases/genética , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Fatores de Risco , Romênia/epidemiologiaRESUMO
Microsatellites are polymorphic tracts of short tandem repeats with one to six base-pair (bp) motifs and are some of the most polymorphic variants in the genome. Using 6084 Icelandic parent-offspring trios we estimate 63.7 (95% CI: 61.9-65.4) microsatellite de novo mutations (mDNMs) per offspring per generation, excluding one bp repeats motifs (homopolymers) the estimate is 48.2 mDNMs (95% CI: 46.7-49.6). Paternal mDNMs occur at longer repeats than maternal ones, which are in turn larger with a mean size of 3.4 bp vs 3.1 bp for paternal ones. mDNMs increase by 0.97 (95% CI: 0.90-1.04) and 0.31 (95% CI: 0.25-0.37) per year of father's and mother's age at conception, respectively. Here, we find two independent coding variants that associate with the number of mDNMs transmitted to offspring; The minor allele of a missense variant (allele frequency (AF) = 1.9%) in MSH2, a mismatch repair gene, increases transmitted mDNMs from both parents (effect: 13.1 paternal and 7.8 maternal mDNMs). A synonymous variant (AF = 20.3%) in NEIL2, a DNA damage repair gene, increases paternally transmitted mDNMs (effect: 4.4 mDNMs). Thus, the microsatellite mutation rate in humans is in part under genetic control.
Assuntos
Reparo de Erro de Pareamento de DNA , Mutação em Linhagem Germinativa , Humanos , Alelos , Mutação em Linhagem Germinativa/genética , Repetições de Microssatélites/genética , Células GerminativasRESUMO
Memory T-cell responses following SARS-CoV-2 infection have been extensively investigated but many studies have been small with a limited range of disease severity. Here we analyze SARS-CoV-2 reactive T-cell responses in 768 convalescent SARS-CoV-2-infected (cases) and 500 uninfected (controls) Icelanders. The T-cell responses are stable three to eight months after SARS-CoV-2 infection, irrespective of disease severity and even those with the mildest symptoms induce broad and persistent T-cell responses. Robust CD4+ T-cell responses are detected against all measured proteins (M, N, S and S1) while the N protein induces strongest CD8+ T-cell responses. CD4+ T-cell responses correlate with disease severity, humoral responses and age, whereas CD8+ T-cell responses correlate with age and functional antibodies. Further, CD8+ T-cell responses associate with several class I HLA alleles. Our results, provide new insight into HLA restriction of CD8+ T-cell immunity and other factors contributing to heterogeneity of T-cell responses following SARS-CoV-2 infection.
Assuntos
COVID-19 , SARS-CoV-2 , Alelos , Linfócitos T CD8-Positivos , COVID-19/genética , Humanos , Índice de Gravidade de DoençaRESUMO
Thousands of genomic structural variants (SVs) segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. Most current approaches identify SVs in single genomes and afterwards merge the identified variants into a joint call set across many genomes. We describe the approach PopDel, which directly identifies deletions of about 500 to at least 10,000 bp in length in data of many genomes jointly, eliminating the need for subsequent variant merging. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDel's running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies.
Assuntos
Genoma Humano/genética , Variação Estrutural do Genoma , Metagenômica/métodos , Deleção de Sequência , Estudos de Viabilidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Padrões de Herança , Masculino , Reprodutibilidade dos Testes , Análise de Sequência de DNARESUMO
A major challenge to long read sequencing data is their high error rate of up to 15%. We present Ratatosk, a method to correct long reads with short read data. We demonstrate on 5 human genome trios that Ratatosk reduces the error rate of long reads 6-fold on average with a median error rate as low as 0.22 %. SNP calls in Ratatosk corrected reads are nearly 99 % accurate and indel calls accuracy is increased by up to 37 %. An assembly of Ratatosk corrected reads from an Ashkenazi individual yields a contig N50 of 45 Mbp and less misassemblies than a PacBio HiFi reads assembly.
Assuntos
Quimera , Genoma Humano , Feminino , Genômica , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.
Assuntos
Genoma Humano , Células Germinativas/metabolismo , Gêmeos Monozigóticos/genética , Desenvolvimento Embrionário/genética , Feminino , Frequência do Gene/genética , Humanos , Masculino , Mosaicismo , Mutação/genética , Zigoto/metabolismoRESUMO
Long-read sequencing (LRS) promises to improve the characterization of structural variants (SVs). We generated LRS data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions). We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association of a rare deletion in PCSK9 with lower low-density lipoprotein (LDL) cholesterol levels, compared to the population average. We also discovered an association of a multiallelic SV in ACAN with height; we found 11 alleles that differed in the number of a 57-bp-motif repeat and observed a linear relationship between the number of repeats carried and height. These results show that SVs can be accurately characterized at the population scale using LRS data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.
Assuntos
Doença/genética , Variação Estrutural do Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Característica Quantitativa Herdável , Alelos , LDL-Colesterol/metabolismo , Cromossomos Humanos/genética , Feminino , Frequência do Gene/genética , Humanos , Islândia , Modelos Lineares , Masculino , Pró-Proteína Convertase 9/genética , Recombinação Genética/genética , Deleção de Sequência/genéticaRESUMO
Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10-22 and OR = 4.2 for heterozygotes, P = 5.7 × 10-27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.
Assuntos
Perda Auditiva/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Feminino , Genes/genética , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 × 10-23, OR = 1.23; Ncases = 4714, Ncontrols = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10-11, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.
Assuntos
Paralisia de Bell/genética , Adulto , Idoso , Músculos Faciais/patologia , Nervo Facial/patologia , Paralisia Facial/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Movimento/fisiologia , Estudos Prospectivos , RiscoRESUMO
The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10-12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10-4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.
Assuntos
Carcinoma Basocelular/genética , Mutação com Perda de Função , Penetrância , Proteínas Tirosina Fosfatases não Receptoras/genética , Neoplasias Cutâneas/genética , Neoplasias do Colo do Útero/genética , Fatores Etários , Carcinoma Basocelular/epidemiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genes Supressores de Tumor , Predisposição Genética para Doença , Testes Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Mutação em Linhagem Germinativa , Humanos , Islândia/epidemiologia , Masculino , Razão de Chances , Neoplasias Cutâneas/epidemiologia , Bancos de Tecidos/estatística & dados numéricos , Reino Unido/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Sequenciamento do Exoma/estatística & dados numéricos , Sequenciamento Completo do Genoma/estatística & dados numéricosRESUMO
Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.
Assuntos
Anemia Ferropriva/genética , Loci Gênicos , Variação Genética , Sobrecarga de Ferro/genética , Ferro/sangue , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Biomarcadores/sangue , Dinamarca , Ferritinas/sangue , Estudo de Associação Genômica Ampla , Genótipo , Homeostase , Humanos , Islândia , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/diagnóstico , Fenótipo , Medição de Risco , Fatores de Risco , Transferrina/metabolismo , Reino UnidoRESUMO
Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P < 5 × 10-8); seven common (minor allele frequency >5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP.