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1.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
2.
Pediatr Res ; 85(7): 955-960, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30862960

RESUMO

BACKGROUND: Recent studies suggest that infantile hypertrophic pyloric stenosis (IHPS) and congenital heart defects (CHDs) may share some genetic risk factors, but little is known about the co-occurrence of the two conditions in patients. METHODS: Our study cohort included 2,212,756 persons born in Denmark 1977-2013. We identified patients with IHPS and CHD in the National Patient Register. Using log-linear Poisson regression, we estimated the (incidence) rate ratios (RRs) comparing the rate of IHPS among children with a CHD diagnosis (exposed) and the rate among those without such a diagnosis. RESULTS: Twenty-seven thousand three hundred and fifty-seven children in the cohort were diagnosed with CHD out of whom 85 developed IHPS (RR = 2.62, 95% confidence interval (CI) 2.09-3.22]). The results were similar for those with and without other congenital malformations, for preterm and term deliveries, and for both sexes. There was, however, a significant effect of calendar period (P = .003). In the period 1977-1996, the RR of IHPS given a CHD diagnosis was 1.96 (95% CI 1.41-2.64); in the period 1997-2014, the RR was 3.75 (95% CI 2.74-4.99). CONCLUSION: CHD was associated with an increased risk of IHPS. Further research is needed to delineate molecular-level mechanisms that may affect both conditions.

3.
Am J Hum Genet ; 103(5): 691-706, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

4.
Epidemiology ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30461527

RESUMO

BACKGROUND: The possible etiologic link between tonsillectomy and inflammatory bowel diseases remains unclear. To investigate the hereditary component, we assessed the risk of inflammatory bowel disease after own tonsillectomy as well as after tonsillectomy among family members. METHODS: A nationwide Danish cohort of 7,045,288 individuals was established and linked to comprehensive national registers with data on kinship, tonsillectomy surgery, and diagnosis of inflammatory bowel disease from all health sectors. We used Poisson regression models to estimate hospital contact rate ratios (RR) for Crohn's disease and ulcerative colitis, with 95% confidence intervals (CI), between individuals with or without tonsillectomy, as well as between individuals with or without tonsillectomized relatives. RESULTS: During 189 million person-years of follow-up between 1977 and 2014, 276,673 individuals were tonsillectomized, 22,015 developed Crohn's disease, and 49,550 developed ulcerative colitis. Rates of inflammatory bowel disease were elevated up to 20 years after own tonsillectomy (Crohn's disease: RR 1.52 (95% CI, 1.43-1.61); ulcerative colitis: RR 1.24 (95% CI, 1.18-1.29)). RRs for Crohn's disease was 1.22 (95% CI, 1.17-1.27) after 1 degree relatives' tonsillectomy, 1.14 (95% CI, 1.08-1.19) after 2 degree relatives' tonsillectomy, and 1.08 (95% CI, 1.01-1.15 after 3 degree relatives' tonsillectomy. Corresponding RRs for ulcerative colitis were 1.10 (95% CI, 1.07-1.13), 1.05 (95% CI, 1.01-1.08), and 1.03 (95% CI, 0.98-1.09). CONCLUSIONS: Even individuals with tonsillectomized family members were at increased risk of inflammatory bowel disease. These findings call into question a direct influence of tonsillectomy on gastrointestinal inflammation and point instead towards shared hereditary or environmental factors.

5.
Hum Mol Genet ; 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30281099

RESUMO

Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ~2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P<5x10-8), including novel associations with two SNPs. One of these SNPs, rs6736913 (odds ratio [OR] = 2.32; P = 3.0x10-15), is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1×10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis (GCTA) method, we estimated the IHPS SNP heritability to be 30%, and using the LD score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.

6.
Hum Mol Genet ; 27(17): 3113-3127, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931343

RESUMO

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

7.
Clin Epidemiol ; 10: 97-105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29391832

RESUMO

Background: The tonsils are immunological gatekeepers against pathogens. Immunological response to tonsillitis may vary clinically from no enlargement of the tonsils to nearly obstructive conditions. In this investigation, we studied the familial aggregation of tonsillectomy, as an indicator of the extent to which tonsillar immune responses to infections might be genetically controlled. Methods: Data on kinship relations and vital status from the Danish Civil Registration System were used to establish a cohort of Danes with relatives born since 1977. Tonsillectomies in all hospitals and clinics from 1977 to 2013 were identified in national registers together with the indication for tonsillectomy. Rate ratios (RRs) for tonsillectomy >1 year after tonsillectomy in specific types of relatives (first to fourth degree) were estimated in Poisson regression models with adjustment for calendar period, sex, age, and total number of specified relatives. Results: A cohort of 2.4 million persons was followed for 44,100,697 million person-years (mean 18.4 years/person), and included 148,190 tonsillectomies. RRs of tonsillectomy were consistently higher when the relatedness and the number of tonsillectomized relatives were higher. RRs were similar in boys and girls, but were larger in early childhood. Additional analyses suggested that this relatively higher RR at younger ages was due to a larger influence of shared environment at younger ages, whereas the genetic influence was similar at all ages. Results were similar for tonsillectomies performed strictly due to tonsillitis. Conclusions: Genetic factors appear to predispose to severe tonsillitis underlying tonsillectomies, regardless of age and sex. Further studies are needed to understand how genes regulate the tonsils' immune response against infections.

8.
Eur J Hum Genet ; 26(4): 561-569, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29379196

RESUMO

Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10-10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

9.
Nat Genet ; 50(1): 42-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273806

RESUMO

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

10.
Ann Rheum Dis ; 77(3): 378-385, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29170203

RESUMO

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

11.
N Engl J Med ; 377(12): 1156-1167, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28877031

RESUMO

BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10-8) or an association with suggestive significance (P<1.0×10-6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).


Assuntos
Predisposição Genética para Doença , Variação Genética , Idade Gestacional , Fatores de Alongamento de Peptídeos/genética , Nascimento Prematuro/genética , Receptor Tipo 2 de Angiotensina/genética , Transativadores/genética , Adenilil Ciclases/genética , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Análise de Regressão , Proteína Wnt4/genética , Proteínas ras/genética
12.
Circ Cardiovasc Genet ; 10(3)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28611031

RESUMO

BACKGROUND: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. METHODS AND RESULTS: Using array-based and targeted genotyping, we found that rs80356779, a p.Pro479Leu variant in CPT1A, was strongly associated with markers of n-3 fatty acid metabolism, including degree of unsaturation (P=1.16×10-34), levels of polyunsaturated fatty acids, n-3 fatty acids, and docosahexaoenic acid relative to total fatty acid levels (P=2.35×10-15, P=4.02×10-19, and P=7.92×10-27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10-9). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. CONCLUSION: Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations.


Assuntos
Tamanho Corporal/genética , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos Ômega-3/metabolismo , Mutação de Sentido Incorreto , Alelos , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Groenlândia , Humanos , Inuítes/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
13.
Nat Commun ; 8: 15789, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28585551

RESUMO

Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 × 10-18, odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 × 10-10, OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 × 10-11, OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study.

14.
Hum Mol Genet ; 26(9): 1759-1769, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334860

RESUMO

Epilepsy is a serious and common neurological disorder. Expression quantitative loci (eQTL) analysis is a vital aid for the identification and interpretation of disease-risk loci. Many eQTLs operate in a tissue- and condition-specific manner. We have performed the first genome-wide cis-eQTL analysis of human hippocampal tissue to include not only normal (n = 22) but also epileptic (n = 22) samples. We demonstrate that disease-associated variants from an epilepsy GWAS meta-analysis and a febrile seizures (FS) GWAS are significantly more enriched with epilepsy-eQTLs than with normal hippocampal eQTLs from two larger independent published studies. In contrast, GWAS meta-analyses of two other brain diseases associated with hippocampal pathology (Alzheimer's disease and schizophrenia) are more enriched with normal hippocampal eQTLs than with epilepsy-eQTLs. These observations suggest that an eQTL analysis that includes disease-affected brain tissue is advantageous for detecting additional risk SNPs for the afflicting and closely related disorders, but not for distinct diseases affecting the same brain regions. We also show that epilepsy eQTLs are enriched within epilepsy-causing genes: an epilepsy cis-gene is significantly more likely to be a causal gene for a Mendelian epilepsy syndrome than to be a causal gene for another Mendelian disorder. Epilepsy cis-genes, compared to normal hippocampal cis-genes, are more enriched within epilepsy-causing genes. Hence, we utilize the epilepsy eQTL data for the functional interpretation of epilepsy disease-risk variants and, thereby, highlight novel potential causal genes for sporadic epilepsy. In conclusion, an epilepsy-eQTL analysis is superior to normal hippocampal tissue eQTL analyses for identifying the variants and genes underlying epilepsy.


Assuntos
Epilepsia/genética , Convulsões Febris/genética , Encéfalo/metabolismo , Encéfalo/fisiologia , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Hipocampo/metabolismo , Hipocampo/fisiologia , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fatores de Risco
15.
J Med Genet ; 54(5): 358-364, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27941131

RESUMO

BACKGROUND: Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered. OBJECTIVE: To identify common genetic variants associated with tonsillectomy. METHODS: We used tonsillectomy information from Danish health registers and carried out a genome-wide association study comprising 1464 patients and 12 019 controls of Northwestern European ancestry, with replication in an independent sample set of 1575 patients and 1367 controls. RESULTS: The variant rs2412971, intronic in HORMAD2 at chromosome 22q12.2, was robustly associated with tonsillectomy (OR=1.22; p=1.48×10-9) and is highly correlated with SNPs previously found to be associated with IgA nephropathy, Crohn's disease (CD) and early onset inflammatory bowel disease (IBD). The risk allele for tonsillectomy corresponded to increased risk of IgA nephropathy and decreased risk of CD and IBD. We further performed lookup analyses of the top SNP for outcomes related to tonsillectomy in the combined discovery and replication sample and found that rs2412971 was associated with acute tonsillitis (OR=1.19; p=7.82×10-4), chronic disease of the tonsils (OR=1.19; p=2.32×10-6) and appendectomy (OR=1.18; p=1.13×10-3). CONCLUSIONS: We identified and replicated a genetic association at 22q12.2 with tonsillectomy. Further functional investigation is required to illuminate whether the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system.


Assuntos
Proteínas de Ciclo Celular/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Tonsilectomia , Cromossomos Humanos/genética , Loci Gênicos , Humanos , Reprodutibilidade dos Testes
16.
Nature ; 538(7624): 248-252, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27680694

RESUMO

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.


Assuntos
Envelhecimento/genética , Peso ao Nascer/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feto/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Antropometria , Pressão Sanguínea/genética , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Loci Gênicos/genética , Variação Genética/genética , Impressão Genômica/genética , Genótipo , Glucose/metabolismo , Glicogênio/biossíntese , Humanos , Insulina/metabolismo , Masculino , Fenótipo , Transdução de Sinais
17.
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
19.
JAMA ; 315(11): 1129-40, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26978208

RESUMO

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.


Assuntos
Peso ao Nascer/genética , Glicemia/genética , Índice de Massa Corporal , Jejum/sangue , Obesidade/genética , Adulto , Pressão Sanguínea/genética , Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Genótipo , Humanos , Recém-Nascido , Análise da Randomização Mendeliana , Obesidade/sangue , Obesidade/etnologia , Polimorfismo de Nucleotídeo Único , Gravidez , Triglicerídeos/genética
20.
Hum Mol Genet ; 25(2): 389-403, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26604143

RESUMO

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.


Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Humanos , Masculino , Risco , Adulto Jovem
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