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1. Phenome-wide association study on miRNA-related sequence variants: the UK Biobank

Author

Rima Mustafa, Mohsen Ghanbari, Ville Karhunen, Marina Evangelou, and Abbas Dehghan

Subjects
microRNA, Genetic variants, Phenome, Pleiotropy, Medicine, Genetics, QH426-470
Abstract

Abstract Background Genetic variants in the coding region could directly affect the structure and expression levels of genes and proteins. However, the importance of variants in the non-coding region, such as microRNAs (miRNAs), remain to be elucidated. Genetic variants in miRNA-related sequences could affect their biogenesis or functionality and ultimately affect disease risk. Yet, their implications and pleiotropic effects on many clinical conditions remain unknown. Methods Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis. Results We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10–162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia. Conclusions Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.

Published
2023
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2. Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

Author

Nicolien A. van Vliet, Maxime M. Bos, Carisha S. Thesing, Layal Chaker, Maik Pietzner, Evelyn Houtman, Matt J. Neville, Ruifang Li-Gao, Stella Trompet, Rima Mustafa, Fariba Ahmadizar, Marian Beekman, Mariska Bot, Kathrin Budde, Constantinos Christodoulides, Abbas Dehghan, Christian Delles, Paul Elliott, Marina Evangelou, He Gao, Mohsen Ghanbari, Antonius E. van Herwaarden, M. Arfan Ikram, Martin Jaeger, J. Wouter Jukema, Ibrahim Karaman, Fredrik Karpe, Margreet Kloppenburg, Jennifer M. T. A. Meessen, Ingrid Meulenbelt, Yuri Milaneschi, Simon P. Mooijaart, Dennis O. Mook-Kanamori, Mihai G. Netea, Romana T. Netea-Maier, Robin P. Peeters, Brenda W. J. H. Penninx, Naveed Sattar, P. Eline Slagboom, H. Eka D. Suchiman, Henry Völzke, Ko Willems van Dijk, Raymond Noordam, Diana van Heemst, and BBMRI Metabolomics Consortium

Subjects
Thyroid hormones, Coronary artery disease, Metabolomics, Mendelian randomization, Medicine
Abstract

Abstract Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

Published
2021
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3. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

Author

John A Todd, Marina Evangelou, Antony J Cutler, Marcin L Pekalski, Neil M Walker, Helen E Stevens, Linsey Porter, Deborah J Smyth, Daniel B Rainbow, Ricardo C Ferreira, Laura Esposito, Kara M D Hunter, Kevin Loudon, Kathryn Irons, Jennie H Yang, Charles J M Bell, Helen Schuilenburg, James Heywood, Ben Challis, Sankalpa Neupane, Pamela Clarke, Gillian Coleman, Sarah Dawson, Donna Goymer, Katerina Anselmiova, Jane Kennet, Judy Brown, Sarah L Caddy, Jia Lu, Jane Greatorex, Ian Goodfellow, Chris Wallace, Tim I Tree, Mark Evans, Adrian P Mander, Simon Bond, Linda S Wicker, and Frank Waldron-Lynch

Subjects
Medicine
Abstract

BackgroundInterleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs.Methods and findingsTo define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only.ConclusionsThe DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D.Trial registrationISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

Published
2016
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4. Comparison of methods for competitive tests of pathway analysis.

Author

Marina Evangelou, Augusto Rendon, Willem H Ouwehand, Lorenz Wernisch, and Frank Dudbridge

Subjects
Medicine, Science
Abstract

It has been suggested that pathway analysis can complement single-SNP analysis in exploring genomewide association data. Pathway analysis incorporates the available biological knowledge of genes and SNPs and is expected to improve the chances of revealing the underlying genetic architecture of complex traits. Methods for pathway analysis can be classified as competitive (enrichment) or self-contained (association) according to the hypothesis tested. Although association tests are statistically more powerful than enrichment tests they can be difficult to calibrate because biases in analysis accumulate across multiple SNPs or genes. Furthermore, enrichment tests can be more scientifically relevant than association tests, as they detect pathways with relatively more evidence for association than the remaining genes. Here we show how some well known association tests can be simply adapted to test for enrichment, and compare their performance to some established enrichment tests. We propose versions of the Adaptive Rank Truncated Product (ARTP), Tail Strength Measure and Fisher's combination of p-values for testing the enrichment null hypothesis. We compare the behaviour of these proposed methods with the established Hypergeometric Test and Gene-Set Enrichment Analysis (GSEA). The results of the simulation study show that the modified version of the ARTP method has generally the best performance across the situations considered. The methods were also applied for finding enriched pathways for body mass index (BMI) and platelet function phenotypes. The pathway analysis of BMI identified the Vasoactive Intestinal Peptide pathway as significantly associated with BMI. This pathway has been previously reported as associated with BMI and the risk of obesity. The ARTP method was the method that identified the largest number of enriched pathways across all tested pathway databases and phenotypes. The simulation and data application results are in agreement with previous work on association tests and suggests that the ARTP should be preferred for both enrichment and association testing.

Published
2012
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5. The link between attention deficit hyperactivity disorder (ADHD) symptoms and obesity-related traits: genetic and prenatal explanations

Author

Irma Moilanen, Marina Evangelou, Alina Rodriguez, Ville Karhunen, Tuula Hurtig, Marjo-Riitta Järvelin, Verena Zuber, and Tom Bond

Subjects
Offspring, Neurosciences. Biological psychiatry. Neuropsychiatry, Article, DISEASE, Body Mass Index, 1117 Public Health and Health Services, Cellular and Molecular Neuroscience, MATERNAL OBESITY, INFLAMMATION, Pregnancy, mental disorders, ADHD, Humans, Medicine, Attention deficit hyperactivity disorder, Clinical genetics, Obesity, Association (psychology), Biological Psychiatry, Genetic association, Psychiatry, Science & Technology, business.industry, 1103 Clinical Sciences, ASSOCIATION, Mendelian Randomization Analysis, medicine.disease, Causality, BODY-MASS INDEX, Psychiatry and Mental health, Attention Deficit Disorder with Hyperactivity, 1701 Psychology, Etiology, MENDELIAN RANDOMIZATION, RISK-FACTORS, Female, DEFICIT/HYPERACTIVITY DISORDER, business, Body mass index, Life Sciences & Biomedicine, Genome-Wide Association Study, Clinical psychology, RC321-571
Abstract

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with obesity, however, the potential causality between the traits remains unclear. We examined both genetic and prenatal evidence for causality using Mendelian Randomisation (MR) and polygenic risk scores (PRS). We conducted bi-directional MR on ADHD liability and six obesity-related traits using summary statistics from the largest available meta-analyses of genome-wide association studies. We also examined the shared genetic aetiology between ADHD symptoms (inattention and hyperactivity) and body mass index (BMI) by PRS association analysis using longitudinal data from Northern Finland Birth Cohort 1986 (NFBC1986, n = 2984). Lastly, we examined the impact of the prenatal environment by association analysis of maternal pre-pregnancy BMI and offspring ADHD symptoms, adjusted for PRS of both traits, in NFBC1986 dataset. Through MR analyses, we found evidence for bidirectional causality between ADHD liability and obesity-related traits. PRS association analyses showed evidence for genetic overlap between ADHD symptoms and BMI. We found no evidence for a difference between inattention and hyperactivity symptoms, suggesting that neither symptom subtype is driving the association. We found evidence for association between maternal pre-pregnancy BMI and offspring ADHD symptoms after adjusting for both BMI and ADHD PRS (association p-value = 0.027 for inattention, p = 0.008 for hyperactivity). These results are consistent with the hypothesis that the co-occurrence between ADHD and obesity has both genetic and prenatal environmental origins.

Published
2021

6. Atopic dermatitis or eczema? Consequences of ambiguity in disease name for biomedical literature mining

Author

Sarah Filippi, Marina Evangelou, Yoann Pitarch, Clément Frainay, Adnan Custovic, Imperial College London, Métabolisme et Xénobiotiques (ToxAlim-MeX), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Recherche d’Information et Synthèse d’Information (IRIT-IRIS), Institut de recherche en informatique de Toulouse (IRIT), Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, and UK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission

Subjects
Medical terminology, GENES, Allergy, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Immunology, Decision tree, Eczema, text mining, computer.software_genre, Terminology, TEXT, Dermatitis, Atopic, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, Terminology as Topic, medical terminology, medicine, Immunology and Allergy, Data Mining, Humans, information retrieval, REVISED NOMENCLATURE, 030304 developmental biology, media_common, 0303 health sciences, Science & Technology, atopic dermatitis, business.industry, Decision tree learning, Subject (documents), Atopic dermatitis, Ambiguity, medicine.disease, 3. Good health, Systematic review, 030228 respiratory system, 1107 Immunology, 1111 Nutrition and Dietetics, Artificial intelligence, business, Psychology, computer, Life Sciences & Biomedicine, Natural language processing
Abstract

International audience; Background: Biomedical research increasingly relies on computational approaches to extract relevant information from large corpora of publications.Objective: To investigate the consequence of the ambiguity between the use of terms "Eczema" and "Atopic Dermatitis" (AD) from the Information Retrieval perspective, and its impact on meta-analyses, systematic reviews and text mining.Methods: Articles were retrieved by querying the PubMed using terms 'eczema' (D003876) and "dermatitis, atopic" (D004485). We used machine learning to investigate the differences between the contexts in which each term is used. We used a decision tree approach and trained model to predict if an article would be indexed with eczema or AD tags. We used text-mining tools to extract biological entities associated with eczema and AD, and investigated the discrepancy regarding the retrieval of key findings according to the terminology used.Results: Atopic dermatitis query yielded more articles related to veterinary science, biochemistry, cellular and molecular biology; the eczema query linked to public health, infectious disease and respiratory system. Medical Subject Headings terms associated with "AD" or "Eczema" differed, with an agreement between the top 40 lists of 52%. The presence of terms related to cellular mechanisms, especially allergies and inflammation, characterized AD literature. The metabolites mentioned more frequently than expected in articles with AD tag differed from those indexed with eczema. Fewer enriched genes were retrieved when using eczema compared to AD query.Conclusions and clinical relevance: There is a considerable discrepancy when using text mining to extract bio-entities related to eczema or AD. Our results suggest that any systematic approach (particularly when looking for metabolites or genes related to the condition) should be performed using both terms jointly. We propose to use decision tree learning as a tool to spot and characterize ambiguity, and provide the source code for disambiguation at https://github.com/cfrainay/ResearchCodeBase.

Published
2021

7. MiR-139-5p is a causal biomarker for type 2 diabetes; Results from genome-wide microRNA profiling and Mendelian randomization analysis in a population-based study

Author

Mohsen Ghanbari, Abbas Dehghan, Fariba Ahmadizar, Marina Evangelou, M. A. Ikram, Maryam Kavousi, Rima Mustafa, and Michelle M. J. Mens

Subjects
education.field_of_study, Population, Mendelian Randomization Analysis, Type 2 diabetes, Biology, Bioinformatics, medicine.disease, Rotterdam Study, Diabetes mellitus, microRNA, Mendelian randomization, medicine, Biomarker (medicine), education
Abstract

MicroRNAs (miRNAs) have emerged as key regulators of gene expression. Differential expression of miRNAs has been linked to diabetes, but underlying pathways remain poorly understood. We performed genome-wide miRNAs profiling and tested the causal associations between miRNAs and type 2 diabetes in the general population. Subsequently, we investigated target genes and metabolites of miRNAs to provide insight into the metabolic disturbances that emerge with type 2 diabetes. Between 2002 and 2005, plasma levels of 2083 circulatory miRNAs were profiled in 1900 participants (mean age 71.4 years) of the population-based Rotterdam Study cohort. The associations of 591 well-expressed miRNAs with prevalent and incident type 2 diabetes were examined until 2015. Two-sample Mendelian Randomization (MR) was conducted to investigate the causal associations and miRNA-target genes and metabolites were studied in relation to type 2 diabetes. At baseline, higher plasma levels of miR-139-5p and miR-193a-5p were associated (FDR9.0 years, 209 participants developed type 2 diabetes. Plasma levels of miR-99a-5p, miR-4664-3p, miR-29a-3p, miR-122-5p, and miR-125b-5p were significantly associated with incident type 2 diabetes (n=209). Two-sample MR confirmed a causal effect for miR-139-5p (MR-IWV-beta=0.10, p=3.51×10−4) on type 2 diabetes. We found several target genes and metabolites that could link miR-139-5p to pathways underlying type 2 diabetes. Our study indicates a causal relationship between miR-139-5p and type 2 diabetes and suggests this miRNA as a plasma biomarker of type 2 diabetes.

Published
2021

8. Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

Author

Maik Pietzner, Mohsen Ghanbari, Fredrik Karpe, Nicolien A. van Vliet, P. Eline Slagboom, Dennis O. Mook-Kanamori, Paul Elliott, Kathrin Budde, Jennifer Meessen, Constantinos Christodoulides, J. Wouter Jukema, E. Houtman, Yuri Milaneschi, Ingrid Meulenbelt, Brenda W.J.H. Penninx, Naveed Sattar, Martin Jaeger, Marian Beekman, Stella Trompet, M.M. Bos, Antonius E. van Herwaarden, Romana T. Netea-Maier, Ko Willems van Dijk, Matt J. Neville, Ibrahim Karaman, Fariba Ahmadizar, Simon P. Mooijaart, Rima Mustafa, H. Eka D. Suchiman, Margreet Kloppenburg, Layal Chaker, He Gao, Diana van Heemst, Raymond Noordam, Mihai G. Netea, Robin P. Peeters, Henry Völzke, Abbas Dehghan, Ruifang Li-Gao, Mariska Bot, Carisha S. Thesing, Marina Evangelou, Christian Delles, M. Arfan Ikram, Epidemiology, Internal Medicine, Home Office, Medical Research Council (MRC), Imperial College Healthcare NHS Trust- BRC Funding, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Consortium, BBMRI Metabolomics, Noordam, Raymond [0000-0001-7801-809X], and Apollo - University of Cambridge Repository

Subjects
Male, endocrine system diseases, Thyroid hormones, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Physiology, RATIONALE, Thyrotropin, Disease, 030204 cardiovascular system & hematology, Coronary artery disease, SERUM, 0302 clinical medicine, SUBCLINICAL HYPOTHYROIDISM, DESIGN, THYROID-HORMONES, EPIDEMIOLOGY, Euthyroid, 11 Medical and Health Sciences, 0303 health sciences, medicine.diagnostic_test, Thyroid, OBJECTIVES, General Medicine, Middle Aged, Lipids, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], medicine.anatomical_structure, Cardiovascular Diseases, Cohort, Medicine, Female, HEALTH, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Research Article, Adult, endocrine system, Reference range, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], BBMRI Metabolomics Consortium, 03 medical and health sciences, Young Adult, Medicine, General & Internal, SDG 3 - Good Health and Well-being, General & Internal Medicine, Mendelian randomization, medicine, Humans, Metabolomics, 030304 developmental biology, Aged, Science & Technology, business.industry, Mendelian Randomization Analysis, medicine.disease, Thyroxine, Lipid profile, business
Abstract

Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

Published
2021

9. S2A MENDELIAN RANDOMISATION STUDY ON CAUSALITY BETWEEN ATTENTION-DEFICIT/HYPERACTIVITY DISORDER AND MULTIPLE OBESITY-RELATED TRAITS

Author

Alina Rodriguez, Marina Evangelou, Marjo-Riitta Järvelin, and Ville Karhunen

Subjects
Pharmacology, medicine.disease, Causality, Obesity, Psychiatry and Mental health, symbols.namesake, Neurology, medicine, Mendelian inheritance, symbols, Attention deficit hyperactivity disorder, Pharmacology (medical), Neurology (clinical), Psychology, Biological Psychiatry, Clinical psychology
Published
2019

10. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author

Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract

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. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)

Published
2018

11. Correlation of pre-operative CT findings with surgical & histological tumor dissemination patterns at cytoreduction for primary advanced and relapsed epithelial ovarian cancer: A retrospective evaluation

Author

Andrea Rockall, Hani Gabra, Christina Fotopoulou, Katherine Nixon, Marina Evangelou, S. Nasser, Benjamin P Jones, A. Lazaridis, Maria Kyrgiou, and Ovarian Cancer Action

Subjects
FIGO Stage IIIC, DEBULKING SURGERY, Carcinoma, Ovarian Epithelial, 0302 clinical medicine, STAGE-III, 1114 Paediatrics And Reproductive Medicine, BENEFIT, Neoplasms, Glandular and Epithelial, PREDICTORS, Lymph node, Cr, Aged, 80 and over, Ovarian Neoplasms, 030219 obstetrics & reproductive medicine, Obstetrics and Gynecology, Obstetrics & Gynecology, Pre-operative imaging, Cytoreduction Surgical Procedures, Middle Aged, Debulking, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, CONSECUTIVE PATIENTS, Female, Radiology, Life Sciences & Biomedicine, MRI, Adult, medicine.medical_specialty, RESECTION, CARCINOMA, PET/CT, 03 medical and health sciences, Ovarian cancer, medicine, Carcinoma, Humans, COMPUTED-TOMOGRAPHY, Oncology & Carcinogenesis, Aged, Retrospective Studies, Porta hepatis, PET-CT, Science & Technology, business.industry, Rectum, medicine.disease, Surgery, Lymph Nodes, Neoplasm Recurrence, Local, business, Tomography, X-Ray Computed, 1112 Oncology And Carcinogenesis
Abstract

Objectives Computed tomography (CT) is an essential part of preoperative planning prior to cytoreductive surgery for primary and relapsed epithelial ovarian cancer (EOC). Our aim is to correlate pre-operative CT results with intraoperative surgical and histopathological findings at debulking surgery. Methods We performed a systematic comparison of intraoperative tumor dissemination patterns and surgical resections with preoperative CT assessments of infiltrative disease at key resection sites, in women who underwent multivisceral debulking surgery due to EOC between January 2013 and December 2014 at a tertiary referral center. The key sites were defined as follows: diaphragmatic involvement(DI), splenic disease (SI), large (LBI) and small (SBI) bowel involvement, rectal involvement (RI), porta hepatis involvement (PHI), mesenteric disease (MI) and lymph node involvement (LNI). Results A total of 155 patients, mostly with FIGO stage IIIC disease (65%) were evaluated (primary=105, relapsed=50). Total macroscopic cytoreduction rates were: 89%. Pre-operative CT findings displayed high specificity across all tumor sites apart from the retroperitoneal lymph node status, with a specificity of 65%. The ability however of the CT to accurately identify sites affected by invasive disease was relatively low with the following sensitivities as relating to final histology: 32% (DI), 26% (SI), 46% (LBI), 44% (SBI), 39% (RI), 57% (PHI), 31% (MI), 63% (LNI). Conclusion Pre-operative CT imaging shows high specificity but low sensitivity in detecting tumor involvement at key sites in ovarian cancer surgery. CT findings alone should not be used for surgical decision making.

Published
2016

12. GENETIC ANALYSIS OF OVER ONE MILLION PEOPLE IDENTIFIES 535 NOVEL LOCI ASSOCIATED WITH BLOOD PRESSURE AND RISK OF CARDIOVASCULAR DISEASE

Author

T Esko, Mark J. Caulfield, Marina Evangelou, Jacklyn N. Hellwege, Paul Elliott, A. Metspalu, Niki Dimou, Raha Pazoki, Louise V. Wain, H. Gao, D. Mosen, Helen R. Warren, Michael R. Barnes, Ioanna Tzoulaki, Borbala Mifsud, Anil K. Giri, Georgios Ntritsos, and Evangelos Evangelou

Subjects
0301 basic medicine, Genetics, Physiology, business.industry, Genetic variants, Disease, Genetic analysis, Genetic architecture, 03 medical and health sciences, 030104 developmental biology, Blood pressure, Internal Medicine, Trait, Medicine, Cardiology and Cardiovascular Medicine, business
Abstract

Objective:Hypertension is the leading cause of cardiovascular morbidity. High blood pressure is highly heritable (∼30–50%), however all genetic variants identified so far only explain ∼3–4% of the trait variance. Hence much of the genetic architecture of blood pressure remains unexplained.Design and

Published
2018

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