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1.
Artigo em Inglês | MEDLINE | ID: mdl-34856637

RESUMO

BACKGROUND: Joint developmental trajectories of internalizing and externalizing problems show considerable heterogeneity; however, this can be parsed into a small number of meaningful subgroups. Doing so offered insights into risk factors that lead to different patterns of internalizing/externalizing trajectories. However, despite both domains of problems showing strong heritability, no study has yet considered genetic risks as predictors of joint internalizing/externalizing problem trajectories. METHODS: Using parallel process latent class growth analysis, we estimated joint developmental trajectories of internalizing and externalizing difficulties assessed across ages 4 to 16 using the Strengths and Difficulties Questionnaire. Multinomial logistic regression was used to evaluate a range of demographic, perinatal, maternal mental health, and child and maternal polygenic predictors of group membership. Participants included 11,049 children taking part in the Avon Longitudinal Study of Parents and Children. Polygenic data were available for 7,127 children and 6,836 mothers. RESULTS: A 5-class model was judged optimal: Unaffected, Moderate Externalizing Symptoms, High Externalizing Symptoms, Moderate Internalizing and Externalizing Symptoms and High Internalizing and Externalizing Symptoms. Male sex, lower maternal age, maternal mental health problems, maternal smoking during pregnancy, higher child polygenic risk scores for ADHD and lower polygenic scores for IQ distinguished affected classes from the unaffected class. CONCLUSIONS: While affected classes could be relatively well separated from the unaffected class, phenotypic and polygenic predictors were limited in their ability to distinguish between different affected classes. Results thus add to existing evidence that internalizing and externalizing problems have mostly shared risk factors.

2.
Nat Commun ; 12(1): 7173, 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887389

RESUMO

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

3.
Nat Commun ; 12(1): 7174, 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887417

RESUMO

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

4.
PLoS Genet ; 17(11): e1009883, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34735433

RESUMO

Spousal comparisons have been proposed as a design that can both reduce confounding and estimate effects of the shared adulthood environment. However, assortative mating, the process by which individuals select phenotypically (dis)similar mates, could distort associations when comparing spouses. We evaluated the use of spousal comparisons, as in the within-spouse pair (WSP) model, for aetiological research such as genetic association studies. We demonstrated that the WSP model can reduce confounding but may be susceptible to collider bias arising from conditioning on assorted spouse pairs. Analyses using UK Biobank spouse pairs found that WSP genetic association estimates were smaller than estimates from random pairs for height, educational attainment, and BMI variants. Within-sibling pair estimates, robust to demographic and parental effects, were also smaller than random pair estimates for height and educational attainment, but not for BMI. WSP models, like other within-family models, may reduce confounding from demographic factors in genetic association estimates, and so could be useful for triangulating evidence across study designs to assess the robustness of findings. However, WSP estimates should be interpreted with caution due to potential collider bias.

5.
Front Immunol ; 12: 727457, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804013

RESUMO

The burden of infections on an individual and public health is profound. Many observational studies have shown a link between infections and the pathogenesis of disease; however a greater understanding of the role of host genetics is essential. Children from the longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children, had 14 antibodies measured in plasma at age 7: Alpha-casein protein, beta-casein protein, cytomegalovirus, Epstein-Barr virus, feline herpes virus, Helicobacter pylori, herpes simplex virus 1, influenza virus subtype H1N1, influenza virus subtype H3N2, measles virus, Saccharomyces cerevisiae, Theiler's virus, Toxoplasma gondii, and SAG1 protein domain, a surface antigen of Toxoplasma gondii measured for greater precision. We performed genome-wide association analyses of antibody levels against these 14 infections (N = 357 - 5010) and identified three genome-wide signals (P < 5×10-8), two associated with measles virus antibodies and one with Toxoplasma gondii antibodies. In an association analysis focused on the human leukocyte antigen (HLA) region of the genome, we further detected 15 HLA alleles at a two-digit resolution and 23 HLA alleles at a four-digit resolution associated with five antibodies, with eight HLA alleles associated with Epstein-Barr virus antibodies showing strong evidence of replication in UK Biobank. We discuss how our findings from antibody levels complement other studies using self-reported phenotypes in understanding the architecture of host genetics related to infections.


Assuntos
Infecções Bacterianas/genética , Toxoplasmose/genética , Viroses/genética , Adolescente , Anticorpos Antibacterianos/sangue , Anticorpos Antiprotozoários/sangue , Anticorpos Antivirais/sangue , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Bactérias/imunologia , Infecções Bacterianas/sangue , Infecções Bacterianas/imunologia , Caseínas/genética , Caseínas/imunologia , Criança , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Estudos Longitudinais , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Toxoplasma/imunologia , Toxoplasmose/sangue , Toxoplasmose/imunologia , Viroses/sangue , Viroses/imunologia , Vírus/imunologia
6.
Nat Genet ; 53(9): 1311-1321, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34493871

RESUMO

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.


Assuntos
Metilação de DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Mapeamento Cromossômico , Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Transcriptoma/genética
7.
Nat Commun ; 12(1): 5618, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34584077

RESUMO

Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin.


Assuntos
Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Locos de Características Quantitativas/genética , Gemelaridade Monozigótica/genética , Gêmeos Monozigóticos/genética , Adulto , Finlândia , Genótipo , Humanos , Pessoa de Meia-Idade , Países Baixos , Polimorfismo de Nucleotídeo Único , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Reino Unido , Adulto Jovem
8.
Nat Genet ; 53(9): 1300-1310, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34475573

RESUMO

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.


Assuntos
Proteínas Sanguíneas/genética , Regulação da Expressão Gênica/genética , Locos de Características Quantitativas/genética , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética
11.
Nat Commun ; 12(1): 5017, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404780

RESUMO

Controlling COVID-19 transmission in universities poses challenges due to the complex social networks and potential for asymptomatic spread. We developed a stochastic transmission model based on realistic mixing patterns and evaluated alternative mitigation strategies. We predict, for plausible model parameters, that if asymptomatic cases are half as infectious as symptomatic cases, then 15% (98% Prediction Interval: 6-35%) of students could be infected during the first term without additional control measures. First year students are the main drivers of transmission with the highest infection rates, largely due to communal residences. In isolation, reducing face-to-face teaching is the most effective intervention considered, however layering multiple interventions could reduce infection rates by 75%. Fortnightly or more frequent mass testing is required to impact transmission and was not the most effective option considered. Our findings suggest that additional outbreak control measures should be considered for university settings.


Assuntos
COVID-19/epidemiologia , COVID-19/transmissão , Universidades , Surtos de Doenças/prevenção & controle , Humanos , Modelos Biológicos , SARS-CoV-2/isolamento & purificação , Estudantes , Inquéritos e Questionários , Reino Unido/epidemiologia
12.
BMC Pulm Med ; 21(1): 246, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294062

RESUMO

BACKGROUND: Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR). METHODS: Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates. RESULTS: We found only weak evidence that reduced lung function (Beta - 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (- 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV1 and FVC do cause lower cognitive function, but that after conditioning for height (- 0.03 (0.03), p-value 0.29 and - 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (- 0.03 (0.03) p-value 0.33 and - 0.01 (0.02), p-value 0.35) the evidence became weak. CONCLUSION: We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.


Assuntos
Cognição/fisiologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/psicologia , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Fatores de Risco
13.
Sci Rep ; 11(1): 11728, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083593

RESUMO

University students have unique living, learning and social arrangements which may have implications for infectious disease transmission. To address this data gap, we created CONQUEST (COroNavirus QUESTionnaire), a longitudinal online survey of contacts, behaviour, and COVID-19 symptoms for University of Bristol (UoB) staff/students. Here, we analyse results from 740 students providing 1261 unique records from the start of the 2020/2021 academic year (14/09/2020-01/11/2020), where COVID-19 outbreaks led to the self-isolation of all students in some halls of residences. Although most students reported lower daily contacts than in pre-COVID-19 studies, there was heterogeneity, with some reporting many (median = 2, mean = 6.1, standard deviation = 15.0; 8% had ≥ 20 contacts). Around 40% of students' contacts were with individuals external to the university, indicating potential for transmission to non-students/staff. Only 61% of those reporting cardinal symptoms in the past week self-isolated, although 99% with a positive COVID-19 test during the 2 weeks before survey completion had self-isolated within the last week. Some students who self-isolated had many contacts (mean = 4.3, standard deviation = 10.6). Our results provide context to the COVID-19 outbreaks seen in universities and are available for modelling future outbreaks and informing policy.


Assuntos
COVID-19/etiologia , COVID-19/psicologia , Quarentena/estatística & dados numéricos , Estudantes/psicologia , Universidades , Adulto , Idoso , COVID-19/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Quarentena/psicologia , Análise de Regressão , Isolamento Social , Estudantes/estatística & dados numéricos , Inquéritos e Questionários , Reino Unido , Adulto Jovem
14.
PLoS Genet ; 17(6): e1009575, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34157017

RESUMO

Over a decade of genome-wide association studies (GWAS) have led to the finding of extreme polygenicity of complex traits. The phenomenon that "all genes affect every complex trait" complicates Mendelian Randomization (MR) studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing MR methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using GWAS summary statistics, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, determine the causal direction and perform multivariable MR to adjust for confounding risk factors. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and potential pleiotropic pathways involved.


Assuntos
Causalidade , Fenótipo , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
15.
Genome Biol ; 22(1): 194, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187551

RESUMO

BACKGROUND: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. RESULTS: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. CONCLUSION: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

16.
BMC Psychiatry ; 21(1): 207, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892675

RESUMO

BACKGROUND: Empirical evidence supporting the distinction between suicide attempt (SA) and non-suicidal self-harm (NSSH) is lacking. Although NSSH is a risk factor for SA, we do not currently know whether these behaviours lie on a continuum of severity, or whether they are discrete outcomes with different aetiologies. We conducted this exploratory genetic epidemiology study to investigate this issue further. METHODS: We explored the extent of genetic overlap between NSSH and SA in a large, richly-phenotyped cohort (the Avon Longitudinal Study of Parents and Children; N = 4959), utilising individual-level genetic and phenotypic data to conduct analyses of genome-wide complex traits and polygenic risk scores (PRS). RESULTS: The single nucleotide polymorphism heritability of NSSH was estimated to be 13% (SE 0.07) and that of SA to be 0% (SE 0.07). Of the traits investigated, NSSH was most strongly correlated with higher IQ (rG = 0.31, SE = 0.22), there was little evidence of high genetic correlation between NSSH and SA (rG = - 0.1, SE = 0.54), likely due to the low heritability estimate for SA. The PRS for depression differentiated between those with NSSH and SA in multinomial regression. The optimal PRS prediction model for SA (Nagelkerke R2 0.022, p < 0.001) included ADHD, depression, income, anorexia and neuroticism and explained more variance than the optimal prediction model for NSSH (Nagelkerke R2 0.010, p < 0.001) which included ADHD, alcohol consumption, autism spectrum conditions, depression, IQ, neuroticism and suicide attempt. CONCLUSIONS: Our findings suggest that SA does not have a large genetic component, and that although NSSH and SA are not discrete outcomes there appears to be little genetic overlap between the two. The relatively small sample size and resulting low heritability estimate for SA was a limitation of the study. Combined with low heritability estimates, this implies that family or population structures in SA GWASs may contribute to signals detected.


Assuntos
Comportamento Autodestrutivo , Tentativa de Suicídio , Criança , Humanos , Estudos Longitudinais , Epidemiologia Molecular , Fatores de Risco , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/genética , Ideação Suicida
17.
Sci Adv ; 7(11)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33692100

RESUMO

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.

19.
Int J Epidemiol ; 50(4): 1350-1361, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-33570130

RESUMO

A key assumption of Mendelian randomization (MR) analysis is that there is no association between the genetic variants used as instruments and the outcome other than through the exposure of interest. One way in which this assumption can be violated is through population stratification, which can introduce confounding of the relationship between the genetic variants and the outcome and so induce an association between them. Negative control outcomes are increasingly used to detect unobserved confounding in observational epidemiological studies. Here we consider the use of negative control outcomes in MR studies to detect confounding of the genetic variants and the exposure or outcome. As a negative control outcome in an MR study, we propose the use of phenotypes which are determined before the exposure and outcome but which are likely to be subject to the same confounding as the exposure or outcome of interest. We illustrate our method with a two-sample MR analysis of a preselected set of exposures on self-reported tanning ability and hair colour. Our results show that, of the 33 exposures considered, genome-wide association studies (GWAS) of adiposity and education-related traits are likely to be subject to population stratification that is not controlled for through adjustment, and so any MR study including these traits may be subject to bias that cannot be identified through standard pleiotropy robust methods. Negative control outcomes should therefore be used regularly in MR studies to detect potential population stratification in the data used.


Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Adiposidade , Viés , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
20.
Genome Biol ; 22(1): 32, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441155

RESUMO

GWAS summary statistics are fundamental for a variety of research applications yet no common storage format has been widely adopted. Existing tabular formats ambiguously or incompletely store information about genetic variants and associations, lack essential metadata and are typically not indexed yielding poor query performance and increasing the possibility of errors in data interpretation and post-GWAS analyses. To address these issues, we adapted the variant call format to store GWAS summary statistics (GWAS-VCF) and developed open-source tools to use this format in downstream analyses. We provide open access to over 10,000 complete GWAS summary datasets converted to this format ( https://gwas.mrcieu.ac.uk ).


Assuntos
Bases de Dados Genéticas , Estudo de Associação Genômica Ampla/métodos , Genômica , Humanos , Software
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