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1.
PLoS Med ; 16(10): e1002937, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626644

RESUMO

BACKGROUND: The role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance. METHODS AND FINDINGS: A phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization. CONCLUSION: In this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.

2.
Int J Epidemiol ; 48(5): 1425-1434, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518429

RESUMO

BACKGROUND: Vitamin D deficiency is highly prevalent across the globe. Existing studies suggest that a low vitamin D level is associated with more than 130 outcomes. Exploring the causal role of vitamin D in health outcomes could support or question vitamin D supplementation. METHODS: We carried out a systematic literature review of previous Mendelian-randomization studies on vitamin D. We then implemented a Mendelian Randomization-Phenome Wide Association Study (MR-PheWAS) analysis on data from 339 256 individuals of White British origin from UK Biobank. We first ran a PheWAS analysis to test the associations between a 25(OH)D polygenic risk score and 920 disease outcomes, and then nine phenotypes (i.e. systolic blood pressure, diastolic blood pressure, risk of hypertension, T2D, ischaemic heart disease, body mass index, depression, non-vertebral fracture and all-cause mortality) that met the pre-defined inclusion criteria for further analysis were examined by multiple MR analytical approaches to explore causality. RESULTS: The PheWAS analysis did not identify any health outcome associated with the 25(OH)D polygenic risk score. Although a selection of nine outcomes were reported in previous Mendelian-randomization studies or umbrella reviews to be associated with vitamin D, our MR analysis, with substantial study power (>80% power to detect an association with an odds ratio >1.2 for per standard deviation increase of log-transformed 25[OH]D), was unable to support an interpretation of causal association. CONCLUSIONS: We investigated the putative causal effects of vitamin D on multiple health outcomes in a White population. We did not support a causal effect on any of the disease outcomes tested. However, we cannot exclude small causal effects or effects on outcomes that we did not have enough power to explore due to the small number of cases.

3.
J Am Soc Nephrol ; 30(10): 2000-2016, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31537649

RESUMO

BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

4.
BMC Med ; 17(1): 165, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31438962

RESUMO

BACKGROUND: The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. METHODS: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. RESULTS: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. CONCLUSIONS: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence.

5.
Ann Rheum Dis ; 78(8): 1055-1061, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31036624

RESUMO

OBJECTIVES: We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response. METHODS: We studied the relation of TNFi response, quantified by change in swollen joint counts ( Δ SJC) and erythrocyte sedimentation rate ( Δ ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation. RESULTS: We detected a statistically significant association between Δ SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between Δ SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance. CONCLUSIONS: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30824919

RESUMO

OBJECTIVES: Imaging of joint inflammation provides a standard against which to derive an updated DAS for RA. Our objectives were to develop and validate a DAS based on reweighting the DAS28 components to maximize association with US-assessed synovitis. METHODS: Early RA patients from two observational cohorts (n = 434 and n = 117) and a clinical trial (n = 59) were assessed at intervals up to 104 weeks from baseline; all US scans were within 1 week of clinical exam. There were 899, 163 and 183 visits in each cohort. Associations of combined US grey scale and power Doppler scores (GSPD) with 28 tender joint count and 28 swollen joint count (SJC28), CRP, ESR and general health visual analogue scale were examined in linear mixed model regressions. Cross-validation evaluated model predictive ability. Coefficients learned from training data defined a re-weighted DAS28 that was validated against radiographic progression in independent data (3037 observations; 717 patients). RESULTS: Of the conventional DAS28 components only SJC28 and CRP were associated with GSPD in all three development cohorts. A two-component model including SJC28 and CRP outperformed a four-component model (R2 = 0.235, 0.392, 0.380 vs 0.232, 0.380, 0.375, respectively). The re-weighted two-component DAS28CRP outperformed conventional DAS28 definitions in predicting GSPD (Δtest log-likelihood <-2.6, P < 0.01), Larsen score and presence of erosions. CONCLUSION: A score based on SJC28 and CRP alone demonstrated stronger associations with synovitis and radiographic progression than the original DAS28 and should be considered in research on pathophysiological manifestations of early RA. Implications for clinical management of RA remain to be established.

7.
Genet Epidemiol ; 42(8): 754-771, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30311271

RESUMO

Although a number of treatments are available for rheumatoid arthritis (RA), each of them shows a significant nonresponse rate in patients. Therefore, predicting a priori the likelihood of treatment response would be of great patient benefit. Here, we conducted a comparison of a variety of statistical methods for predicting three measures of treatment response, between baseline and 3 or 6 months, using genome-wide SNP data from RA patients available from the MAximising Therapeutic Utility in Rheumatoid Arthritis (MATURA) consortium. Two different treatments and 11 different statistical methods were evaluated. We used 10-fold cross validation to assess predictive performance, with nested 10-fold cross validation used to tune the model hyperparameters when required. Overall, we found that SNPs added very little prediction information to that obtained using clinical characteristics only, such as baseline trait value. This observation can be explained by the lack of strong genetic effects and the relatively small sample sizes available; in analysis of simulated and real data, with larger effects and/or larger sample sizes, prediction performance was much improved. Overall, methods that were consistent with the genetic architecture of the trait were able to achieve better predictive ability than methods that were not. For treatment response in RA, methods that assumed a complex underlying genetic architecture achieved slightly better prediction performance than methods that assumed a simplified genetic architecture.

8.
Pharmacogenomics J ; 18(5): 657-664, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30166627

RESUMO

Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 × 10-9). Capture Hi-C data show chromatin interactions in GM12878 cells between rs2540767, in high linkage disequilibrium with rs7195994 (R2 = 0.9) and IRX3, a neighbouring gene of FTO. IRX3 encodes a transcription factor involved in adipocyte remodelling and is regarded as the obesity gene at the FTO locus. Importantly, the rs7195994 association remained significantly associated following adjustment for BMI. In addition, using capture Hi-C data we showed interactions between TNFi-response associated variants and 16 RA susceptibility variants.

9.
BMC Med ; 16(1): 142, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30103784

RESUMO

BACKGROUND: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. METHODS: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. RESULTS: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10- 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P = 0.48). CONCLUSIONS: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.


Assuntos
Neoplasias Colorretais/etiologia , Análise da Randomização Mendeliana/métodos , Vitamina D/análogos & derivados , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitamina D/efeitos adversos
11.
Nat Commun ; 9(1): 2536, 2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959320

RESUMO

We have been alerted that in our recent Article the calculations used to transform the heritability from the observed scale to the liability scale did not take into account the individuals in category 2 of the baldness scale, who were removed in our original analysis. This led to an overestimation of the heritability on the liability scale, which should have been 0.62 instead of 0.94. Moreover, in the Title and in the Abstract, we report that we can explain 38% of the risk, while in fact that is the proportion of heritability explained by the loci we discovered. These errors do not substantially change the paper or its conclusions apart from the statement MBP is therefore probably one of the most heritable complex traits. Genome-wide significant associations and pathway analyses are not affected in any way and male-pattern baldness remains less genetically complex than other complex traits. We wish to thank Yap et al. for bringing this to our attention.

12.
Pharmacogenomics J ; 18(4): 528-538, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29795407

RESUMO

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10-7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

13.
Ann Rheum Dis ; 77(7): 1039-1047, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29437585

RESUMO

OBJECTIVES: We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank. METHODS: We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage. RESULTS: Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus (ATXN2/S2HB3) that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy. CONCLUSIONS: Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases.

14.
Nat Commun ; 8(1): 1584, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29146897

RESUMO

Male pattern baldness (MPB) or androgenetic alopecia is one of the most common conditions affecting men, reaching a prevalence of ~50% by the age of 50; however, the known genes explain little of the heritability. Here, we present the results of a genome-wide association study including more than 70,000 men, identifying 71 independently replicated loci, of which 30 are novel. These loci explain 38% of the risk, suggesting that MPB is less genetically complex than other complex traits. We show that many of these loci contain genes that are relevant to the pathology and highlight pathways and functions underlying baldness. Finally, despite only showing genome-wide genetic correlation with height, pathway-specific genetic correlations are significant for traits including lifespan and cancer. Our study not only greatly increases the number of MPB loci, illuminating the genetic architecture, but also provides a new approach to disentangling the shared biological pathways underlying complex diseases.


Assuntos
Alopecia/epidemiologia , Alopecia/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Risco , Inquéritos e Questionários
15.
Genetics ; 206(1): 91-104, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28348060

RESUMO

We address the task of genotype imputation to a dense reference panel given genotype likelihoods computed from ultralow coverage sequencing as inputs. In this setting, the data have a high-level of missingness or uncertainty, and are thus more amenable to a probabilistic representation. Most existing imputation algorithms are not well suited for this situation, as they rely on prephasing for computational efficiency, and, without definite genotype calls, the prephasing task becomes computationally expensive. We describe GeneImp, a program for genotype imputation that does not require prephasing and is computationally tractable for whole-genome imputation. GeneImp does not explicitly model recombination, instead it capitalizes on the existence of large reference panels-comprising thousands of reference haplotypes-and assumes that the reference haplotypes can adequately represent the target haplotypes over short regions unaltered. We validate GeneImp based on data from ultralow coverage sequencing (0.5×), and compare its performance to the most recent version of BEAGLE that can perform this task. We show that GeneImp achieves imputation quality very close to that of BEAGLE, using one to two orders of magnitude less time, without an increase in memory complexity. Therefore, GeneImp is the first practical choice for whole-genome imputation to a dense reference panel when prephasing cannot be applied, for instance, in datasets produced via ultralow coverage sequencing. A related future application for GeneImp is whole-genome imputation based on the off-target reads from deep whole-exome sequencing.


Assuntos
Biologia Computacional , Genoma Humano , Genótipo , Software , Algoritmos , Frequência do Gene , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA
16.
Hum Mol Genet ; 24(14): 4167-82, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25918167

RESUMO

We explore the prediction of individuals' phenotypes for complex traits using genomic data. We compare several widely used prediction models, including Ridge Regression, LASSO and Elastic Nets estimated from cohort data, and polygenic risk scores constructed using published summary statistics from genome-wide association meta-analyses (GWAMA). We evaluate the interplay between relatedness, trait architecture and optimal marker density, by predicting height, body mass index (BMI) and high-density lipoprotein level (HDL) in two data cohorts, originating from Croatia and Scotland. We empirically demonstrate that dense models are better when all genetic effects are small (height and BMI) and target individuals are related to the training samples, while sparse models predict better in unrelated individuals and when some effects have moderate size (HDL). For HDL sparse models achieved good across-cohort prediction, performing similarly to the GWAMA risk score and to models trained within the same cohort, which indicates that, for predicting traits with moderately sized effects, large sample sizes and familial structure become less important, though still potentially useful. Finally, we propose a novel ensemble of whole-genome predictors with GWAMA risk scores and demonstrate that the resulting meta-model achieves higher prediction accuracy than either model on its own. We conclude that although current genomic predictors are not accurate enough for diagnostic purposes, performance can be improved without requiring access to large-scale individual-level data. Our methodologically simple meta-model is a means of performing predictive meta-analysis for optimizing genomic predictions and can be easily extended to incorporate multiple population-level summary statistics or other domain knowledge.


Assuntos
Genômica/métodos , Modelos Genéticos , Fenótipo , Índice de Massa Corporal , Estudos de Coortes , Croácia , Bases de Dados Genéticas , Pesquisa Empírica , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lipoproteínas HDL/sangue , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Tamanho da Amostra , Escócia
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