Imperial College London

Dr Ioanna (Joanna) Tzoulaki

Faculty of MedicineSchool of Public Health

Professor of Chronic Disease Epidemiology
 
 
 
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Contact

 

+44 (0)20 7594 3462i.tzoulaki

 
 
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Location

 

Building E - Sir Michael UrenWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

311 results found

Gill D, 2024, Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization, BMC Medicine, ISSN: 1741-7015

Journal article

Zagkos L, Dib M-J, Cronjé HT, Elliott P, Dehghan A, Tzoulaki I, Gill D, Daghlas Iet al., 2024, Cerebrospinal fluid C1-esterase inhibitor and tie-1 levels affect cognitive performance: evidence from proteome-wide mendelian randomization., Genes, Vol: 15, ISSN: 2073-4425

OBJECTIVE: The association of cerebrospinal fluid (CSF) protein levels with cognitive function in the general population remains largely unexplored. We performed Mendelian randomization (MR) analyses to query which CSF proteins may have potential causal effects on cognitive performance. METHODS AND ANALYSIS: Genetic associations with CSF proteins were obtained from a genome-wide association study conducted in up to 835 European-ancestry individuals and for cognitive performance from a meta-analysis of GWAS including 257,841 European-ancestry individuals. We performed Mendelian randomization (MR) analyses to test the effect of randomly allocated variation in 154 genetically predicted CSF protein levels on cognitive performance. Findings were validated by performing colocalization analyses and considering cognition-related phenotypes. RESULTS: Genetically predicted C1-esterase inhibitor levels in the CSF were associated with a better cognitive performance (SD units of cognitive performance per 1 log-relative fluorescence unit (RFU): 0.23, 95% confidence interval: 0.12 to 0.35, p = 7.91 × 10-5), while tyrosine-protein kinase receptor Tie-1 (sTie-1) levels were associated with a worse cognitive performance (-0.43, -0.62 to -0.23, p = 2.08 × 10-5). These findings were supported by colocalization analyses and by concordant effects on distinct cognition-related and brain-volume measures. CONCLUSIONS: Human genetics supports a role for the C1-esterase inhibitor and sTie-1 in cognitive performance.

Journal article

Lau C-HE, Manou M, Markozannes G, Ala-Korpela M, Ben-Shlomo Y, Chaturvedi N, Engmann J, Gentry-Maharaj A, Herzig K-H, Hingorani A, Järvelin M-R, Kähönen M, Kivimäki M, Lehtimäki T, Marttila S, Menon U, Munroe PB, Palaniswamy S, Providencia R, Raitakari O, Schmidt F, Sebert S, Wong A, Vineis P, Tzoulaki I, Robinson Oet al., 2023, NMR metabolomic modelling of age and lifespan: a multi-cohort analysis., medRxiv

Metabolomic age models have been proposed for the study of biological aging, however they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age-related disease. 98 metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈ 31,000 individuals, age range 24-86 years). We used non-linear and penalised regression to model CA and time to all-cause mortality. We examined associations of four new and two previously published metabolomic age models, with ageing risk factors and phenotypes. Within the UK Biobank (N≈ 102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type-2 diabetes mellitus, cancer, dementia, chronic obstructive pulmonary disease) and all-cause mortality. Cross-validated Pearson's r between metabolomic age models and CA ranged between 0.47-0.65 in the training set (mean absolute error: 8-9 years). Metabolomic age models, adjusted for CA, were associated with C-reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with chronological age were modest (r = 0.29-0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06 / metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability.

Journal article

Wood AC, Graca G, Gadgil M, Senn MK, Allison MA, Tzoulaki I, Greenland P, Ebbels T, Elliott P, Goodarzi MO, Tracy R, Rotter JI, Herrington Det al., 2023, Untargeted metabolomic analysis investigating links between unprocessed red meat intake and markers of inflammation., American Journal of Clinical Nutrition, Vol: 118, Pages: 989-999, ISSN: 0002-9165

BACKGROUND: Whether red meat consumption is associated with higher inflammation or confounded by increased adiposity remains unclear. Plasma metabolites capture the effects of diet after food is processed, digested, and absorbed, and correlate with markers of inflammation, so they can help clarify diet-health relationships. OBJECTIVE: To identify whether any metabolites associated with red meat intake are also associated with inflammation. METHODS: A cross-sectional analysis of observational data from older adults (52.84% women, mean age 63 ± 0.3 y) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Dietary intake was assessed by food-frequency questionnaire, alongside C-reactive protein (CRP), interleukin-2, interleukin-6, fibrinogen, homocysteine, and tumor necrosis factor alpha, and untargeted proton nuclear magnetic resonance (1H NMR) metabolomic features. Associations between these variables were examined using linear regression models, adjusted for demographic factors, lifestyle behaviors, and body mass index (BMI). RESULTS: In analyses that adjust for BMI, neither processed nor unprocessed forms of red meat were associated with any markers of inflammation (all P > 0.01). However, when adjusting for BMI, unprocessed red meat was inversely associated with spectral features representing the metabolite glutamine (sentinel hit: β = -0.09 ± 0.02, P = 2.0 × 10-5), an amino acid which was also inversely associated with CRP level (β = -0.11 ± 0.01, P = 3.3 × 10-10). CONCLUSIONS: Our analyses were unable to support a relationship between either processed or unprocessed red meat and inflammation, over and above any confounding by BMI. Glutamine, a plasma correlate of lower unprocessed red meat intake, was associated with lower CRP levels. The differences in diet-inflammation associations, compared with diet metabolite-inflammation associations, warrant further investigation to understand the extent that these

Journal article

Chalitsios CV, Meena D, Manou M, Papagiannopoulos C, Markozannes G, Gill D, Su B, Tsilidis KK, Evangelou E, Tzoulaki Iet al., 2023, Multiple long-term conditions in people with psoriasis: a latent class and bidirectional Mendelian randomisation analysis., Br J Dermatol

BACKGROUND: Co-existing long-term conditions (LTC) in psoriasis and their potential causal associations with the disease are not well-established. OBJECTIVES: This study aims to determine distinct clusters of LTC in people with psoriasis and the potential bi-directional causal association between these LTC and psoriasis. METHODS: Using latent class analysis, cross-sectional data of people with psoriasis from the UK Biobank were analysed to identify distinct psoriasis-related co-morbidity profiles. Linkage disequilibrium score regression (LDSR) was applied to compute the genetic correlation between psoriasis and LTC. Two-sample bidirectional Mendelian randomisation (MR) analysis assessed potential causal direction using independent genetic variants that reached genome-wide significance (P < 5 × 10-8). RESULTS: Five co-morbidity clusters were identified in a population of 10,873 people with psoriasis. LDSR revealed that psoriasis was positively genetically correlated with heart failure (rg = 0.23, p = 8.8 × 10-8), depression (rg = 0.12, p = 2.7 × 10-5), coronary artery disease (CAD) (rg = 0.15, p = 2 × 10-4), and type 2 diabetes (rg = 0.19, p = 3 × 10-3). Genetic liability to CAD was associated with an increased risk of psoriasis (ORIVW = 1.159; 95%CI 1.055-1.274; p = 2 × 10-3). The MR-PRESSO (ORMR-PRESSO = 1.13; 95%CI 1.042-1.228; p = 6 × 10-3) and the MR-RAPS (ORMR-RAPS = 1.149; 95%CI 1.062-1.242; p = 5 × 10-4) approaches corroborate the IVW findings. The weighted median generated similar and consistent effect estimates but was not statistically significant (ORWM = 1.076; 95%CI 0.949-1.221; p = 0.251). Evidence for a suggestive increased risk was detected for CAD (ORIVW&

Journal article

Georgiou AN, Zagkos L, Markozannes G, Chalitsios CV, Asimakopoulos AG, Xu W, Wang L, Mesa-Eguiagaray I, Zhou X, Loizidou EM, Kretsavos N, Theodoratou E, Gill D, Burgess S, Evangelou E, Tsilidis KK, Tzoulaki Iet al., 2023, Appraising the Causal Role of Risk Factors in Coronary Artery Disease and Stroke: A Systematic Review of Mendelian Randomization Studies., J Am Heart Assoc, Vol: 12

BACKGROUND Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes by using genetic variants associated with an exposure as instrumental variables. In this systematic review, we aimed to summarize previous MR studies and to evaluate the evidence for causality for a broad range of exposures in relation to coronary artery disease and stroke. METHODS AND RESULTS MR studies investigating the association of any genetically predicted exposure with coronary artery disease or stroke were identified. Studies were classified into 4 categories built on the significance of the main MR analysis results and its concordance with sensitivity analyses, namely, robust, probable, suggestive, and insufficient. Studies reporting associations that did not perform any sensitivity analysis were classified as nonevaluable. We identified 2725 associations eligible for evaluation, examining 535 distinct exposures. Of them, 141 were classified as robust, 353 as probable, 110 as suggestive, and 926 had insufficient evidence. The most robust associations were observed for anthropometric traits, lipids, and lipoproteins and type 2 diabetes with coronary artery; disease and clinical measurements with coronary artery disease and stroke; and thrombotic factors with stroke. CONCLUSIONS Despite the large number of studies that have been conducted, only a limited number of associations were supported by robust evidence. Approximately half of the studies reporting associations presented an MR sensitivity analysis along with the main analysis that further supported the causality of associations. Future research should focus on more thorough assessments of sensitivity MR analyses and further assessments of mediation effects or nonlinearity of associations.

Journal article

Dominguez-Barragan J, Fernandez-Sanles A, Hernaez A, Llaurado-Pont J, Marrugat J, Robinson O, Tzoulaki I, Elosua R, Lassale Cet al., 2023, Blood DNA methylation signature of diet quality and association with cardiometabolic traits, EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY, ISSN: 2047-4873

Journal article

Wood AC, Goodarzi MO, Senn MK, Gadgil MD, Graca G, Allison MA, Tzoulaki I, Mi MY, Greenland P, Ebbels T, Elliott P, Tracy RP, Herrington DM, Rotter JIet al., 2023, Associations between metabolomic biomarkers of avocado intake and glycemia in the multi-ethnic study of atherosclerosis, The Journal of Nutrition, Vol: 153, Pages: 2797-2807, ISSN: 0022-3166

BACKGROUND: Avocado consumption is linked to better glucose homeostasis, but small associations suggest potential population heterogeneity. Metabolomic data capture the effects of food intake after digestion and metabolism, thus accounting for individual differences in these processes. OBJECTIVES: To identify metabolomic biomarkers of avocado intake and to examine their associations with glycemia. METHODS: Baseline data from 6224 multi-ethnic older adults (62% female) included self-reported avocado intake, fasting glucose and insulin, and untargeted plasma proton nuclear magnetic resonance metabolomic features (metabolomic data were available for a randomly selected subset; N = 3438). Subsequently, incident type 2 diabetes (T2D) was assessed over an ∼18 y follow-up period. A metabolome-wide association study of avocado consumption status (consumer compared with nonconsumer) was conducted, and the relationship of these features with glycemia via cross-sectional associations with fasting insulin and glucose and longitudinal associations with incident T2D was examined. RESULTS: Three highly-correlated spectral features were associated with avocado intake at metabolome-wide significance levels (P < 5.3 ∗ 10-7) and combined into a single biomarker. We did not find evidence that these features were additionally associated with overall dietary quality, nor with any of 47 other food groups (all P > 0.001), supporting their suitability as a biomarker of avocado intake. Avocado intake showed a modest association only with lower fasting insulin (β = -0.07 +/- 0.03, P = 0.03), an association that was attenuated to nonsignificance when additionally controlling for body mass index (kg/m2). However, our biomarker of avocado intake was strongly associated with lower fasting glucose (β = -0.22 +/- 0.02, P < 2.0 ∗ 10-16), lower fasting insulin (β = -0.17 +/- 0.02, P < 2.0 ∗ 10-16), and a lower incidence of T2D (hazard ratio: 0.68; 0

Journal article

Hunter WG, Smith AG, Pinto RC, Saldanha S, Gangwar A, Pahlavani M, Deodhar S, Wilkins J, Pandey A, Herrington D, Greenland P, Tzoulaki I, Rohatgi Aet al., 2023, Metabolomic Profiling of Cholesterol Efflux Capacity in a Multiethnic Population: Insights From MESA, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 43, Pages: 2030-2041, ISSN: 1079-5642

Journal article

Kanai M, Andrews SJ, Cordioli M, Stevens C, Neale BM, Daly M, Ganna A, Pathak GA, Iwasaki A, Karjalainen J, Mehtonen J, Pirinen M, Chwialkowska K, Trankiem A, Balaconis MK, Veerapen K, Wolford BN, Ahmad HF, Andrews S, von Hohenstaufen Puoti KA, Boer C, Boua PR, Butler-Laporte G, Cadilla CL, Chwiałkowska K, Colombo F, Douillard V, Dueker N, Dutta AK, El-Sherbiny YM, Eltoukhy MM, Esmaeeli S, Faucon A, Fave M-J, Cadenas IF, Francescatto M, Francioli L, Franke L, Fuentes M, Durán RG, Cabrero DG, Harry EN, Jansen P, Szentpéteri JL, Kaja E, Kanai M, Kirk C, Kousathanas A, Krieger JE, Patel SK, Lemaçon A, Limou S, Lió P, Marouli E, Marttila MM, Medina-Gómez C, Michaeli Y, Migeotte I, Mondal S, Moreno-Estrada A, Moya L, Nakanishi T, Nasir J, Pasko D, Pearson NM, Pereira AC, Priest J, Prijatelj V, Prokić I, Teumer A, Várnai R, Romero-Gómez M, Roos C, Rosenfeld J, Ruolin L, Schulte EC, Schurmann C, Sedaghati-khayat B, Shaheen D, Shivanathan I, Sipeky C, Sirui Z, Striano P, Tanigawa Y, Remesal AU, Vadgama N, Vallerga CL, van der Laan S, Verdugo RA, Wang QS, Wei Z, Zainulabid UA, Zárate RN, Auton A, Shelton JF, Shastri AJ, Weldon CH, Filshtein-Sonmez T, Coker D, Symons A, Aslibekyan S, OConnell J, Ye C, Hatoum AS, Agrawal A, Bogdan R, Colbert SMC, Thompson WK, Fan CC, Johnson EC, Niazyan L, Davidyants M, Arakelyan A, Avetyan D, Bekbossynova M, Tauekelova A, Tuleutayev M, Sailybayeva A, Ramankulov Y, Zholdybayeva E, Dzharmukhanov J, Kassymbek K, Tsechoeva T, Turebayeva G, Smagulova Z, Muratov T, Khamitov S, Kwong ASF, Timpson NJ, Niemi MEK, Rahmouni S, Guntz J, Beguin Y, Cordioli M, Pigazzini S, Nkambule L, Georges M, Moutschen M, Misset B, Darcis G, Gofflot S, Bouysran Y, Busson A, Peyrassol X, Wilkin F, Pichon B, Smits G, Vandernoot I, Goffard J-C, Tiembe N, Morrison DR, Afilalo J, Mooser V, Richards JB, Rousseau S, Durand M, Butler-Laporte G, Forgetta V, Laurent L, Afrasiabi Z, Bouab M, Tselios C, Xue X, Afilalo M, Oliveira M, St-Cyr J, Boisclair A, Ragoussis J, Auld D, Kaufet al., 2023, A second update on mapping the human genetic architecture of COVID-19, Nature, Vol: 621, Pages: E7-E26, ISSN: 0028-0836

Journal article

Lagou V, Jiang L, Ulrich A, Zudina L, González KSG, Balkhiyarova Z, Faggian A, Maina JG, Chen S, Todorov PV, Sharapov S, David A, Marullo L, Mägi R, Rujan R-M, Ahlqvist E, Thorleifsson G, Gao Η, Εvangelou Ε, Benyamin B, Scott RA, Isaacs A, Zhao JH, Willems SM, Johnson T, Gieger C, Grallert H, Meisinger C, Müller-Nurasyid M, Strawbridge RJ, Goel A, Rybin D, Albrecht E, Jackson AU, Stringham HM, Corrêa IR, Farber-Eger E, Steinthorsdottir V, Uitterlinden AG, Munroe PB, Brown MJ, Schmidberger J, Holmen O, Thorand B, Hveem K, Wilsgaard T, Mohlke KL, Wang Z, GWA-PA Consortium, Shmeliov A, den Hoed M, Loos RJF, Kratzer W, Haenle M, Koenig W, Boehm BO, Tan TM, Tomas A, Salem V, Barroso I, Tuomilehto J, Boehnke M, Florez JC, Hamsten A, Watkins H, Njølstad I, Wichmann H-E, Caulfield MJ, Khaw K-T, van Duijn CM, Hofman A, Wareham NJ, Langenberg C, Whitfield JB, Martin NG, Montgomery G, Scapoli C, Tzoulaki I, Elliott P, Thorsteinsdottir U, Stefansson K, Brittain EL, McCarthy MI, Froguel P, Sexton PM, Wootten D, Groop L, Dupuis J, Meigs JB, Deganutti G, Demirkan A, Pers TH, Reynolds CA, Aulchenko YS, Kaakinen MA, Jones B, Prokopenko I, Meta-Analysis of Glucose and Insulin-Related Traits Consortium MAGICet al., 2023, GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification, Nature Genetics, Vol: 55, Pages: 1448-1461, ISSN: 1061-4036

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Journal article

Gill D, Woolf B, Zagkos L, Cronje HT, Tzoulaki Iet al., 2023, The cardiovascular efficacy of lipid-lowering drug targets is not entirely explained by apolipoprotein B reduction: Mendelian randomization evidence, Circulation: Genomic and Precision Medicine, Vol: 16, Pages: 490-492, ISSN: 2574-8300

Journal article

Gadgil MD, Wood AC, Karaman I, Graca G, Tzoulaki I, Zhong VW, Greenland P, Kanaya AM, Herrington DMet al., 2023, Metabolomic Profile of the Healthy Eating Index-2015 in the Multiethnic of Atherosclerosis, JOURNAL OF NUTRITION, Vol: 153, Pages: 2174-2180, ISSN: 0022-3166

Journal article

Giontella A, Zagkos L, Geybels M, Larsson SC, Tzoulaki I, Mantzoros CS, Andersen B, Gill D, Cronje HTet al., 2023, Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study, METABOLISM-CLINICAL AND EXPERIMENTAL, Vol: 145, ISSN: 0026-0495

Journal article

Zheng B, Su B, Ahmadi-Abhari S, Kapogiannis D, Tzoulaki I, Riboli E, Middleton Let al., 2023, Dementia risk in patients with type 2 diabetes: Comparing metformin with no pharmacological treatment, ALZHEIMERS & DEMENTIA, ISSN: 1552-5260

Journal article

Rapti I, Asimakopoulos A, Liontos A, Kosmidou M, Christaki E, Biros D, Milionis O, Tsourlos S, Ntotsikas E, Ntzani E, Evangelou E, Gartzonika K, Georgiou I, Tzoulaki I, Tsilidis K, Milionis Het al., 2023, Association of patient characteristics with clinical outcomes in a cohort of hospitalised patients with SARS-CoV-2 infection in a Greek referral centre for COVID-19 (vol 150, pg E160, 2022), EPIDEMIOLOGY AND INFECTION, Vol: 151, ISSN: 0950-2688

Journal article

Chalitsios CV, Georgiou A, Bouras E, Evangelou E, Gill D, Tsilidis KK, Tzoulaki Iet al., 2023, Investigating modifiable pathways in psoriasis: A Mendelian randomization study, JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, Vol: 88, Pages: 593-601, ISSN: 0190-9622

Journal article

Liontos A, Asimakopoulos A-G, Markopoulos GSS, Biros D, Athanasiou L, Tsourlos S, Dova L, Rapti I-C, Tsiakas I, Ntzani E, Evangelou E, Tzoulaki I, Tsilidis K, Vartholomatos G, Dounousi E, Milionis H, Christaki Eet al., 2023, Correlation of Lymphocyte Subpopulations, Clinical Features and Inflammatory Markers during Severe COVID-19 Onset, PATHOGENS, Vol: 12

Journal article

Chalitsios CV, Tsilidis KK, Tzoulaki I, 2023, Response to comment on "Psoriasis and COVID-19: A bidirectional Mendelian randomization study", JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, Vol: 88, Pages: E149-E149, ISSN: 0190-9622

Journal article

Sud A, Horton RH, Hingorani AD, Tzoulaki I, Turnbull C, Houlston RS, Lucassen Aet al., 2023, Realistic expectations are key to realising the benefits of polygenic scores., BMJ: British Medical Journal, Vol: 380, Pages: 1-7, ISSN: 0959-535X

We must not let enthusiasm around polygenic scores allow us to forget other factors that are bigger, more modifiable, and relevant for everyone, argue Amit Sud, Rachel Horton, and colleagues

Journal article

Huang J, Gill D, Zuber V, Matthews PAUL, Elliott PAUL, Tzoulaki I, Dehghan ABBASet al., 2023, Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study, Frontiers in Genetics, Vol: 14, Pages: 1-11, ISSN: 1664-8021

Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment.Methods: We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD-related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb from the coding gene); and 3) brain-specific cis-expression QTL (cis-eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g Factor constructed using genomic structural equation modelling (N = 11,263–331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559).Results: A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (p < 0.05) using different selection criteria for genetic instruments. Particularly, brain-specific cis-eQTL predicted MPO, which accounts for protein-coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4 × 10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.577. Findings for MPO were replicated using the Icelandic GWAS. Although we did not find evidence for colocalization, we found that higher gene

Journal article

Zhao Y, Zhang H, Liu X, Desloge A, Wang Q, Zhao S, Song L, Tzoulaki Iet al., 2023, The prevalence of cardiometabolic multimorbidity and its associations with health outcomes among women in China, FRONTIERS IN CARDIOVASCULAR MEDICINE, Vol: 10, ISSN: 2297-055X

Journal article

Kojouri M, Pinto R, Mustafa R, Huang J, He G, Elliott P, Tzoulaki I, Dehghan Aet al., 2023, Metabolome-wide association study on physical activity, Scientific Reports, Vol: 13, Pages: 1-9, ISSN: 2045-2322

The underlying mechanisms linking physical activity to better health are not fully understood. Here we examined the associations between physical activity and small circulatory molecules, the metabolome, to highlight relevant biological pathways. We examined plasma metabolites associated with self-reported physical activity among 2217 participants from the Airwave Health Monitoring Study. Metabolic profiling was conducted using the mass spectrometry-based Metabolon platform (LC/GC–MS), measuring 828 known metabolites. We replicated our findings in an independent subset of the study (n = 2971) using untargeted LC–MS. Mendelian randomisation was carried out to investigate potential causal associations between physical activity, body mass index, and metabolites. Higher vigorous physical activity was associated (P < 0.05/828 = 6.03 × 10–5) with circulatory levels of 28 metabolites adjusted for age, sex and body mass index. The association was inverse for glutamate and diacylglycerol lipids, and direct for 3–4-hydroxyphenyllactate, phenyl lactate (PLA), alpha-hydroxy isovalerate, tiglylcarnitine, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, isobutyrylcarnitine, imidazole lactate, methionine sulfone, indole lactate, plasmalogen lipids, pristanate and fumarate. In the replication panel, we found 23 untargeted LC–MS features annotated to the identified metabolites, for which we found nominal associations with the same direction of effect for three features annotated to 1-(1-enyl-palmitoyl)-2-oleoyl-GPC (P-16:0/18:1), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2), 1-stearoyl-2-dihomo-linolenoyl-GPC (18:0/20:3n3 or 6). Using Mendelian randomisation, we showed a potential causal relationship between body mass index and three identified metabolites. Circulatory metabolites are associated with physical activity and may play a role in mediating its health effects.

Journal article

Huang J, Su B, Karhunen V, Gill D, Zuber V, Ahola-Olli A, Palaniswamy S, Auvinen J, Herzig K-H, Keinänen-Kiukaanniemi S, Salmi M, Jalkanen S, Lehtimäki T, Salomaa V, Raitakari OT, Matthews PM, Elliott P, Tsilidis KK, Jarvelin M-R, Tzoulaki I, Dehghan Aet al., 2023, Inflammatory diseases, inflammatory biomarkers, and Alzheimer disease: an observational analysis and mendelian randomization, Neurology, Vol: 100, Pages: e568-e581, ISSN: 0028-3878

OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of AD is controversial. We characterised the relationship between inflammatory diseases and the risk of AD and explore the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large scale genome-wide association study (GWAS) datasets, we performed two-sample Mendelian randomisation (MR) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that overall incidence of AD was higher among patients with inflammatory bowel disease (IBD) (hazard ratio (HR)=1.17; 95%CI 1.15 to 1.19; P-value=2.1×10-4), other inflammatory polyarthropathies & systematic connective tissue disorders (OID) (HR=1.13; 95%CI 1.12 to 1.14; P-value=8.6×10-5), psoriasis (HR=1.13; 95%CI 1.10 to 1.16; P-value=2.6×10-4), rheumatoid arthritis (RA) (HR=1.08; 95%CI 1.06 to 1.11; P-value=4.0×10-4), and multiple sclerosis (MS) (HR=1.06; 95%CI 1.04 to 1.07; P-value=2.8×10-4) compared to the age (± 5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted (ORIVW)=1.23; 95%CI 1.06 to 1.42; PIVW=0.007), and lower risk of Crohn's disease (ORIVW=0.73; 95%CI -0.62, 0.86; PIVW=1.3×10

Journal article

Ryan D, Karhunen V, Su B, Traylor M, Richardson TG, Burgess S, Tzoulaki I, Gill Det al., 2023, Genetic evidence for protective effects of angiotensin converting enzyme against Alzheimer's disease but not other neurodegenerative diseases, Pharmacology Annual Meeting, Publisher: WILEY, Pages: 565-567, ISSN: 0007-1188

Conference paper

Papandreou C, Papagiannopoulos C, Koutsonida M, Kanellopoulou A, Markozannes G, Polychronidis G, Tzakos AG, Fragkiadakis GA, Evangelou E, Ntzani E, Tzoulaki I, Aretouli E, Tsilidis KKet al., 2023, Mediterranean diet related metabolite profiles and cognitive performance., Clinical Nutrition, Vol: 42, Pages: 173-181, ISSN: 0261-5614

BACKGROUND & AIMS: Evidence suggests that adherence to the Mediterranean diet (MedDiet) affects human metabolism and may contribute to better cognitive performance. However, the underlying mechanisms are not clear. OBJECTIVE: We generated a metabolite profile for adherence to MedDiet and evaluated its cross-sectional association with aspects of cognitive performance. METHODS: A total of 1250 healthy Greek middle-aged adults from the Epirus Health Study cohort were included in the analysis. Adherence to the MedDiet was assessed using the 14-point Mediterranean Diet Adherence Screener (MEDAS); cognition was measured using the Trail Making Test, the Verbal Fluency test and the Logical Memory test. A targeted metabolite profiling (n = 250 metabolites) approach was applied, using a high-throughput nuclear magnetic resonance platform. We used elastic net regularized regressions, with a 10-fold cross-validation procedure, to identify a metabolite profile for MEDAS. We evaluated the associations of the identified metabolite profile and MEDAS with cognitive tests, using multivariable linear regression models. RESULTS: We identified a metabolite profile composed of 42 metabolites, mainly lipoprotein subclasses and fatty acids, significantly correlated with MedDiet adherence (Pearson r = 0.35, P-value = 5.5 × 10-37). After adjusting for known risk factors and accounting for multiple testing, the metabolite profile and MEDAS were not associated with the cognitive tests. CONCLUSIONS: A plasma metabolite profile related to better adherence to the MedDiet was not associated with the tested aspects of cognitive performance, in a middle-aged Mediterranean population.

Journal article

Elliott J, Bodinier B, Whitaker M, Tzoulaki I, Elliott P, Chadeau-Hyam Met al., 2023, Improving cardiovascular risk prediction beyond pooled cohort equations: a prospective cohort of 304,356 participants

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Pooled Cohort Equations (PCE) are used to predict cardiovascular disease (CVD) risk. Inclusion of other variables may improve risk prediction.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>Identify variables improving CVD risk prediction beyond recalibrated PCE.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Prospective cohort study; sex-stratified Cox survival models with LASSO stability selection to predict CVD in non-overlapping subsets: variable selection (40%), model training (30%) and testing (30%).</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>UK population.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>UK Biobank: 121,724 and 182,632 healthy men and women, respectively, aged 38-73 years at baseline.</jats:p></jats:sec><jats:sec><jats:title>Measurements</jats:title><jats:p>Personal/family medical history; lifestyle factors; genetic, biochemical, hematological, and metabolomic blood markers. Outcomes were incident hospitalization or mortality from CVD.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>There were 11,899 (men) and 9,110 (women) incident CVD cases with median 12.1 years follow-up. Variables selected for both men and women were: age, albumin, antihypertensive medication, apolipoprotein B, atrial fibrillation, C-reactive protein, current smoker, cystatin C, family history of coronary artery disease, glycated hemoglobin, polygenic risk score (PRS) for CVD and systolic blood pressure. Also selected: apolipoprotein A1, lipoprotein(a), white blood cell count, deprivation index (men); triglycerides (women).

Journal article

Garcia-Segura ME, Durainayagam BR, Liggi S, Graça G, Jimenez B, Dehghan A, Tzoulaki I, Karaman I, Elliott P, Griffin JLet al., 2023, Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer´s Disease mouse model and risk loci carriers, Journal of Neurochemistry, Vol: 164, Pages: 57-76, ISSN: 0022-3042

Alzheimer´s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of the importance of metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, transcription factor, pathway, and cell-type enrichment analyses. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA-7 null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and genes associated with AD risk. We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabol

Journal article

Zagkos L, Dib M-J, Pinto R, Gill D, Koskeridis F, Drenos F, Markozannes G, Elliott P, Zuber V, Tsilidis K, Dehghan A, Tzoulaki Iet al., 2022, Associations of genetically predicted fatty acid levels across the phenome: a mendelian randomisation study, PLoS Medicine, Vol: 19, ISSN: 1549-1277

BACKGROUND: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. METHODS AND FINDINGS: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.

Journal article

Charpignon M-L, Vakulenko-Lagun B, Zheng B, Magdamo C, Su B, Evans K, Rodriguez S, Sokolov A, Boswell S, Sheu Y-H, Somai M, Middleton L, Hyman BT, Betensky RA, Finkelstein SN, Welsch RE, Tzoulaki I, Blacker D, Das S, Albers MWet al., 2022, Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia, NATURE COMMUNICATIONS, Vol: 13

Journal article

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