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1.
Transl Psychiatry ; 11(1): 523, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642301

RESUMO

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (ßrange = -0.057 to -0.104, all PFDR < 0.05). Increased levels of hair cortisone were significantly associated with MDD (lifetime-MDD status, current symptoms, and severity; ßrange = 0.071 to 0.115, all PFDR = < 0.05), with early-life adversity (ß = 0.083, P = 0.017), and with reduced global and regional brain volumes (global: ß = -0.059, P = 0.043; nucleus accumbens: ß = -0.075, PFDR = 0.044). Associations with total glucocorticoids followed a similar pattern to the cortisol findings. In this large community-based sample, elevated glucocorticoids were significantly associated with MDD, with early, but not later-life stress, and with reduced global and regional brain phenotypes. These findings provide important foundations for future mechanistic studies to formally explore causal relationships between early adversity, chronic rather than acute measures of glucocorticoids, and neurobiological associations relevant to the aetiology of MDD.

2.
PLoS Genet ; 17(9): e1009750, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34499657

RESUMO

Variation in obesity-related traits has a genetic basis with heritabilities between 40 and 70%. While the global obesity pandemic is usually associated with environmental changes related to lifestyle and socioeconomic changes, most genetic studies do not include all relevant environmental covariates, so the genetic contribution to variation in obesity-related traits cannot be accurately assessed. Some studies have described interactions between a few individual genes linked to obesity and environmental variables but there is no agreement on their total contribution to differences between individuals. Here we compared self-reported smoking data and a methylation-based proxy to explore the effect of smoking and genome-by-smoking interactions on obesity related traits from a genome-wide perspective to estimate the amount of variance they explain. Our results indicate that exploiting omic measures can improve models for complex traits such as obesity and can be used as a substitute for, or jointly with, environmental records to better understand causes of disease.

3.
Hepatol Commun ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535985

RESUMO

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.

4.
Clin Chem ; 67(10): 1351-1360, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34240125

RESUMO

BACKGROUND: Cardiac troponin concentrations differ in women and men, but how this influences risk prediction and whether a sex-specific approach is required is unclear. We evaluated whether sex influences the predictive ability of cardiac troponin I and T for cardiovascular events in the general population. METHODS: High-sensitivity cardiac troponin (hs-cTn) I and T were measured in the Generation Scotland Scottish Family Health Study of randomly selected volunteers drawn from the general population between 2006 and 2011. Cox-regression models evaluated associations between hs-cTnI and hs-cTnT and the primary outcome of cardiovascular death, myocardial infarction, or stroke. RESULTS: In 19 501 (58% women, mean age 47 years) participants, the primary outcome occurred in 2.7% (306/11 375) of women and 5.1% (411/8126) of men during the median follow-up period of 7.9 (IQR, 7.1-9.2) years. Cardiac troponin I and T concentrations were lower in women than men (P < 0.001 for both), and both were more strongly associated with cardiovascular events in women than men. For example, at a hs-cTnI concentration of 10 ng/L, the hazard ratio relative to the limit of blank was 9.7 (95% CI 7.6-12.4) and 5.6 (95% CI 4.7-6.6) for women and men, respectively. The hazard ratio for hs-cTnT at a concentration of 10 ng/L relative to the limit of blank was 3.7 (95% CI 3.1-4.3) and 2.2 (95% CI 2.0-2.5) for women and men, respectively. CONCLUSIONS: Cardiac troponin concentrations differ in women and men and are stronger predictors of cardiovascular events in women. Sex-specific approaches are required to provide equivalent risk prediction.

5.
Cell Syst ; 12(8): 780-794.e7, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34139154

RESUMO

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.


Assuntos
Biomarcadores/análise , COVID-19/patologia , Progressão da Doença , Proteoma/fisiologia , Fatores Etários , Contagem de Células Sanguíneas , Gasometria , Ativação Enzimática , Humanos , Inflamação/patologia , Aprendizado de Máquina , Prognóstico , Proteômica , SARS-CoV-2/imunologia
6.
Eur J Hum Genet ; 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34088990

RESUMO

Orkney and Shetland, the population isolates that make up the Northern Isles of Scotland, are of particular interest to multiple sclerosis (MS) research. While MS prevalence is high in Scotland, Orkney has the highest global prevalence, higher than more northerly Shetland. Many hypotheses for the excess of MS cases in Orkney have been investigated, including vitamin D deficiency and homozygosity: neither was found to cause the high prevalence of MS. It is possible that this excess prevalence may be explained through unique genetics. We used polygenic risk scores (PRS) to look at the contribution of common risk variants to MS. Analyses were conducted using ORCADES (97/2118 cases/controls), VIKING (15/2000 cases/controls) and Generation Scotland (30/8708 cases/controls) data sets. However, no evidence of a difference in MS-associated common variant frequencies was found between the three control populations, aside from HLA-DRB1*15:01 tag SNP rs9271069. This SNP had a significantly higher risk allele frequency in Orkney (0.23, p value = 8 × 10-13) and Shetland (0.21, p value = 2.3 × 10-6) than mainland Scotland (0.17). This difference in frequency is estimated to account for 6 (95% CI 3, 8) out of 150 observed excess cases per 100,000 individuals in Shetland and 9 (95% CI 8, 11) of the observed 257 excess cases per 100,000 individuals in Orkney, compared with mainland Scotland. Common variants therefore appear to account for little of the excess burden of MS in the Northern Isles of Scotland.

7.
Hum Mol Genet ; 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961016

RESUMO

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI and HF development in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.

8.
Transl Psychiatry ; 11(1): 135, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608504

RESUMO

A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.


Assuntos
Proteínas do Tecido Nervoso , Esquizofrenia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Parvalbuminas/metabolismo , Esquizofrenia/genética
9.
Genome Med ; 13(1): 1, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397400

RESUMO

BACKGROUND: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. METHODS: Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. RESULTS: We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10-100 ≤ P ≤ 2.44 × 10-8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10-4 ≤ P ≤ 3.01 × 10-2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24. CONCLUSIONS: APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.

10.
Mol Psychiatry ; 26(2): 483-491, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-30842574

RESUMO

Autosomal variants have successfully been associated with trait neuroticism in genome-wide analysis of adequately powered samples. But such studies have so far excluded the X chromosome from analysis. Here, we report genetic association analyses of X chromosome and XY pseudoautosomal single nucleotide polymorphisms (SNPs) and trait neuroticism using UK Biobank samples (N = 405,274). Significant association was found with neuroticism on the X chromosome for 204 markers found within three independent loci (a further 783 were suggestive). Most of the lead neuroticism-related X chromosome variants were located in intergenic regions (n = 397). Involvement of HS6ST2, which has been previously associated with sociability behaviour in the dog, was supported by single SNP and gene-based tests. We found that the amino acid and nucleotide sequences are highly conserved between dogs and humans. From the suggestive X chromosome variants, there were 19 nearby genes which could be linked to gene ontology information. Molecular function was primarily related to binding and catalytic activity; notable biological processes were cellular and metabolic, and nucleic acid binding and transcription factor protein classes were most commonly involved. X-variant heritability of neuroticism was estimated at 0.22% (SE = 0.05) from a full dosage compensation model. A polygenic X-variant score created in an independent sample (maximum N ≈ 7,300) did not predict significant variance in neuroticism, psychological distress, or depressive disorder. We conclude that the X chromosome harbours significant variants influencing neuroticism, and might prove important for other quantitative traits and complex disorders.


Assuntos
Cães/genética , Herança Multifatorial , Neuroticismo , Polimorfismo de Nucleotídeo Único , Cromossomo X/genética , Animais , Estudos de Associação Genética , Fenótipo
11.
Brain Behav Immun ; 92: 39-48, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33221487

RESUMO

Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases = 271, Ncontrols = 609). Serum CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (ß = 0.145, PFDR = 6 × 10-4) and energy levels (ß = 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (ß = -0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, ßFA= -0.12 to -0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (ßaverage = -0.15 versus ßaverage = 0.01 respectively). These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.


Assuntos
Transtorno Depressivo Maior , Biomarcadores , Encéfalo/diagnóstico por imagem , Transtorno Depressivo Maior/genética , Epigênese Genética , Humanos , Inflamação/genética , Escócia
12.
Epigenetics ; 16(7): 783-796, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33079621

RESUMO

The Developmental Origins of Health and Disease (DOHaD) theory predicts that prenatal and early life events shape adult health outcomes. Birth weight is a useful indicator of the foetal experience and has been associated with multiple adult health outcomes. DNA methylation (DNAm) is one plausible mechanism behind the relationship of birth weight to adult health. Through data linkage between Generation Scotland and historic Scottish birth cohorts, and birth records held through the NHS Information and Statistics Division, a sample of 1,757 individuals with available birth weight and DNAm data was derived. Epigenome-wide association studies (EWAS) were performed in two independently generated DNAm subgroups (nSet1 = 1,395, nSet2 = 362), relating adult DNAm from whole blood to birth weight. Meta-analysis yielded one genome-wide significant CpG site (p = 5.97x10-9), cg00966482. There was minimal evidence for attenuation of the effect sizes for the lead loci upon adjustment for numerous potential confounder variables (body mass index, educational attainment, and socioeconomic status). Associations between birth weight and epigenetic measures of biological age were also assessed. Associations between lower birth weight and higher Grim Age acceleration (p(FDR) = 3.6x10-3) and shorter DNAm-derived telomere length (p(FDR) = 1.7x10-3) are described, although results for three other epigenetic clocks were null. Our results provide support for an association between birth weight and DNAm both locally at one CpG site, and globally via biological ageing estimates.

13.
Nature ; 591(7848): 92-98, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33307546

RESUMO

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.


Assuntos
COVID-19/genética , COVID-19/fisiopatologia , Estado Terminal , 2',5'-Oligoadenilato Sintetase/genética , COVID-19/patologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 21/genética , Cuidados Críticos , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Reposicionamento de Medicamentos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/virologia , Masculino , Família Multigênica/genética , Receptor de Interferon alfa e beta/genética , Receptores CCR2/genética , TYK2 Quinase/genética , Reino Unido
14.
Am J Psychiatry ; 177(10): 917-927, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32998551

RESUMO

OBJECTIVE: Death by suicide is a highly preventable yet growing worldwide health crisis. To date, there has been a lack of adequately powered genomic studies of suicide, with no sizable suicide death cohorts available for analysis. To address this limitation, the authors conducted the first comprehensive genomic analysis of suicide death using previously unpublished genotype data from a large population-ascertained cohort. METHODS: The analysis sample comprised 3,413 population-ascertained case subjects of European ancestry and 14,810 ancestrally matched control subjects. Analytical methods included principal component analysis for ancestral matching and adjusting for population stratification, linear mixed model genome-wide association testing (conditional on genetic-relatedness matrix), gene and gene set-enrichment testing, and polygenic score analyses, as well as single-nucleotide polymorphism (SNP) heritability and genetic correlation estimation using linkage disequilibrium score regression. RESULTS: Genome-wide association analysis identified two genome-wide significant loci (involving six SNPs: rs34399104, rs35518298, rs34053895, rs66828456, rs35502061, and rs35256367). Gene-based analyses implicated 22 genes on chromosomes 13, 15, 16, 17, and 19 (q<0.05). Suicide death heritability was estimated at an h2SNP value of 0.25 (SE=0.04) and a value of 0.16 (SE=0.02) when converted to a liability scale. Notably, suicide polygenic scores were significantly predictive across training and test sets. Polygenic scores for several other psychiatric disorders and psychological traits were also predictive, particularly scores for behavioral disinhibition and major depressive disorder. CONCLUSIONS: Multiple genome-wide significant loci and genes were identified and polygenic score prediction of suicide death case-control status was demonstrated, adjusting for ancestry, in independent training and test sets. Additionally, the suicide death sample was found to have increased genetic risk for behavioral disinhibition, major depressive disorder, depressive symptoms, autism spectrum disorder, psychosis, and alcohol use disorder compared with the control sample.


Assuntos
Herança Multifatorial/genética , Suicídio Consumado/psicologia , Adulto , Estudos de Casos e Controles , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Escócia/epidemiologia , Fatores Sexuais , Suicídio Consumado/prevenção & controle , Suicídio Consumado/estatística & dados numéricos , Utah/epidemiologia , Adulto Jovem
16.
Clin Epigenetics ; 12(1): 115, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736664

RESUMO

BACKGROUND: Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These measures include five 'epigenetic clocks' which provide an index of how much an individual's biological age differs from their chronological age at the time of measurement. The five clocks encompass methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). A sixth epigenetic measure of ageing differs from these clocks in that it acts as a speedometer providing a single time-point measurement of the pace of an individual's biological ageing. This measure of ageing is termed DunedinPoAm. In this study, we test the association between these six epigenetic measures of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries (n ≤ 9537, Generation Scotland: Scottish Family Health Study). RESULTS: DNAm GrimAge predicted incidence of clinically diagnosed chronic obstructive pulmonary disease (COPD), type 2 diabetes and ischemic heart disease after 13 years of follow-up (hazard ratios = 2.22, 1.52 and 1.41, respectively). DunedinPoAm predicted the incidence of COPD and lung cancer (hazard ratios = 2.02 and 1.45, respectively). DNAm PhenoAge predicted incidence of type 2 diabetes (hazard ratio = 1.54). DNAm Telomere Length associated with the incidence of ischemic heart disease (hazard ratio = 0.80). DNAm GrimAge associated with all-cause mortality, the prevalence of COPD and spirometry measures at the study baseline. These associations were present after adjusting for possible confounding risk factors including alcohol consumption, body mass index, deprivation, education and tobacco smoking and surpassed stringent Bonferroni-corrected significance thresholds. CONCLUSIONS: Our data suggest that epigenetic measures of ageing may have utility in clinical settings to complement gold-standard methods for disease assessment and management.

17.
Alzheimers Dement (Amst) ; 12(1): e12078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32789163

RESUMO

Introduction: Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)-free participants. Methods: Associations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland. Results: AD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption. Discussion: Dementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.

18.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.


Assuntos
Transtorno Depressivo Maior/genética , Síndrome Metabólica/genética , Fatores Etários , Idade de Início , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Estudos de Casos e Controles , Comorbidade , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas , Depressão/genética , Depressão/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Diabetes Mellitus Tipo 2/genética , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Síndrome Metabólica/fisiopatologia , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética
19.
Wellcome Open Res ; 5: 24, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724860

RESUMO

Background: The UK hosts some of the world's longest-running longitudinal cohort studies, who make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. Methods: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. Results: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a 'Fit-bit' (78% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). Conclusions: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts.

20.
Cell Syst ; 11(1): 11-24.e4, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32619549

RESUMO

The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.


Assuntos
Proteínas Sanguíneas/metabolismo , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Proteômica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/isolamento & purificação , Biomarcadores/sangue , Proteínas Sanguíneas/análise , COVID-19 , Infecções por Coronavirus/classificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias/classificação , Pneumonia Viral/classificação , Pneumonia Viral/patologia , Pneumonia Viral/virologia , SARS-CoV-2 , Adulto Jovem
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