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1.
Nat Genet ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

2.
Philos Trans R Soc Lond B Biol Sci ; 374(1787): 20190026, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31630655

RESUMO

Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme-colour synaesthesia (n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index (R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.

3.
Proc Natl Acad Sci U S A ; 116(38): 19064-19070, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31481615

RESUMO

Britain and Ireland are known to show population genetic structure; however, large swathes of Scotland, in particular, have yet to be described. Delineating the structure and ancestry of these populations will allow variant discovery efforts to focus efficiently on areas not represented in existing cohorts. Thus, we assembled genotype data for 2,554 individuals from across the entire archipelago with geographically restricted ancestry, and performed population structure analyses and comparisons to ancient DNA. Extensive geographic structuring is revealed, from broad scales such as a NE to SW divide in mainland Scotland, through to the finest scale observed to date: across 3 km in the Northern Isles. Many genetic boundaries are consistent with Dark Age kingdoms of Gaels, Picts, Britons, and Norse. Populations in the Hebrides, the Highlands, Argyll, Donegal, and the Isle of Man show characteristics of isolation. We document a pole of Norwegian ancestry in the north of the archipelago (reaching 23 to 28% in Shetland) which complements previously described poles of Germanic ancestry in the east, and "Celtic" to the west. This modern genetic structure suggests a northwestern British or Irish source population for the ancient Gaels that contributed to the founding of Iceland. As rarer variants, often with larger effect sizes, become the focus of complex trait genetics, more diverse rural cohorts may be required to optimize discoveries in British and Irish populations and their considerable global diaspora.

4.
Int J Epidemiol ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263887

RESUMO

BACKGROUND: People who opt to participate in scientific studies tend to be healthier, wealthier and more educated than the broader population. Although selection bias does not always pose a problem for analysing the relationships between exposures and diseases or other outcomes, it can lead to biased effect size estimates. Biased estimates may weaken the utility of genetic findings because the goal is often to make inferences in a new sample (such as in polygenic risk score analysis). METHODS: We used data from UK Biobank, Generation Scotland and Partners Biobank and conducted phenotypic and genome-wide association analyses on two phenotypes that reflected mental health data availability: (i) whether participants were contactable by e-mail for follow-up; and (ii) whether participants responded to follow-up surveys of mental health. RESULTS: In UK Biobank, we identified nine genetic loci associated (P <5 × 10-8) with e-mail contact and 25 loci associated with mental health survey completion. Both phenotypes were positively genetically correlated with higher educational attainment and better health and negatively genetically correlated with psychological distress and schizophrenia. One single nucleotide polymorphism association replicated along with the overall direction of effect of all association results. CONCLUSIONS: Re-contact availability and follow-up participation can act as further genetic filters for data on mental health phenotypes.

5.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
6.
Nat Commun ; 10(1): 2373, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147538

RESUMO

We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance.


Assuntos
Deficiências do Desenvolvimento/genética , Testes Genéticos , Genoma Humano , Sequenciamento Completo do Exoma , Alelos , Genótipo , Humanos , Técnicas de Diagnóstico Molecular , Mutação , Fenótipo , Análise de Sequência de DNA , Sequenciamento Completo do Genoma
7.
Nat Commun ; 10(1): 2154, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089142

RESUMO

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.


Assuntos
Neoplasias Colorretais/genética , Loci Gênicos , Predisposição Genética para Doença , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Conjuntos de Dados como Assunto , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Nat Commun ; 10(1): 2069, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043600

RESUMO

In the original version of this Article, the legend in the upper panel of Figure 2 incorrectly read 'paternal imprinting' and should have read 'maternal imprinting'. This has been corrected in both the PDF and HTML versions of the Article.

9.
Circulation ; 139(24): 2754-2764, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31014085

RESUMO

BACKGROUND: There is great interest in widening the use of high-sensitivity cardiac troponins for population cardiovascular disease (CVD) and heart failure screening. However, it is not clear whether cardiac troponin T (cTnT) and troponin I (cTnI) are equivalent measures of risk in this setting. We aimed to compare and contrast (1) the association of cTnT and cTnI with CVD and non-CVD outcomes, and (2) their determinants in a genome-wide association study. METHODS: High-sensitivity cTnT and cTnI were measured in serum from 19 501 individuals in Generation Scotland Scottish Family Health Study. Median follow-up was 7.8 years (quartile 1 to quartile 3, 7.1-9.2). Associations of each troponin with a composite CVD outcome (1177 events), CVD death (n=266), non-CVD death (n=374), and heart failure (n=216) were determined by using Cox models. A genome-wide association study was conducted using a standard approach developed for the cohort. RESULTS: Both cTnI and cTnT were strongly associated with CVD risk in unadjusted models. After adjusting for classical risk factors, the hazard ratio for a 1 SD increase in log transformed troponin was 1.24 (95% CI, 1.17-1.32) and 1.11 (1.04-1.19) for cTnI and cTnT, respectively; ratio of hazard ratios 1.12 (1.04-1.21). cTnI, but not cTnT, was associated with myocardial infarction and coronary heart disease. Both cTnI and cTnT had strong associations with CVD death and heart failure. By contrast, cTnT, but not cTnI, was associated with non-CVD death; ratio of hazard ratios 0.77 (0.67-0.88). We identified 5 loci (53 individual single-nucleotide polymorphisms) that had genome-wide significant associations with cTnI, and a different set of 4 loci (4 single-nucleotide polymorphisms) for cTnT. CONCLUSIONS: The upstream genetic causes of low-grade elevations in cTnI and cTnT appear distinct, and their associations with outcomes also differ. Elevations in cTnI are more strongly associated with some CVD outcomes, whereas cTnT is more strongly associated with the risk of non-CVD death. These findings help inform the selection of an optimal troponin assay for future clinical care and research in this setting.

10.
EBioMedicine ; 43: 576-586, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30935889

RESUMO

BACKGROUND: The causes of poor respiratory function and COPD are incompletely understood, but it is clear that genes and the environment play a role. As DNA methylation is under both genetic and environmental control, we hypothesised that investigation of differential methylation associated with these phenotypes would permit mechanistic insights, and improve prediction of COPD. We investigated genome-wide differential DNA methylation patterns using the recently released 850 K Illumina EPIC array. This is the largest single population, whole-genome epigenetic study to date. METHODS: Epigenome-wide association studies (EWASs) of respiratory function and COPD were performed in peripheral blood samples from the Generation Scotland: Scottish Family Health Study (GS:SFHS) cohort (n = 3781; 274 COPD cases and 2919 controls). In independent COPD incidence data (n = 149), significantly differentially methylated sites (DMSs; p < 3.6 × 10-8) were evaluated for their added predictive power when added to a model including clinical variables, age, sex, height and smoking history using receiver operating characteristic analysis. The Lothian Birth Cohort 1936 (LBC1936) was used to replicate association (n = 895) and prediction (n = 178) results. FINDINGS: We identified 28 respiratory function and/or COPD associated DMSs, which mapped to genes involved in alternative splicing, JAK-STAT signalling, and axon guidance. In prediction analyses, we observed significant improvement in discrimination between COPD cases and controls (p < .05) in independent GS:SFHS (p = .016) and LBC1936 (p = .010) datasets by adding DMSs to a clinical model. INTERPRETATION: Identification of novel DMSs has provided insight into the molecular mechanisms regulating respiratory function and aided prediction of COPD risk. Further studies are needed to assess the causality and clinical utility of identified associations. FUND: Wellcome Trust Strategic Award 10436/Z/14/Z.

11.
Int J Obes (Lond) ; 43(9): 1795-1802, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30842548

RESUMO

BACKGROUND: The relationship between obesity and adverse health is well established, but little is known about the contribution of DNA methylation to obesity-related health outcomes. This study tests associations between an epigenetic score for body mass index (BMI) and health-related, cognitive, psychosocial and lifestyle outcomes in the Lothian Birth Cohort 1936. This study also tests whether these associations are independent of phenotypic BMI. METHOD: Analyses were conducted using data from the Lothian Birth Cohort 1936 (n = 892). Weights for the epigenetic BMI score were derived using penalised regression on methylation data from unrelated Generation Scotland participants (n = 2562). Associations were tested for replication in an independent sample: the Lothian Birth Cohort 1921 (n = 433). RESULTS: A higher epigenetic BMI score was associated with higher BMI (R2 = 0.1), greater body weight (R2 = 0.06), greater time taken to walk 6 m, poorer lung function and poorer general physical health (all R2 = 0.02), greater levels of triglycerides (R2 = 0.09), greater %total HbA1c (R2 = 0.06), lower levels of high-density lipoprotein cholesterol (HDL; R2 = 0.08), higher HDL ratio (HDL/total cholesterol; R2 = 0.03), lower health-related quality of life, physical inactivity, and greater social deprivation (all R2 = 0.02). The epigenetic BMI score (per SD) was also associated with type 2 diabetes (OR 2.17, 95% CI 1.67, 2.84), cardiovascular disease (OR 1.45, 95% CI 1.24, 1.71) and high blood pressure (OR 1.30, 95% CI 1.13, 1.49; all p < 0.00026 after Bonferroni correction). Associations were replicated for BMI (R2 = 0.06), body weight (R2 = 0.04), health-related quality of life (R2 = 0.02), HbA1c (R2 = 0.07) and triglycerides (R2 = 0.07; all p < 0.0045 after Bonferroni correction). CONCLUSIONS: We observed and replicated associations between an epigenetic score for BMI and variables related to poor physical health and metabolic syndrome. Regression models with both epigenetic and phenotypic BMI scores as predictors accounted for a greater proportion of variance in all outcome variables than either predictor alone, demonstrating independent and additive effects of epigenetic and phenotypic BMI scores.

12.
Nat Commun ; 10(1): 1383, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30918249

RESUMO

Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.


Assuntos
Metilação de DNA/genética , Regulação da Expressão Gênica , Impressão Genômica/genética , Locos de Características Quantitativas/genética , Adulto , Ilhas de CpG , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escócia
13.
Pharmacogenomics J ; 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30700811

RESUMO

Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power.

14.
J Psychopharmacol ; 33(4): 482-493, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30808242

RESUMO

OBJECTIVES:: Antidepressants are the most commonly prescribed psychiatric medication but concern has been raised about significant increases in their usage in high income countries. We aimed to quantify antidepressant prevalence, incidence, adherence and predictors of use in the adult population. METHODS:: The study record-linked administrative prescribing and morbidity data to the Generation Scotland cohort ( N = 11,052), between 2009 and 2016. Prevalence and incidence of any antidepressant use was determined. Antidepressant adherence was measured using Proportion of Days Covered and Medication Possession Ratio. Time-to-event analysis for incident antidepressant use within 5 years of Generation Scotland: Scottish Family Health Study (GS:SFHS) recruitment was performed to reveal patient-level predictors of use. RESULTS:: Almost one-third (28.0%, 95%CI 26.9-29.1) of the adults in our sample were prescribed at least one antidepressant in the 5-year period 2012-2016. There was a 36.2% increase in annual prevalence between 2010 and 2016. Incidence was 2.4(2.1-2.7)% per year. The majority of antidepressant episodes (57.6%) were greater than 9 months duration and adherence was generally high (69.0% with Proportion of Days Covered >80%). Predictors of new antidepressant use included history of affective disorder, being female, physical comorbidities, higher neuroticism scores, and lower cognitive function scores. CONCLUSIONS:: Antidepressant prevalence is greater than previously reported but incidence remains relatively stable. We found the majority of antidepressant episodes to be of relatively long duration with good estimated adherence. Our study supports the hypothesis that increased long-term use among existing (and returning) users, along with wider ranges of indications for antidepressants, has significantly increased the prevalence of these medications.

15.
Nat Commun ; 10(1): 376, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670697

RESUMO

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.


Assuntos
Exercício , Loci Gênicos/genética , Lipídeos/sangue , Lipídeos/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metabolismo dos Lipídeos/genética , Masculino , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue , Triglicerídeos/genética , Adulto Jovem
16.
EBioMedicine ; 37: 214-220, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30389506

RESUMO

BACKGROUND: Multiple studies have made robust associations between differential DNA methylation and exposure to cigarette smoke. But whether a DNA methylation phenotype is established immediately upon exposure, or only after prolonged exposure is less well-established. Here, we assess DNA methylation patterns from peripheral blood samples in current smokers in response to dose and duration of exposure, along with the effects of smoking cessation on DNA methylation in former smokers. METHODS: Dimensionality reduction was applied to DNA methylation data at 90 previously identified smoking-associated CpG sites for over 4900 individuals in the Generation Scotland cohort. K-means clustering was performed to identify clusters associated with current and never smoker status based on these methylation patterns. Cluster assignments were assessed with respect to duration of exposure in current smokers (years as a smoker), time since smoking cessation in former smokers (years), and dose (cigarettes per day). FINDINGS: Two clusters were specified, corresponding to never smokers (97·5% of whom were assigned to Cluster 1) and current smokers (81·1% of whom were assigned to Cluster 2). The exposure time point from which >50% of current smokers were assigned to the smoker-enriched cluster varied between 5 and 9 years in heavier smokers and between 15 and 19 years in lighter smokers. Low-dose former smokers were more likely to be assigned to the never smoker-enriched cluster in the first year following cessation. In contrast, a period of at least two years was required before the majority of former high-dose smokers were assigned to the never smoker-enriched cluster. INTERPRETATION: Our findings suggest that smoking-associated DNA methylation changes are a result of prolonged exposure to cigarette smoke, and can be reversed following cessation. The length of time in which these signatures are established and recovered is dose dependent. Should DNA methylation-based signatures of smoking status be predictive of smoking-related health outcomes, our findings may provide an additional criterion on which to stratify risk.

17.
Diabetes ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30352878

RESUMO

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such "favourable adiposity" alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined magnetic resonance imaging (MRI) data with genome-wide association studies (GWAS) of body fat % and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity, but a favourable metabolic profile. Consistent with previous studies, individuals carrying more "favourable adiposity" alleles had higher body fat % and higher BMI, but lower risk of type 2 diabetes, heart disease and hypertension. These individuals also had higher subcutaneous fat, but lower liver fat and lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14 and IRS1, whilst the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified "favourable adiposity" alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglyceride in metabolically low risk depots.

18.
Genome Biol ; 19(1): 136, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30257690

RESUMO

BACKGROUND: Genome-wide DNA methylation (DNAm) profiling has allowed for the development of molecular predictors for a multitude of traits and diseases. Such predictors may be more accurate than the self-reported phenotypes and could have clinical applications. RESULTS: Here, penalized regression models are used to develop DNAm predictors for ten modifiable health and lifestyle factors in a cohort of 5087 individuals. Using an independent test cohort comprising 895 individuals, the proportion of phenotypic variance explained in each trait is examined for DNAm-based and genetic predictors. Receiver operator characteristic curves are generated to investigate the predictive performance of DNAm-based predictors, using dichotomized phenotypes. The relationship between DNAm scores and all-cause mortality (n = 212 events) is assessed via Cox proportional hazards models. DNAm predictors for smoking, alcohol, education, and waist-to-hip ratio are shown to predict mortality in multivariate models. The predictors show moderate discrimination of obesity, alcohol consumption, and HDL cholesterol. There is excellent discrimination of current smoking status, poorer discrimination of college-educated individuals and those with high total cholesterol, LDL with remnant cholesterol, and total:HDL cholesterol ratios. CONCLUSIONS: DNAm predictors correlate with lifestyle factors that are associated with health and mortality. They may supplement DNAm-based predictors of age to identify the lifestyle profiles of individuals and predict disease risk.

19.
PLoS Genet ; 14(9): e1007601, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30261039

RESUMO

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

20.
Alzheimers Dement (Amst) ; 10: 429-437, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30167451

RESUMO

Introduction: The "epigenetic clock" is a DNA methylation-based estimate of biological age and is correlated with chronological age-the greatest risk factor for Alzheimer's disease (AD). Genetic and environmental risk factors exist for AD, several of which are potentially modifiable. In this study, we assess the relationship between the epigenetic clock and AD risk factors. Methods: Multilevel models were used to assess the relationship between age acceleration (the residual of biological age regressed onto chronological age) and AD risk factors relating to cognitive reserve, lifestyle, disease, and genetics in the Generation Scotland study (n = 5100). Results: We report significant associations between age acceleration and body mass index, total cholesterol to high-density lipoprotein cholesterol ratios, socioeconomic status, high blood pressure, and smoking behavior (Bonferroni-adjusted P < .05). Discussion: Associations are present between environmental risk factors for AD and age acceleration. Measures to modify such risk factors might improve the risk profile for AD and the rate of biological ageing. Future longitudinal analyses are therefore warranted.

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