Publications
62 results found
Said S, Pazoki R, Karhunen V, et al., 2022, Genetic analysis of over half a million people characterises C-reactive protein loci (vol 13, 2198, 2022), Nature Communications, Vol: 13, Pages: 1-1, ISSN: 2041-1723
Jiang X, Anasanti MD, Drenos F, et al., 2022, Urinary Sodium Excretion Enhances the Effect of Alcohol on Blood Pressure, HEALTHCARE, Vol: 10
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- Citations: 1
O'Farrell F, Jiang X, Aljifri S, et al., 2022, Molecular Alterations Caused by Alcohol Consumption in the UK Biobank: A Mendelian Randomisation Study, NUTRIENTS, Vol: 14
Said S, Karhunen V, vosa U, et al., 2022, Genetic analysis of over half a million people characterises C-reactive protein loci, Nature Communications, Vol: 13, ISSN: 2041-1723
Chronic low-grade inflammation is linked to a multitude of chronic diseases. We report the largest genome-wide association study (GWAS) on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367, European descent) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N = 575,531 European descent). We identify 266 independent loci, of which 211 are not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 ×10−6) and tissue expression analysis indicated a strong association of CRP related genes with liver and whole blood gene expression. Phenome-wide association study identified 27 clinical outcomes associated with genetically determined CRP and subsequent Mendelian randomisation analyses supported a causal association with schizophrenia, chronic airway obstruction and prostate cancer. Our findings identified genetic loci and functional properties of chronic low-grade inflammation and provided evidence for causal associations with a range of diseases.
Jiang X, Gao H, Elliott P, et al., 2022, Percentage of explained variance in alcohol consumption by genetic risk score in the UK Biobank, Publisher: SPRINGERNATURE, Pages: 528-529, ISSN: 1018-4813
Pazoki R, Vujkovic M, Elliott J, et al., 2022, Genome-wide association study and replication of liver enzyme loci, Publisher: SPRINGERNATURE, Pages: 47-48, ISSN: 1018-4813
Roa-Diaz ZM, Asllanaj E, Amin HA, et al., 2021, Age at Natural Menopause and Blood Pressure Traits: Mendelian Randomization Study, JOURNAL OF CLINICAL MEDICINE, Vol: 10
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- Citations: 7
Evangelou E, Suzuki H, Bai W, et al., 2021, Alcohol consumption in the general population is associated with structural changes in multiple organ systems., eLife, Vol: 10, Pages: 1-15, ISSN: 2050-084X
Background:Excessive alcohol consumption is associated with damage to various organs, but its multi-organ effects have not been characterised across the usual range of alcohol drinking in a large general population sample.Methods:We assessed global effect sizes of alcohol consumption on quantitative magnetic resonance imaging phenotypic measures of the brain, heart, aorta, and liver of UK Biobank participants who reported drinking alcohol.Results:We found a monotonic association of higher alcohol consumption with lower normalised brain volume across the range of alcohol intakes (–1.7 × 10−3 ± 0.76 × 10−3 per doubling of alcohol consumption, p=3.0 × 10−14). Alcohol consumption was also associated directly with measures of left ventricular mass index and left ventricular and atrial volume indices. Liver fat increased by a mean of 0.15% per doubling of alcohol consumption.Conclusions:Our results imply that there is not a ‘safe threshold’ below which there are no toxic effects of alcohol. Current public health guidelines concerning alcohol consumption may need to be revisited.
Pazoki R, Elliott J, Evangelou E, et al., 2021, Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes, Nature Communications, Vol: 12, ISSN: 2041-1723
Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
Pazoki R, Lin BD, van Eijk KR, et al., 2021, Phenome-wide and genome-wide analyses of quality of life in schizophrenia (vol 7, e13, 2021), BJPSYCH OPEN, Vol: 7, ISSN: 2056-4724
Pazoki R, Lin BD, van Eijk KR, et al., 2020, Phenome-wide and genome-wide analyses of quality of life in schizophrenia, BJPSYCH OPEN, Vol: 7, ISSN: 2056-4724
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- Citations: 4
Elliott P, Muller DC, Schneider-Luftman D, et al., 2020, Estimated 24-hour urinary sodium excretion and incident cardiovascular disease and mortality among 398 628 individuals in UK biobank., Hypertension, Vol: 76, Pages: 1-9, ISSN: 0194-911X
We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.
Robinson O, Chadeau Hyam M, Karaman I, et al., 2020, Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort, Aging Cell, Vol: 19, Pages: 1-13, ISSN: 1474-9718
Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.
Schmidt AF, Holmes MV, Preiss D, et al., 2019, Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9, BMC Cardiovascular Disorders, Vol: 19, ISSN: 1471-2261
BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
Evangelou E, Gao H, Blakeley P, et al., 2019, New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders, Nature Human Behaviour, Vol: 3, Pages: 950-961, ISSN: 2397-3374
Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d−1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.
Pazoki R, Lin BD, van Eijk KR, et al., 2019, Phenome-wide and Genome-wide Analyses of Quality of Life in Schizophrenia
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Schizophrenia negatively impacts quality of life (QoL). A handful of variables from small studies have been reported to influence QoL of schizophrenia patients, but a study comprehensively dissecting the genetic and non-genetic contributing factors to QoL in these patients is currently lacking. We adopted a hypothesis-generating approach to assess the phenotypic and genotypic determinants of QoL in schizophrenia.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>The study population consisted of 1,119 patients with a psychotic disorder, 1,979 relatives and 586 healthy controls. Using linear regression, we tested >100 independent demographic, cognitive and clinical phenotypes for their association with QoL in patients. We then performed genome-wide association analyses of QoL and examined the association between polygenic risk scores (PRSs) for schizophrenia, major depressive disorder (MDD), and subjective wellbeing (SW) with QoL.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We found nine phenotypes to be significantly and independently associated with QoL in patients, the most significant ones being negative (Beta=-1.17; SE=0.05, P=1×10<jats:sup>-83</jats:sup>; r<jats:sup>2</jats:sup>=53%), depressive (Beta=-1.07; SE=0.05; P=2×10<jats:sup>-79</jats:sup>; r<jats:sup>2</jats:sup>=51%) and emotional distress (Beta=-0.09; SE=0.01; P=4×10<jats:sup>-59</jats:sup>, r<jats:sup>2</jats:sup>=38%) symptoms. Schizophrenia and subjective wellbeing PRSs using various P-value thresholds were significantly and consistently associated with QoL (lowest association p-value = 6.8×10<jats:sup>-6</jats:sup>). Several sensitivity analyses confi
Pazoki R, Evangelou E, Mosen-Ansorena D, et al., 2019, GWAS for urinary sodium and potassium excretion highlights pathways shared with cardiovascular traits, Nature Communications, Vol: 10, ISSN: 2041-1723
Urinary sodium and potassium excretion are associated with blood pressure (BP) and cardiovascular disease (CVD). The exact biological link between these traits is yet to be elucidated. Here, we identify 51 loci for sodium and 13 for potassium excretion in a large-scale genome-wide association study (GWAS) on urinary sodium and potassium excretion using data from 446,237 individuals of European descent from the UK Biobank study. We extensively interrogate the results using multiple analyses such as Mendelian randomization, functional assessment, co localization, genetic risk score, and pathway analyses. We identify a shared genetic component between urinary sodium and potassium expression and cardiovascular traits. Ingenuity pathway analysis shows that urinary sodium and potassium excretion loci are over represented in behavioural response to stimuli. Our study highlights pathways that are shared between urinary sodium and potassium excretion and cardiovascular traits.
Pazoki R, 2019, Cardiovascular disease, ABO locus, and markers of platelet functionality, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 286, Pages: 162-163, ISSN: 0167-5273
de Vries PS, Brown MR, Bentley AR, et al., 2019, Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions, American Journal of Epidemiology, Vol: 188, Pages: 1033-1054, ISSN: 1476-6256
An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
Davies G, Lam M, Harris SE, et al., 2019, Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (vol 9, 2098, 2018), NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723
Kilpelainen TO, Bentley AR, Noordam R, et al., 2019, Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity, Nature Communications, Vol: 10, ISSN: 2041-1723
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.
Pazoki R, Dehghan A, Evangelou E, et al., 2019, Genetic Predisposition to High Blood Pressure and Lifestyle Factors: Associations With Midlife Blood Pressure Levels and Cardiovascular Events (vol 137, pg 653, 2018), CIRCULATION, Vol: 139, Pages: E2-E2, ISSN: 0009-7322
Evangelou E, Warren HR, Mosen-Ansorena D, et al., 2018, Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018), NATURE GENETICS, Vol: 50, Pages: 1755-1755, ISSN: 1061-4036
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- Citations: 10
Ashar FN, Mitchell RN, Albert CM, et al., 2018, A comprehensive evaluation of the genetic architecture of sudden cardiac arrest, EUROPEAN HEART JOURNAL, Vol: 39, Pages: 3961-+, ISSN: 0195-668X
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- Citations: 45
Evangelou E, Warren HR, Mosen-Ansorena D, et al., 2018, Publisher correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits, Nature Genetics, Vol: 50, Pages: 1755-1755, ISSN: 1061-4036
Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0205-x, published online 17 September 2018.
Iotchkova V, Huang J, Morris JA, et al., 2018, Author Correction: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps, Nature Genetics, Vol: 50, Pages: 1752-1752, ISSN: 1061-4036
Correction to: Nature Genetics https://doi.org/10.1038/ng.3668, published online 26 September 2016.In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs.
Evangelou E, Gao H, Chu C, et al., 2018, Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders, bioRxiv The preprint server for biology
Abstract Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila . Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.
Robinson O, Hyam MC, Karaman I, et al., 2018, Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort
<jats:title>Abstract</jats:title><jats:p>Markers of biological ageing have potential utility in primary care and public health. We developed an elastic net regression model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum (almost 100,000 features assayed), within a large sample (N=2,239) from the UK occupational Airwave cohort. We investigated the determinants of accelerated ageing, including genetic, lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (r=0.85 in independent test set). Increased metabolomic age acceleration (mAA) was associated (p<0.0025) with overweight/obesity and depression and nominally associated (p<0.05) with high alcohol use and low income. DNA methylation age acceleration (N=1,102) was nominally associated (p<0.05) with high alcohol use, anxiety and post-traumatic stress disorder, but not correlated with mAA. Biological age acceleration may present an important mechanism linking psycho-social stress to age-related disease.</jats:p>
Evangelou E, Warren HR, Mosen-Ansorena D, et al., 2018, Genetic analysis of over one million people identifies 535 new loci associated with blood pressure traits, Nature Genetics, Vol: 50, Pages: 1412-1425, ISSN: 1061-4036
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
Davies G, Lam M, Harris SE, et al., 2018, Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function, Nature Communications, Vol: 9, ISSN: 2041-1723
General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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