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1.
Commun Biol ; 4(1): 1132, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580418

RESUMO

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.

2.
Nat Genet ; 53(8): 1135-1142, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282336

RESUMO

Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome.


Assuntos
Peso ao Nascer/genética , Desenvolvimento Fetal/genética , Adulto , Glicemia/genética , Pressão Sanguínea/genética , Estatura/genética , Doenças Cardiovasculares/genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Islândia , Recém-Nascido , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
3.
Commun Biol ; 4(1): 156, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536631

RESUMO

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 Unido
4.
Eur Heart J ; 42(20): 1959-1971, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33580673

RESUMO

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.


Assuntos
Fibrilação Atrial , Diabetes Mellitus Tipo 2 , Marca-Passo Artificial , Fibrilação Atrial/genética , Estudo de Associação Genômica Ampla , Humanos , Canal de Sódio Disparado por Voltagem NAV1.8 , Síndrome do Nó Sinusal/genética
5.
Nat Commun ; 11(1): 5976, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239696

RESUMO

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.


Assuntos
Predisposição Genética para Doença , Hipertensão Induzida pela Gravidez/genética , Herança Multifatorial , Pré-Eclâmpsia/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Ásia Central/epidemiologia , Pressão Sanguínea/genética , Estudos de Casos e Controles , Conjuntos de Dados como Assunto , Europa (Continente)/epidemiologia , Feminino , Fator 5 de Crescimento de Fibroblastos/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Proteína do Locus do Complexo MDS1 e EVI1/genética , Pessoa de Meia-Idade , Pré-Eclâmpsia/epidemiologia , Gravidez , Estudos Prospectivos
6.
Nature ; 584(7822): 619-623, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581359

RESUMO

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2-7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10-24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10-4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10-4) and coeliac disease (OR = 1.62, P = 1.20 × 10-4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10-3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.


Assuntos
Códon sem Sentido/genética , Predisposição Genética para Doença/genética , Ligantes , Mutação , Tireoidite Autoimune/genética , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Alelos , Doenças Autoimunes/genética , Bases de Dados Factuais , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Islândia , Íntrons/genética , Leucemia Mieloide Aguda , Mutação com Perda de Função , Sítios de Splice de RNA/genética , Reino Unido
7.
Commun Biol ; 3(1): 189, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327693

RESUMO

Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.


Assuntos
Eritropoese/genética , Mutação com Ganho de Função , Hemoglobinas/metabolismo , Proteína 1 Reguladora do Ferro/genética , Mutação com Perda de Função , Biomarcadores/sangue , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Humanos , Islândia , Proteína 1 Reguladora do Ferro/metabolismo , Reino Unido
8.
Commun Biol ; 3(1): 129, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184442

RESUMO

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.


Assuntos
Proteínas da Matriz Extracelular/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Prolapso Uterino/genética , Proteína Wnt4/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Comorbidade , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia/epidemiologia , Fenótipo , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia , Prolapso Uterino/diagnóstico , Prolapso Uterino/epidemiologia
9.
Nat Commun ; 11(1): 393, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959851

RESUMO

Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFßR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.


Assuntos
Remodelação das Vias Aéreas/genética , Asma/genética , Antígeno Ki-1/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Linfócitos T/imunologia , Regiões 3' não Traduzidas/genética , Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Eosinófilos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Antígeno Ki-1/imunologia , Antígeno Ki-1/metabolismo , Contagem de Leucócitos , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/imunologia , Locos de Características Quantitativas/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo I/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Reino Unido
10.
Nat Genet ; 51(2): 267-276, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643255

RESUMO

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10-27, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.


Assuntos
Araquidonato 15-Lipoxigenase/genética , Variação Genética/genética , Pólipos Nasais/genética , Sinusite/genética , Adulto , Asma/genética , Doença Crônica , Eosinófilos/patologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Islândia , Contagem de Leucócitos/métodos , Masculino , Pólipos Nasais/patologia , Sinusite/patologia
11.
Nat Commun ; 9(1): 4568, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30410027

RESUMO

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, rg = 0.77 (P = 2.6 × 10-11), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10-55). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.


Assuntos
Estudo de Associação Genômica Ampla , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/sangue , Hiperplasia Prostática/genética , Acetilação , Idoso , Biologia Computacional , Predisposição Genética para Doença , Histonas/metabolismo , Humanos , Islândia , Sintomas do Trato Urinário Inferior/sangue , Sintomas do Trato Urinário Inferior/genética , Lisina/metabolismo , Masculino , Metanálise como Assunto , Herança Multifatorial/genética , Mutação/genética , Fenótipo , Locos de Características Quantitativas/genética , Fatores de Risco , Reino Unido
12.
Nat Genet ; 50(12): 1681-1687, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374069

RESUMO

Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10-12, p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10-11, p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10-10, OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL1 (rs117018441, P = 1.8 × 10-25, OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis.


Assuntos
Colágeno Tipo XI/genética , Loci Gênicos , Interleucina-11/genética , Mutação de Sentido Incorreto , Osteoartrite/genética , Receptor Smoothened/genética , Adulto , Idoso , Estudos de Casos e Controles , Conjuntos de Dados como Assunto/estatística & dados numéricos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Islândia/epidemiologia , Masculino , Pessoa de Meia-Idade , Osteoartrite/epidemiologia , Polimorfismo de Nucleotídeo Único , Reino Unido/epidemiologia
13.
Nat Commun ; 9(1): 3636, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30194396

RESUMO

Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth.


Assuntos
Leiomioma/genética , Neoplasias Uterinas/genética , Estudos de Casos e Controles , Endometriose/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos
14.
J Natl Cancer Inst ; 110(9): 967-974, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29767749

RESUMO

Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.


Assuntos
Carcinoma de Células Escamosas/genética , Genes BRCA2 , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Neoplasias Cutâneas/genética , Carcinoma de Pequenas Células do Pulmão/genética , Alelos , Genótipo , Humanos , Islândia/epidemiologia , Mutação , Países Baixos/epidemiologia , Razão de Chances , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia
15.
Sci Rep ; 7(1): 3119, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28596592

RESUMO

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10-11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.


Assuntos
Apendicite/genética , Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Alelos , Biologia Computacional/métodos , Genótipo , Humanos , Anotação de Sequência Molecular , Razão de Chances
16.
Nat Genet ; 49(8): 1255-1260, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628106

RESUMO

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.


Assuntos
Feto , Predisposição Genética para Doença , Pré-Eclâmpsia/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Estudos de Coortes , Feminino , Seguimentos , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez , Proteínas da Gravidez/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
17.
Nat Commun ; 8: 14517, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28195142

RESUMO

The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with Pcombined<3 × 10-8): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10-7) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.


Assuntos
Carcinoma Papilar/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Neoplasias da Glândula Tireoide/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Cromossomos Humanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Frequência do Gene/genética , Predisposição Genética para Doença , Variação Estrutural do Genoma , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Hormônios Hipofisários/análise , Fatores de Risco , Câncer Papilífero da Tireoide , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Sequenciamento Completo do Genoma
18.
Nat Commun ; 7: 13490, 2016 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-27848971

RESUMO

Adult height is a highly heritable trait. Here we identified 31.6 million sequence variants by whole-genome sequencing of 8,453 Icelanders and tested them for association with adult height by imputing them into 88,835 Icelanders. Here we discovered 13 novel height associations by testing four different models including parent-of-origin (|ß|=0.4-10.6 cm). The minor alleles of three parent-of-origin signals associate with less height only when inherited from the father and are located within imprinted regions (IGF2-H19 and DLK1-MEG3). We also examined the association of these sequence variants in a set of 12,645 Icelanders with birth length measurements. Two of the novel variants, (IGF2-H19 and TET1), show significant association with both adult height and birth length, indicating a role in early growth regulation. Among the parent-of-origin signals, we observed opposing parental effects raising questions about underlying mechanisms. These findings demonstrate that common variations affect human growth by parental imprinting.


Assuntos
Estatura/genética , Epigênese Genética , Estudos de Associação Genética , Adulto , Loci Gênicos , Variação Genética , Genótipo , Humanos , Islândia , Modelos Genéticos
19.
Proc Natl Acad Sci U S A ; 111(14): 5083-7, 2014 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-24706877

RESUMO

The lateral mobility of proteins within cell membranes is usually thought to be dependent on their size and modulated by local heterogeneities of the membrane. Experiments using single-particle tracking on reconstituted membranes demonstrate that protein diffusion is significantly influenced by the interplay of membrane curvature, membrane tension, and protein shape. We find that the curvature-coupled voltage-gated potassium channel (KvAP) undergoes a significant increase in protein mobility under tension, whereas the mobility of the curvature-neutral water channel aquaporin 0 (AQP0) is insensitive to it. Such observations are well explained in terms of an effective friction coefficient of the protein induced by the local membrane deformation.


Assuntos
Forma Celular , Proteínas de Membrana/metabolismo , Aquaporinas/metabolismo , Proteínas do Olho/metabolismo , Bicamadas Lipídicas , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Transporte Proteico
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