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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.
Cancer Res ; 81(8): 1954-1964, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33602785

RESUMO

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 Completo do Exoma/estatística & dados numéricos , Sequenciamento Completo do Genoma/estatística & dados numéricos
4.
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
5.
Eur Heart J ; 41(28): 2618-2628, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32702746

RESUMO

AIMS: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols. METHODS AND RESULTS: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4). CONCLUSIONS: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.


Assuntos
Doença da Artéria Coronariana , Fitosteróis , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Humanos , Islândia , Esteróis
6.
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
7.
J Am Coll Cardiol ; 74(24): 2982-2994, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31865966

RESUMO

BACKGROUND: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). OBJECTIVES: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. METHODS: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. RESULTS: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. CONCLUSIONS: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.


Assuntos
Doença da Artéria Coronariana/sangue , Variações do Número de Cópias de DNA , Diabetes Mellitus Tipo 2/sangue , Lipoproteína(a)/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Humanos , Islândia , Kringles , Lipoproteína(a)/genética , Análise da Randomização Mendeliana , Peso Molecular , Isoformas de Proteínas/sangue , Fatores de Risco
8.
Nat Commun ; 10(1): 1777, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992453

RESUMO

Nerve conduction (NC) studies generate measures of peripheral nerve function that can reveal underlying pathology due to axonal loss, demyelination or both. We perform a genome-wide association study of sural NC amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH (c.996+1G>A; MAF = 1.32%) associating with decreased NC amplitude but not velocity. PRPH encodes peripherin, an intermediate filament (IF) protein involved in cytoskeletal development and maintenance of neurons. Through RNA and protein studies, we show that the variant leads to loss-of-function (LoF), as when over-expressed in a cell line devoid of other IFs, it does not allow formation of the normal filamentous structure of peripherin, yielding instead punctate protein inclusions. Recall of carriers for neurological assessment confirms that from an early age, homozygotes have significantly lower sural NC amplitude than non-carriers and are at risk of a mild, early-onset, sensory-negative, axonal polyneuropathy.


Assuntos
Condução Nervosa/genética , Periferinas/genética , Polineuropatias/genética , Sítios de Splice de RNA/genética , Nervo Sural/fisiopatologia , Adulto , Idade de Início , Idoso , Axônios/patologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Islândia/epidemiologia , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Polineuropatias/epidemiologia , Polineuropatias/fisiopatologia , Prevalência , Splicing de RNA/fisiologia
9.
Hum Mol Genet ; 28(7): 1199-1211, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476138

RESUMO

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context.


Assuntos
Biomarcadores/análise , Biomarcadores/urina , Variação Genética/genética , Adulto , Idoso , Alelos , Feminino , Hematúria/genética , Hematúria/urina , Humanos , Concentração de Íons de Hidrogênio , Islândia , Cetose/genética , Cetose/urina , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Proteinúria/genética , Proteinúria/urina , Transportador 2 de Glucose-Sódio/genética , Sequenciamento Completo do Genoma/métodos
10.
Nat Genet ; 50(11): 1505-1513, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30297969

RESUMO

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).


Assuntos
Mapeamento Cromossômico/métodos , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Genoma Humano/genética , Ilhotas Pancreáticas/metabolismo , Polimorfismo de Nucleotídeo Único , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Ensaios de Triagem em Larga Escala/métodos , Humanos , Ilhotas Pancreáticas/patologia , Desequilíbrio de Ligação , Masculino , Metanálise como Assunto , Fatores Sexuais
11.
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
12.
Nat Commun ; 9(1): 2252, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899519

RESUMO

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.


Assuntos
Proteína 4 Semelhante a Angiopoietina/deficiência , Proteína 4 Semelhante a Angiopoietina/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Substituição de Aminoácidos , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Glicemia/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/etiologia , Feminino , Inativação Gênica , Estudos de Associação Genética , Variação Genética , Heterozigoto , Homeostase , Humanos , Resistência à Insulina/genética , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Risco , Sequenciamento Completo do Exoma
13.
Nat Genet ; 50(4): 559-571, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29632382

RESUMO

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.


Assuntos
Diabetes Mellitus Tipo 2/genética , Alelos , Mapeamento Cromossômico/estatística & dados numéricos , Diabetes Mellitus Tipo 2/classificação , Diabetes Mellitus Tipo 2/fisiopatologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , Sequenciamento Completo do Exoma/estatística & dados numéricos
14.
Nat Commun ; 9(1): 987, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29511194

RESUMO

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10-10) and aortic root diameter (P = 1.30 × 10-8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10-3) and coronary artery disease (OR = 1.05, P = 9.3 × 10-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.


Assuntos
Estenose da Valva Aórtica/genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Fatores de Risco
15.
Sci Rep ; 7(1): 11380, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28900119

RESUMO

Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10-9) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.


Assuntos
Endometriose/genética , Endometriose/metabolismo , Grupo com Ancestrais do Continente Europeu , Variação Genética , Estudo de Associação Genômica Ampla , Biomarcadores , Estudos de Casos e Controles , Mapeamento Cromossômico , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
16.
Nat Genet ; 49(9): 1398-1402, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28783164

RESUMO

Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10-10), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10-11 and 7.3% per allele, P = 7.5 × 10-18, respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r2 = 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética , Alelos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Jejum , Feminino , Frequência do Gene , Glucoquinase/genética , Glucose-6-Fosfatase/genética , Hemoglobina A Glicada/metabolismo , Humanos , Islândia , Masculino , Penetrância , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética
17.
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
18.
Diabetes ; 66(11): 2888-2902, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28566273

RESUMO

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Variação Genética , Humanos
19.
Nat Commun ; 8: 15539, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28537267

RESUMO

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10-8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.


Assuntos
Endometriose/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Hormônios Esteroides Gonadais/metabolismo , Redes e Vias Metabólicas/genética , Adulto , Idoso , Endometriose/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
20.
Nat Commun ; 7: 12350, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27453397

RESUMO

We conducted a genome-wide association scan (GWAS) of endometriosis using 25.5 million sequence variants detected through whole-genome sequencing (WGS) of 8,453 Icelanders and imputed into 1,840 cases and 129,016 control women, followed by testing of associated variants in Danish samples. Here we report the discovery of a new endometriosis susceptibility locus on 4q12 (rs17773813[G], OR=1.28; P=3.8 × 10(-11)), upstream of KDR encoding vascular endothelial growth factor receptor 2 (VEGFR2). The variant correlates with disease severity (P=0.0046) when moderate/severe endometriosis cases are tested against minimal/mild cases. We further report association of rs519664[T] in TTC39B on 9p22 with endometriosis (P=4.8 × 10(-10); OR=1.29). The involvement of KDR in endometriosis risk highlights the importance of the VEGF pathway in the pathogenesis of the disease.


Assuntos
Endometriose/genética , Predisposição Genética para Doença , Lipoproteínas HDL/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Cromossomos Humanos Par 17/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos
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