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1.
Int J Epidemiol ; 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33221865

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI) are associated. However, it remains unclear whether this association reflects causal relationships in either direction or confounding. Here, we implemented genetically informed methods to examine bidirectional causality and potential confounding. METHODS: Three genetically informed methods were employed: (i) cross-lagged twin-differences analyses to assess bidirectional effects of ADHD symptoms and BMI at ages 8, 12, 14 and 16 years in 2386 pairs of monozygotic twins from the Twins Early Development Study (TEDS); (ii) within- and between-family ADHD and BMI polygenic score (PS) analyses in 3320 pairs of dizygotic TEDS twins; and (iii) two-sample bidirectional Mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) on ADHD (N = 55,374) and BMI (N = 806,834). RESULTS: Mixed results were obtained across the three methods. Twin-difference analyses provided little support for cross-lagged associations between ADHD symptoms and BMI over time. PS analyses were consistent with bidirectional relationships between ADHD and BMI, with plausible time-varying effects from childhood to adolescence. MR findings also suggested bidirectional causal effects between ADHD and BMI. Multivariable MR indicated the presence of substantial confounding in bidirectional relationships. CONCLUSIONS: The three methods converged to highlight multiple sources of confounding in the association between ADHD and BMI. PS and MR analyses suggested plausible causal relationships in both directions. Possible explanations for mixed causal findings across methods are discussed.

3.
Commun Biol ; 3(1): 679, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173067

RESUMO

A Correction to this paper has been published: https://doi.org/10.1038/s42003-020-01447-6 .

4.
BMJ Open Respir Res ; 7(1)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33239407

RESUMO

INTRODUCTION: Family history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown. METHODS: We assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses. RESULTS: In COPDGene, family history and PRS were significantly associated with COPD in a single model (PFamHx <0.0001; PPRS<0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs. CONCLUSION: Family history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.

5.
Nat Commun ; 11(1): 5976, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239696

RESUMO

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

6.
Commun Biol ; 3(1): 634, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33128006

RESUMO

Walking is a simple form of exercise, widely promoted for its health benefits. Self-reported walking pace has been associated with a range of cardiorespiratory and cancer outcomes, and is a strong predictor of mortality. Here we perform a genome-wide association study of self-reported walking pace in 450,967 European ancestry UK Biobank participants. We identify 70 independent associated loci (P < 5 × 10-8), 11 of which are novel. We estimate the SNP-based heritability as 13.2% (s.e. = 0.21%), reducing to 8.9% (s.e. = 0.17%) with adjustment for body mass index. Significant genetic correlations are observed with cardiometabolic, respiratory and psychiatric traits, educational attainment and all-cause mortality. Mendelian randomization analyses suggest a potential causal link of increasing walking pace with a lower cardiometabolic risk profile. Given its low heritability and simple measurement, these findings suggest that self-reported walking pace is a pragmatic target for interventions aiming for general benefits on health.

7.
Circulation ; 142(6): 546-555, 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32654539

RESUMO

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

8.
Lancet Respir Med ; 8(7): 696-708, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32649918

RESUMO

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. FUNDING: US National Institutes of Health, Wellcome Trust.


Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Fatores de Risco , Capacidade Vital
9.
Stat Methods Med Res ; 29(12): 3492-3510, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32594841

RESUMO

Risk prediction models have been developed in many contexts to classify individuals according to a single outcome, such as risk of a disease. Emerging "-omic" biomarkers provide panels of features that can simultaneously predict multiple outcomes from a single biological sample, creating issues of multiplicity reminiscent of exploratory hypothesis testing. Here I propose definitions of some basic criteria for evaluating prediction models of multiple outcomes. I define calibration in the multivariate setting and then distinguish between outcome-wise and individual-wise prediction, and within the latter between joint and panel-wise prediction. I give examples such as screening and early detection in which different senses of prediction may be more appropriate. In each case I propose definitions of sensitivity, specificity, concordance, positive and negative predictive value and relative utility. I link the definitions through a multivariate probit model, showing that the accuracy of a multivariate prediction model can be summarised by its covariance with a liability vector. I illustrate the concepts on a biomarker panel for early detection of eight cancers, and on polygenic risk scores for six common diseases.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32229610

RESUMO

Many exposures considered in Mendelian randomization (MR) studies are polygenic in that they are influenced by thousands of genetic variants. By using many single-nucleotide polymorphisms (SNPs) as instrumental variables, more variation in the exposure is explained, increasing the precision of MR. Furthermore, methods can be designed that relax the assumptions of MR, especially concerning direct pleiotropic effects on the outcome. This article reviews the concepts and assumptions underlying the commonly used polygenic MR methods. Using a polygenic score as an instrument is equivalent to a weighted mean of individual SNP results, and the other fundamental averages, median and mode, may also be used to estimate causal effects. Outlier detection is useful for identifying pleiotropic SNPs to be excluded from analysis. Bayesian approaches are available to incorporate prior beliefs about pleiotropy. These methods each entail different assumptions, and together provide a set of sensitivity analyses to help triangulate evidence about causality.

11.
Transl Psychiatry ; 10(1): 86, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152294

RESUMO

This study explores the degree to which genetic influences on psychotic experiences are stable across adolescence and adulthood, and their overlap with psychiatric disorders. Genome-wide association results were obtained for adolescent psychotic experiences and negative symptom traits (N = 6297-10,098), schizotypy (N = 3967-4057) and positive psychotic experiences in adulthood (N = 116,787-117,794), schizophrenia (N = 150,064), bipolar disorder (N = 41,653), and depression (N = 173,005). Linkage disequilibrium score regression was used to estimate genetic correlations. Implicated genes from functional and gene-based analyses were compared. Mendelian randomization was performed on trait pairs with significant genetic correlations. Results indicated that subclinical auditory and visual hallucinations and delusions of persecution during adulthood were significantly genetically correlated with schizophrenia (rg = 0.27-0.67) and major depression (rg = 0.41-96) after correction for multiple testing. Auditory and visual subclinical hallucinations were highly genetically correlated (rg = 0.95). Cross-age genetic correlations for psychotic experiences were not significant. Gene mapping and association analyses revealed 14 possible genes associated with psychotic experiences that overlapped across age for psychotic experiences or between psychotic experiences and psychiatric disorders. Mendelian randomization indicated bidirectional associations between auditory and visual hallucinations in adults but did not support causal relationships between psychotic experiences and psychiatric disorders. These findings indicate that psychotic experiences in adulthood may be more linked genetically to schizophrenia and major depression than psychotic experiences in adolescence. Our study implicated specific genes that are associated with psychotic experiences across development, as well as genes shared between psychotic experiences and psychiatric disorders.

12.
Genome Biol ; 21(1): 80, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216834

RESUMO

BACKGROUND: Osteoporosis is a complex disease with a strong genetic contribution. A recently published genome-wide association study (GWAS) for estimated bone mineral density (eBMD) identified 1103 independent genome-wide significant association signals. Most of these variants are non-coding, suggesting that regulatory effects may drive many of the associations. To identify genes with a role in osteoporosis, we integrate the eBMD GWAS association results with those from our previous osteoclast expression quantitative trait locus (eQTL) dataset. RESULTS: We identify sixty-nine significant cis-eQTL effects for eBMD GWAS variants after correction for multiple testing. We detect co-localisation of eBMD GWAS and osteoclast eQTL association signals for 21 of the 69 loci, implicating a number of genes including CCR5, ZBTB38, CPE, GNA12, RIPK3, IQGAP1 and FLCN. Summary-data-based Mendelian Randomisation analysis of the eBMD GWAS and osteoclast eQTL datasets identifies significant associations for 53 genes, with TULP4 presenting as a strong candidate for pleiotropic effects on eBMD and gene expression in osteoclasts. By performing analysis using the GARFIELD software, we demonstrate significant enrichment of osteoporosis risk variants among high-confidence osteoclast eQTL across multiple GWAS P value thresholds. Mice lacking one of the genes of interest, the apoptosis/necroptosis gene RIPK3, show disturbed bone micro-architecture and increased osteoclast number, highlighting a new biological pathway relevant to osteoporosis. CONCLUSION: We utilise a unique osteoclast eQTL dataset to identify a number of potential effector genes for osteoporosis risk variants, which will help focus functional studies in this area.

13.
Hum Mol Genet ; 29(8): 1388-1395, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32219344

RESUMO

BACKGROUND: There is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. METHODS: Using two baseline subsamples of UK Biobank: prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes. RESULTS: A 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P < 0.001]. CONCLUSIONS: Bias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research.

14.
PLoS One ; 15(1): e0228269, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995593

RESUMO

BACKGROUND: Dyslipidemia and abnormal glycemic traits are leading causes of morbidity and mortality. Although the association between the two traits is well established, there still exists a gap in the evidence for the direction of causality. OBJECTIVE: This study aimed to examine the direction of the causal relationship between lipids and glycemic traits in an Indian population using bidirectional Mendelian randomization (BMR). METHODS: The BMR analysis was conducted on 4900 individuals (2450 sib-pairs) from the Indian Migration Study. Instrument variables were generated for each lipid and glycemic trait (fasting insulin, fasting glucose, HOMA-IR, HOMA-ß, LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides) to examine the causal relationship by applying two-stage least squares (2SLS) regression in both directions. RESULTS: Lipid and glycemic traits were found to be associated observationally, however, results from 2SLS showed that only triglycerides, defined by weighted genetic risk score (wGRS) of 3 SNPs (rs662799 at APOAV, rs780094 at GCKR and rs4420638 at APOE/C1/C4), were observed to be causally effecting 1.15% variation in HOMA-IR (SE = 0.22, P = 0.010), 1.53% in HOMA- ß (SE = 0.21, P = 0.001) and 1.18% in fasting insulin (SE = 0.23, P = 0.009). No evidence for a causal effect was observed in the reverse direction or between any other lipid and glycemic traits. CONCLUSION: The study findings suggest that triglycerides may causally impact various glycemic traits. However, the findings need to be replicated in larger studies.


Assuntos
Glicemia/análise , Lipídeos/sangue , Característica Quantitativa Herdável , Adulto , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Transversais , Feminino , Técnicas de Genotipagem , Humanos , Índia , Insulina/sangue , Resistência à Insulina/genética , Análise dos Mínimos Quadrados , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue
15.
Hypertens Pregnancy ; 39(1): 56-63, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31910697

RESUMO

Objective: To determine whether family history of pre-eclampsia and cardiovascular disease is consistently associated with the occurrence of pre-eclampsia sub-phenotypes and fetal growth restriction (FGR).Material and Methods: We conducted a case-control study in which cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight Colombian cities between 2000 and 2012. Odds of pre-eclampsia among women with a positive family history of pre-eclampsia or cardiovascular disease were compared to women without affected relatives (logistic regression modeling and multinomial logistic regression model [Ajusted]).Results: A total of 3510 pre-eclampsia cases and 4512 controls with data on family history of pre-eclampsia were included in analyses. A subsample of 3086 cases and 3888 controls also provided information on family history of cardiovascular disease. Women whose mothers had pre-eclampsia had 3.38 (95% CI 2.89, 3.96) higher odds than those who did not, and having an affected sister increased pre-eclampsia odds by 2.43 (95% CI 2.02, 2.93). The effect of having both mother and sister affected with pre-eclampsia was stronger than the two independent risk factors (OR 4.17 [95% CI 2.60, 6.69]). Women with parental history of cardiovascular disease also had an increased risk of pre-eclampsia (OR 1.58 [95% CI 1.24, 2.01]).Conclusions: Family history of pre-eclampsia increased the risk of PE. The impact of family history of cardiovascular disease on pre-eclampsia was more conservative, but serves to support the hypothesis that pre-eclampsia may reflect the premature exposure of underlying cardiovascular dysfunction, precipitated by the stress test of pregnancy.


Assuntos
Doenças Cardiovasculares/etiologia , Interação Gene-Ambiente , Hereditariedade , Anamnese , Pré-Eclâmpsia/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Pré-Eclâmpsia/diagnóstico , Gravidez , Fatores de Risco , Adulto Jovem
16.
Eur J Vasc Endovasc Surg ; 59(1): 92-97, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31680049

RESUMO

OBJECTIVE: A recently published genome wide association study of abdominal aortic aneurysms (AAA), based on pooled case control data of European ancestry, identified four new loci for AAA: SMYD2 (top single nucleotide polymorphism [SNP] rs1795061), LINC00540 (rs9316871), PCIF1/MMP9/ZNF335 (rs3827066), and ERG (rs2836411). Of the four, rs1795061 and rs2836411 showed significant heterogeneity across studies and the p value for rs9316871 did not reach the genome wide significance threshold until discovery and replication data were pooled together in that study. The objective of this study was to replicate these newly identified genetic associations for AAA in a US based prospective cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, and a Greece based case control study. METHODS: ARIC identified 408 clinically diagnosed AAAs among 8 962 individuals of European ancestry during a median of 22 years of follow up. The Greek case control study included 341 AAAs of European ancestry recruited in a tertiary referral centre and 292 geographically and ethnically matched controls recruited from the same institution. A Cox proportional hazards model was used to analyse the ARIC data and logistic regression to analyse the Greek data. RESULTS: In ARIC, rs9316871 and rs3827066 were significantly associated with AAA risk (HR [p] was 0.77 [.004] and 1.22 [.03], respectively), rs2836411 was associated at borderline significance (1.13 [.08]), whereas rs1795061 was not associated (p = .55). In the Greek case control study, rs1795061 and rs2836411 were significantly associated with AAA (OR [p] was 1.66 [< .001] and 1.29 [.04], respectively), whereas rs9316871 was not (p = .81). Genotyping of rs3827066 did not succeed. In the meta-analysis of the two studies, the association for rs9316871and rs2836411 was statistically significant and consistent between the two studies: p = .02 and .007, respectively. CONCLUSIONS: Associations between rs9316871and rs2836411 and AAA risk were replicated in the meta-analysis of the two independent cohorts, providing further support for the importance of these loci in the aetiology of AAA.


Assuntos
Aneurisma da Aorta Abdominal/genética , Predisposição Genética para Doença , RNA Longo não Codificante/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Aneurisma da Aorta Abdominal/epidemiologia , Proteínas de Ligação a DNA/genética , Grécia/epidemiologia , Histona-Lisina N-Metiltransferase/genética , Humanos , Metaloproteinase 9 da Matriz/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores de Transcrição/genética , Regulador Transcricional ERG/genética , Estados Unidos/epidemiologia
17.
Eur J Prev Cardiol ; : 2047487319885041, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31711304

RESUMO

AIMS: Brisk walking and a greater muscle strength have been associated with a longer life; whether these associations are influenced by other lifestyle behaviours, however, is less well known. METHODS: Information on usual walking pace (self-defined as slow, steady/average, or brisk), dynamometer-assessed handgrip strength, lifestyle behaviours (physical activity, TV viewing, diet, alcohol intake, sleep and smoking) and body mass index was collected at baseline in 450,888 UK Biobank study participants. We estimated 10-year standardised survival for individual and combined lifestyle behaviours and body mass index across levels of walking pace and handgrip strength. RESULTS: Over a median follow-up of 7.0 years, 3808 (1.6%) deaths in women and 6783 (3.2%) in men occurred. Brisk walkers had a survival advantage over slow walkers, irrespective of the degree of engagement in other lifestyle behaviours, except for smoking. Estimated 10-year survival was higher in brisk walkers who otherwise engaged in an unhealthy lifestyle compared to slow walkers who engaged in an otherwise healthy lifestyle: 97.1% (95% confidence interval: 96.9-97.3) vs 95.0% (94.6-95.4) in women; 94.8% (94.7-95.0) vs 93.7% (93.3-94.2) in men. Body mass index modified the association between walking pace and survival in men, with the largest survival benefits of brisk walking observed in underweight participants. Compared to walking pace, for handgrip strength there was more overlap in 10-year survival across lifestyle behaviours. CONCLUSION: Except for smoking, brisk walkers with an otherwise unhealthy lifestyle have a lower mortality risk than slow walkers with an otherwise healthy lifestyle.

18.
Mol Autism ; 10: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31719968

RESUMO

Background: A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Methods: Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis. Results: In the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation. Limitations: Identical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis. Conclusions: Using a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals.


Assuntos
Transtorno Autístico/sangue , Transtorno Autístico/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Análise de Sequência de RNA , Transcrição Genética , Gêmeos Monozigóticos/genética , Transtorno Autístico/genética , Estudos de Casos e Controles , Análise por Conglomerados , Metilação de DNA/genética , Feminino , Humanos , Masculino
19.
PLoS One ; 14(9): e0222362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31545794

RESUMO

Methods have been developed for Mendelian randomization that can obtain consistent causal estimates under weaker assumptions than the standard instrumental variable assumptions. The median-based estimator and MR-Egger are examples of such methods. However, these methods can be sensitive to genetic variants with heterogeneous causal estimates. Such heterogeneity may arise from over-dispersion in the causal estimates, or specific variants with outlying causal estimates. In this paper, we develop three extensions to robust methods for Mendelian randomization with summarized data: 1) robust regression (MM-estimation); 2) penalized weights; and 3) Lasso penalization. Methods using these approaches are considered in two applied examples: one where there is evidence of over-dispersion in the causal estimates (the causal effect of body mass index on schizophrenia risk), and the other containing outliers (the causal effect of low-density lipoprotein cholesterol on Alzheimer's disease risk). Through an extensive simulation study, we demonstrate that robust regression applied to the inverse-variance weighted method with penalized weights is a worthwhile additional sensitivity analysis for Mendelian randomization to provide robustness to variants with outlying causal estimates. The results from the applied examples and simulation study highlight the importance of using methods that make different assumptions to assess the robustness of findings from Mendelian randomization investigations with multiple genetic variants.


Assuntos
Causalidade , Análise da Randomização Mendeliana , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Índice de Massa Corporal , LDL-Colesterol/sangue , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Modelos Estatísticos , Análise de Regressão , Fatores de Risco , Esquizofrenia/etiologia , Esquizofrenia/genética
20.
Genet Epidemiol ; 43(7): 730-741, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31328830

RESUMO

The heritability of most complex traits is driven by variants throughout the genome. Consequently, polygenic risk scores, which combine information on multiple variants genome-wide, have demonstrated improved accuracy in genetic risk prediction. We present a new two-step approach to constructing genome-wide polygenic risk scores from meta-GWAS summary statistics. Local linkage disequilibrium (LD) is adjusted for in Step 1, followed by, uniquely, long-range LD in Step 2. Our algorithm is highly parallelizable since block-wise analyses in Step 1 can be distributed across a high-performance computing cluster, and flexible, since sparsity and heritability are estimated within each block. Inference is obtained through a formal Bayesian variable selection framework, meaning final risk predictions are averaged over competing models. We compared our method to two alternative approaches: LDPred and lassosum using all seven traits in the Welcome Trust Case Control Consortium as well as meta-GWAS summaries for type 1 diabetes (T1D), coronary artery disease, and schizophrenia. Performance was generally similar across methods, although our framework provided more accurate predictions for T1D, for which there are multiple heterogeneous signals in regions of both short- and long-range LD. With sufficient compute resources, our method also allows the fastest runtimes.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Área Sob a Curva , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 1/genética , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Curva ROC , Fatores de Risco , Esquizofrenia/genética
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