Author: "Leo Pekka, Lyytikäinen" / Topic: medicine - Searchworks@Jio Institute Digital Library Search Results

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1. Uncovering the complex genetic architecture of human plasma lipidome using machine learning methods

Author: Miikael Lehtimäki, Binisha H. Mishra, Coral Del-Val, Leo-Pekka Lyytikäinen, Mika Kähönen, C. Robert Cloninger, Olli T. Raitakari, Reijo Laaksonen, Igor Zwir, Terho Lehtimäki, and Pashupati P. Mishra
Subjects: Medicine, Science
Abstract: Abstract Genetic architecture of plasma lipidome provides insights into regulation of lipid metabolism and related diseases. We applied an unsupervised machine learning method, PGMRA, to discover phenotype-genotype many-to-many relations between genotype and plasma lipidome (phenotype) in order to identify the genetic architecture of plasma lipidome profiled from 1,426 Finnish individuals aged 30–45 years. PGMRA involves biclustering genotype and lipidome data independently followed by their inter-domain integration based on hypergeometric tests of the number of shared individuals. Pathway enrichment analysis was performed on the SNP sets to identify their associated biological processes. We identified 93 statistically significant (hypergeometric p-value
Published: 2023
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2. Adulthood blood levels of hsa-miR-29b-3p associate with preterm birth and adult metabolic and cognitive health

Author: Saara Marttila, Suvi Rovio, Pashupati P. Mishra, Ilkka Seppälä, Leo-Pekka Lyytikäinen, Markus Juonala, Melanie Waldenberger, Niku Oksala, Mika Ala-Korpela, Emily Harville, Nina Hutri-Kähönen, Mika Kähönen, Olli Raitakari, Terho Lehtimäki, and Emma Raitoharju
Subjects: Medicine, Science
Abstract: Abstract Preterm birth (PTB) is associated with increased risk of type 2 diabetes and neurocognitive impairment later in life. We analyzed for the first time the associations of PTB with blood miRNA levels in adulthood. We also investigated the relationship of PTB associated miRNAs and adulthood phenotypes previously linked with premature birth. Blood MicroRNA profiling, genome-wide gene expression analysis, computer-based cognitive testing battery (CANTAB) and serum NMR metabolomics were performed for Young Finns Study subjects (aged 34–49 years, full-term n = 682, preterm n = 84). Preterm birth (vs. full-term) was associated with adulthood levels of hsa-miR-29b-3p in a fully adjusted regression model (p = 1.90 × 10–4, FDR = 0.046). The levels of hsa-miR-29b-3p were down-regulated in subjects with PTB with appropriate birthweight for gestational age (p = 0.002, fold change [FC] = − 1.20) and specifically in PTB subjects with small birthweight for gestational age (p = 0.095, FC = − 1.39) in comparison to individuals born full term. Hsa-miR-29b-3p levels correlated with the expressions of its target-mRNAs BCL11A and CS and the gene set analysis results indicated a target-mRNA driven association between hsa-miR-29b-3p levels and Alzheimer's disease, Parkinson's disease, Insulin signaling and Regulation of Actin Cytoskeleton pathway expression. The level of hsa-miR-29b-3p was directly associated with visual processing and sustained attention in CANTAB test and inversely associated with serum levels of VLDL subclass component and triglyceride levels. In conlcusion, adult blood levels of hsa-miR-29b-3p were lower in subjects born preterm. Hsa-miR-29b-3p associated with cognitive function and may be linked with adulthood morbidities in subjects born preterm, possibly through regulation of gene sets related to neurodegenerative diseases and insulin signaling as well as VLDL and triglyceride metabolism.
Published: 2021
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3. Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

Author: Jaakko Laaksonen, Pashupati P. Mishra, Ilkka Seppälä, Leo-Pekka Lyytikäinen, Emma Raitoharju, Nina Mononen, Maija Lepistö, Henrikki Almusa, Pekka Ellonen, Nina Hutri-Kähönen, Markus Juonala, Olli Raitakari, Mika Kähönen, Jukka T. Salonen, and Terho Lehtimäki
Subjects: Medicine, Science
Abstract: Abstract High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.
Published: 2021
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4. Prevalence and long-term prognostic implications of prolonged QRS duration in left ventricular hypertrophy: a population-based observational cohort study

Author: Harri Rissanen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Kjell Nikus, Mika Kähönen, Markku Eskola, Jussi Hernesniemi, Heini Huhtala, Antti Jula, Jani Rankinen, Petri Haataja, Suvi Tuohinen, and Andrés Ricardo Pérez-Riera
Subjects: Medicine
Published: 2022
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5. Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved]

Author: Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain
Subjects: Medicine, Science
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P
Published: 2021
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6. Variants associated with HHIP expression have sex-differential effects on lung function [version 1; peer review: 2 approved]

Author: Katherine A. Fawcett, Ma'en Obeidat, Carl Melbourne, Nick Shrine, Anna L. Guyatt, Catherine John, Jian'an Luan, Anne Richmond, Marta R. Moksnes, Raquel Granell, Stefan Weiss, Medea Imboden, Sebastian May-Wilson, Pirro Hysi, Thibaud S. Boutin, Laura Portas, Claudia Flexeder, Sarah E. Harris, Carol A. Wang, Leo-Pekka Lyytikäinen, Teemu Palviainen, Rachel E. Foong, Dirk Keidel, Cosetta Minelli, Claudia Langenberg, Yohan Bossé, Maarten Van den Berge, Don D. Sin, Ke Hao, Archie Campbell, David Porteous, Sandosh Padmanabhan, Blair H. Smith, David M. Evans, Sue Ring, Arnulf Langhammer, Kristian Hveem, Cristen Willer, Ralf Ewert, Beate Stubbe, Nicola Pirastu, Lucija Klaric, Peter K. Joshi, Karina Patasova, Mangino Massimo, Ozren Polasek, John M. Starr, Stefan Karrasch, Konstantin Strauch, Thomas Meitinger, Igor Rudan, Taina Rantanen, Kirsi Pietiläinen, Mika Kähönen, Olli T. Raitakari, Graham L. Hall, Peter D. Sly, Craig E. Pennell, Jaakko Kaprio, Terho Lehtimäki, Veronique Vitart, Ian J. Deary, Debbie Jarvis, James F. Wilson, Tim Spector, Nicole Probst-Hensch, Nicholas J. Wareham, Henry Völzke, John Henderson, David P. Strachan, Ben M. Brumpton, Caroline Hayward, Ian P. Hall, Martin D. Tobin, and Louise V. Wain
Subjects: Medicine, Science
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P
Published: 2020
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7. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 3; referees: 2 approved]

Author: Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London
Subjects: Genomics, Medicine, Science
Abstract: Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P
Published: 2018
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8. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 2; referees: 2 approved]

Author: Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. Harris, Ani Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Understanding Society Scientific Group, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall, Martin D. Tobin, and Stephanie J. London
Subjects: Genomics, Medicine, Science
Abstract: Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P
Published: 2018
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9. Prehospital Adenosine Diphosphate Receptor Blocker Use, Culprit Artery Flow, and Mortality in STEMI: The MADDEC Study

Author: Jussi Hernesniemi, Terho Lehtimäki, Markku Eskola, Juho Tynkkynen, Niku Oksala, Markus Hautamäki, Kjell Nikus, Leo-Pekka Lyytikäinen, Tampere University, TAYS Heart Centre, Clinical Medicine, Department of Clinical Chemistry, Verisuoni- ja toimenpideradiologinen keskus, and Department of Radiology
Subjects: Male, Ticagrelor, medicine.medical_specialty, Prasugrel, medicine.medical_treatment, Population, 030204 cardiovascular system & hematology, 3121 Internal medicine, 030226 pharmacology & pharmacy, 03 medical and health sciences, Percutaneous Coronary Intervention, 0302 clinical medicine, Risk Factors, Internal medicine, Odds Ratio, Humans, Medicine, Pharmacology (medical), Registries, Original Research Article, cardiovascular diseases, Myocardial infarction, education, Aged, Retrospective Studies, Aged, 80 and over, education.field_of_study, Management of acute coronary syndrome, business.industry, Percutaneous coronary intervention, General Medicine, Middle Aged, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Clopidogrel, Coronary Vessels, 3. Good health, Survival Rate, Logistic Models, Conventional PCI, Purinergic P2Y Receptor Antagonists, Cardiology, ST Elevation Myocardial Infarction, Female, business, Prasugrel Hydrochloride, medicine.drug
Abstract: Background and Objective The newer adenosine diphosphate (ADP) receptor blockers ticagrelor and prasugrel are superior to clopidogrel in the long-term management of acute coronary syndrome (ACS). We evaluated the acute performance (prehospital loading) of these ADP receptor blockers in a primary percutaneous coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods In a retrospective, single-center registry study, data on all STEMI patients admitted for their first primary PCI between January 2007 and April 2020 were analyzed (n = 3218). The three ADP receptor blockers were mainly used during consecutive periods (clopidogrel 2007–2010, prasugrel 2011–2014, and ticagrelor 2014–2020), and were compared with risk factor-adjusted multivariate logistic regression for acute 3- and 7-day mortality and culprit artery flow before and after PCI. Results Of the 3218 total patients, 47.6% (n = 1532) were treated with ticagrelor, 22.1% (n = 711) were treated with prasugrel, and 30.3% (n = 975) were treated with clopidogrel. The use of ticagrelor or prasugrel as opposed to clopidogrel was associated with better culprit artery flow before PCI (odds ratio [OR] 1.21 for moderate or good flow, 95% confidence interval [CI] 1.03–1.42, p = 0.022), as well as lower acute mortality (OR 0.66 for 3-day mortality, 95% CI 0.46–0.95, p = 0.025; and OR 0.71 for 7-day mortality, 95% CI 0.52–0.98, p = 0.039). The results in regard to acute mortality were highlighted among patients with short treatment delays (disappearing with longer treatment delays; p
Published: 2021
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10. Systemic vascular resistance predicts the development of hypertension: the cardiovascular risk in young Finns study

Author: Heikki Aatola, Leo-Pekka Lyytikäinen, Atte Haarala, Mika Kähönen, Olli T. Raitakari, Kalle Sipilä, Teemu Koivistoinen, Terho Lehtimäki, Markus Juonala, Emilia Kähönen, and Nina Hutri-Kähönen
Subjects: Adult, Male, medicine.medical_specialty, Hemodynamics, Blood Pressure, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, Longitudinal Studies, 030212 general & internal medicine, Finland, business.industry, General Medicine, medicine.anatomical_structure, Blood pressure, Heart Disease Risk Factors, Systemic hemodynamics, Hypertension, Vascular resistance, Cardiology, Female, Vascular Resistance, Cardiology and Cardiovascular Medicine, business
Abstract: To study whether systemic hemodynamics, especially systemic vascular resistance, predicts the development of hypertension and improves the risk prediction of incident hypertension beyond common risk factors in the risk models in young adults.Typical risk factors for hypertension in the risk prediction models (systolic and diastolic blood pressure, parental history of hypertension, age, sex, body-mass index, smoking), laboratory values (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, C-reactive protein), heart rate (HR), stroke index (SI), and systemic vascular resistance index (SVRI) calculated by whole-body impedance cardiography were evaluated in 2007 and blood pressure in 2011 in 1293 Finnish adults (aged 30-45 years; females 56%;Of hemodynamic variables, SVRI and HR evaluated in 2007 were independently associated with systolic blood pressure (These findings suggest that systemic vascular resistance index predicts the incidence of hypertension in young adults and that the evaluation of systemic hemodynamics could provide an additional tool for hypertension risk prediction.
Published: 2020
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11. Serum apolipoprotein A-I concentration differs in coronary and peripheral artery disease

Author: Leo-Pekka Lyytikäinen, Jahangir Khan, Terho Lehtimäki, Niku Oksala, Jari Laurikka, Niina Khan, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
Subjects: Lung Diseases, Male, Apolipoprotein B, Arterial disease, Clinical Biochemistry, coronary artery bypass grafting, Gene Expression, Coronary Artery Disease, Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, Coronary Artery Bypass, Peripheral Artery Diseases, Aged, 80 and over, biology, Smoking, General Medicine, Middle Aged, medicine.anatomical_structure, Cardiology, Female, coronary artery disease, Artery, Adult, medicine.medical_specialty, Biolääketieteet - Biomedicine, Kirurgia, anestesiologia, tehohoito, radiologia - Surgery, anesthesiology, intensive care, radiology, lipids, Peripheral Arterial Disease, 03 medical and health sciences, peripheral arterial disease, Internal medicine, medicine, Humans, Triglycerides, Aged, Retrospective Studies, Apolipoprotein A-I, business.industry, Cholesterol, HDL, Cholesterol, LDL, Atherosclerosis, medicine.disease, Logistic Models, Disease Presentation, biology.protein, Neural Networks, Computer, atherosclerosis, business
Abstract: Coronary artery and peripheral artery diseases represent different clinical outcomes of atherosclerosis and despite sharing common risk factors the ultimate reasons determining disease presentation are still unclear. The present study sought to define and compare the serum lipid and apolipoprotein profiles of patients undergoing coronary artery bypass grafting and those treated invasively for symptomatic lower extremity peripheral artery disease. Altogether 218 coronary and 280 peripheral artery disease patients treated between 2013 and 2014 in the Tampere University Hospital, Tampere, Finland, with available lipid measurements within two years prior to the intervention were retrospectively analysed. The Extended Friedewald formula neural network model was used to obtain apolipoprotein and lipoprotein subfraction values. Patients undergoing coronary artery bypass surgery had a clear male predominance (82% versus 53%
Published: 2020
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12. Extensive phenotype data and machine learning in prediction of mortality in acute coronary syndrome – the MADDEC study

Author: Markku Eskola, Jussi Hernesniemi, Kjell Nikus, Terho Lehtimäki, Juho Tynkkynen, Niku Oksala, Pashupati P. Mishra, Leo-Pekka Lyytikäinen, Kari Antila, and Shadi Mahdiani
Subjects: Male, Acute coronary syndrome, Comorbidity, 030204 cardiovascular system & hematology, Machine learning, computer.software_genre, Coronary Angiography, Risk Assessment, acute coronary syndrome, 03 medical and health sciences, 0302 clinical medicine, Medicine, Electronic Health Records, Humans, risk factors, 030212 general & internal medicine, Registries, ta512, Aged, Retrospective Studies, ta217, ta213, business.industry, General Medicine, Middle Aged, medicine.disease, Phenotype, mortality, Logistic Models, machine learning, Female, Original Article, Artificial intelligence, business, Value (mathematics), computer
Abstract: Objective: Investigation of the clinical potential of extensive phenotype data and machine learning (ML) in the prediction of mortality in acute coronary syndrome (ACS). Methods: The value of ML and extensive clinical data was analyzed in a retrospective registry study of 9066 consecutive ACS patients (January 2007 to October 2017). Main outcome was six-month mortality. Prediction models were developed using two ML methods, logistic regression and extreme gradient boosting (xgboost). The models were fitted in training set of patients treated in 2007–2014 and 2017 (81%, n = 7344) and validated in a separate validation set of patients treated in 2015–2016 with full GRACE score data available for comparison of model accuracy (19%, n = 1722). Results: Overall, six-month mortality was 7.3% (n = 660). Several variables were found to be significantly associated with six-month mortality by both ML methods. The xgboost scored the best performance: AUC 0.890 (0.864–0.916). The AUC values for logistic regression and GRACE score were 0.867(0.837–0.897) and 0.822 (0.785–0.859), respectively. The AUC value of xgboost was better when compared to logistic regression (p = .012) and GRACE score (p Conclusions: The use of extensive phenotype data and novel machine learning improves prediction of mortality in ACS over traditional GRACE score.KEY MESSAGESThe collection of extensive cardiovascular phenotype data from electronic health records as well as from data recorded by physicians can be used highly effectively in prediction of mortality after acute coronary syndrome.Supervised machine learning methods such as logistic regression and extreme gradient boosting using extensive phenotype data significantly outperform conventional risk assessment by the current golden standard GRACE score.Integration of electronic health records and the use of supervised machine learning methods can be easily applied in a single centre level to model the risk of mortality. The collection of extensive cardiovascular phenotype data from electronic health records as well as from data recorded by physicians can be used highly effectively in prediction of mortality after acute coronary syndrome. Supervised machine learning methods such as logistic regression and extreme gradient boosting using extensive phenotype data significantly outperform conventional risk assessment by the current golden standard GRACE score. Integration of electronic health records and the use of supervised machine learning methods can be easily applied in a single centre level to model the risk of mortality.
Published: 2022
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13. Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

Author: Peter W. Macfarlane, Niels Grarup, Ruth J. F. Loos, Marcus Dörr, Peter P. Pramstaller, Torben Hansen, James F. Wilson, Lu-Chen Weng, Eduardo Tarazona-Santos, Honghuang Lin, Yong Qian, Jeffrey R. O'Connell, Maria Pina Concas, Claudia Schurmann, Michele Orini, Joshua C. Bis, Archie Campbell, Susan R. Heckbert, Jie Yao, Eulalia Catamo, Claus Graff, James G. Wilson, Pashupati P. Mishra, Massimo Mangino, Martina Müller-Nurasyid, Borbala Mifsud, Linda Repetto, Stephan B. Felix, Julia Ramirez, Rebecca D. Jackson, Eric Boerwinkle, Monika Stoll, Elsayed Z. Soliman, Maryam Kavousi, David J. Porteous, Nina Mononen, Dan E. Arking, Laura Andreasen, Lorenz Risch, Antonio Luiz Pinho Ribeiro, Pier D. Lambiase, Mika Kähönen, Xia Shen, Kenneth Rice, Eric A. Whitsel, Nona Sotoodehnia, Victor Nauffal, Konstantin Strauch, Jørgen K. Kanters, Henry Völzke, Daniel S. Evans, Jonas L. Isaksen, Alessandro De Grandi, Hao Mei, Alexander P. Reiner, Christy L. Avery, Thiago P. Leal, Alanna C. Morrison, Christian Fuchsberger, M. Arfan Ikram, Moritz Sinner, Yongmei Liu, Bruno H. Stricker, Francesco Cucca, Allan Linneberg, Patricia B. Munroe, Christina Ellervik, Olli T. Raitakari, Melanie Waldenberger, Reem Salman, Xiuqing Guo, Sandosh Padmanabhan, ThuyVy Duong, Dawood Darbar, Stefan Weiss, Arden Moscati, Alvaro Alonso, Cornelia M. van Duijn, Gianfranco Sinagra, Luisa Foco, Matthias Nauck, Kathleen A. Ryan, Kjell Nikus, Gustav Ahlberg, Helen R. Warren, Kent D. Taylor, Niek Verweij, Rebecca Freudling, Cristian Pattaro, Michael Preuss, Charles Kooperberg, Anne Richmond, David Conen, Oliver Hines, Juhani Junttila, Leo-Pekka Lyytikäinen, Nina Hutri-Kähönen, Kirill V. Tarasov, Ulrich Schotten, M. Benjamin Shoemaker, Marten E. van den Berg, Jerome I. Rotter, Michael J. Cutler, Adolfo Correa, Bruce M. Psaty, Caroline Hayward, Yalda Jamshidi, Pau Navarro, J W Benjamins, Patrick T. Ellinor, Massimo Mezzavilla, William J Young, Stefan Kääb, Lars Lind, Antonio De Luca, Heikki V. Huikuri, Marjo-Riitta Järvelin, Guillaume Paré, Stefan van Duijvenboden, Uwe Völker, Maria Fernanda Lima-Costa, Philippe Froguel, Jan A. Kors, Annette Peters, David Schlessinger, Christopher Newton-Cheh, J. Wouter Jukema, Andrew Tinker, Dennis O. Mook-Kanamori, Antoine R Baldassari, Stefanie Aeschbacher, Mariaelisa Graff, Najim Lahrouchi, Henry J. Lin, Giorgia Girotto, Giulia Pelliccione, Jeffrey Haessler, Aaron Isaacs, Rebecca N. Mitchell, Carolina Roselli, Massimiliano Cocca, Sina A. Gharib, Rozenn N. Lemaitre, Raymond Noordam, Morten S. Olesen, Steven A. Lubitz, Jun Ding, May E. Montasser, Jennifer A. Brody, Stella Trompet, Traci M. Bartz, Dania Raza, Thomas Meitinger, Andrew P. Morris, James P. Cook, Sébastien Thériault, Martin Gögele, André G. Uitterlinden, Pim van der Harst, Alan Pittman, Farah Ahmed, Simin Liu, Casia Nursyifa, Paul L. Huang, Kristen K. Patton, and Terho Lehtimäki
Subjects: medicine.medical_specialty, business.industry, Locus (genetics), Atrial fibrillation, medicine.disease, QT interval, Genetic architecture, Sudden cardiac death, QRS complex, Internal medicine, cardiovascular system, medicine, Cardiology, Repolarization, cardiovascular diseases, business, Ventricular depolarization
Abstract: The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2021

14. Assessment of plasma ceramides as predictor for subclinical atherosclerosis

Author: Mika Hilvo, Leo-Pekka Lyytikäinen, Pashupati P. Mishra, Dimitrios I. Fotiadis, Nina Hutri-Kähönen, Reijo Laaksonen, Terho Lehtimäki, Olli T. Raitakari, Mika Kähönen, Binisha H. Mishra, Markus Juonala, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, and Department of Paediatrics
Subjects: Oncology, medicine.medical_specialty, Disease, Logistic regression, Age and sex, 3121 Internal medicine, Prediction models, SDG 3 - Good Health and Well-being, Internal medicine, Carotid intima media thickness, Internal Medicine, medicine, Diseases of the circulatory (Cardiovascular) system, cardiovascular diseases, Subclinical atherosclerosis, Receiver operating characteristic, Surrogate endpoint, business.industry, Regression analysis, Cardiovascular diseases, RC666-701, Lipidomics, Plasma ceramides, cardiovascular system, 3111 Biomedicine, Cardiology and Cardiovascular Medicine, business, Predictive modelling
Abstract: Background and aims: Ceramides have been identified as novel biomarkers for cardiovascular disease (CVD) related events and mortality but their role in etiology of subclinical atherosclerosis is unknown. We aimed to assess association between plasma ceramides and carotid intima-media thickness (CIMT) and evaluate predictive value of the ceramides for high CIMT over traditional CVD risk factors. Methods: Association between plasma ceramides and CIMT in the Young Finns Study participants was analyzed with CIMT as outcome and ceramides along with traditional risk factors as predictors with regression model. Predictive value of the ceramides and related coronary event risk test (CERT) score for high CIMT as surrogate marker of subclinical atherosclerosis was assessed by comparing logistic regression-based prediction models including, i) traditional risk factors and ceramides, ii) traditional risk factors and CERT score, iii) age, sex and ceramides or alternatively CERT score with a reference model including only traditional risk factors. The prediction models were fitted to training data (70% data) and tested on test data (30% data). The predictive models were assessed with area under the receiver operating curve (AUC). The variance of AUC was estimated by repeating the model fitting and testing for 1000 bootstraps of the original data. Results: Predictive models with plasma ceramides or alternatively with CERT score in addition to age and sex variables were able to predict high CIMT with AUC 0.726 and 0.720 respectively. However, the ceramides and CERT score did not have statistically significant added predictive value for high CIMT over traditional risk factors. Conclusions: The new systemic biomarkers, high-risk plasma ceramides and CERT score, showed promising predictive performance for high CIMT with only age and sex as additional variables. This may help in predicting subclinical atherosclerosis for primary prevention. publishedVersion
Published: 2021
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15. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Author: Andrew D Beswick, Tõnu Esko, Niki Dimou, Xue Zhong, Jette Bork-Jensen, Petra Schubert, Masato Akiyama, Girish N. Nadkarni, Ruth J. F. Loos, Huijun Qian, Michele K. Evans, Stephen S. Rich, Nicole Soranzo, Henry Völzke, Yongmei Liu, Nicholas A. Watkins, Markus M. Lerch, Richard C. Trembath, Adam S. Butterworth, Erwin P. Bottinger, Jennifer E. Huffman, Bruce M. Psaty, Jingzhong Ding, Michael Preuss, Yoav Ben-Shlomo, Bhavi Trivedi, Yoichiro Kamatani, David A. van Heel, Kjell Nikus, Torben Hansen, Adolfo Correa, Mohsen Ghanbari, Paul L. Auer, Véronique Laplante, Ken Sin Lo, Hua Tang, Peter W.F. Wilson, Paul Elliott, David J. Roberts, Hilary C. Martin, Jean-Claude Tardif, Praveen Surendran, Regina Manansala, Terho Lehtimäki, Emanuele Di Angelantonio, Fotis Koskeridis, Alexander P. Reiner, Mélissa Beaudoin, Vijay G. Sankaran, Benjamin Rodriguez, William J. Astle, Parsa Akbari, Frank J. A. van Rooij, Yun Li, Andreas Greinacher, Abdou Mousas, Andrew D. Johnson, Yukinori Okada, Michael H. Guo, Leo-Pekka Lyytikäinen, Traci M. Bartz, Minhui Chen, Alan B. Zonderman, Niels Grarup, Oluf Pedersen, Kumaraswamynaidu Chitrala, Jeffrey Haessler, Ming-Huei Chen, Cassandra N. Spracklen, Karen L. Mohlke, Guillaume Lettre, Erik L. Bao, Bingshan Li, James S. Floyd, Wei Huang, Ani Manichaikul, John Danesh, Uwe Völker, Allan Linneberg, Evangelos Evangelou, Joanna M. M. Howson, Olli T. Raitakari, Tim Kacprowski, Jean-François Gauchat, Hélène Choquet, Arden Moscati, Saori Sakaue, Mika Kähönen, Linda Broer, Caleb A. Lareau, Qin Qin Huang, Matthias Nauck, Yoshinori Murakami, Charleston W. K. Chiang, VA Million Veteran Program, Nina Mononen, Tao Jiang, Laura M. Raffield, Jerome I. Rotter, Leslie A. Lange, Jonathan D. Rosen, Eric Jorgenson, Savita Karthikeyan, Karen A. Hunt, Nathan Pankratz, Kelly Cho, Masahiro Kanai, Willem H. Ouwehand, Jennifer A. Brody, Koichi Matsuda, Dragana Vuckovic, Epidemiology, and Internal Medicine
Subjects: LOCI, Mutation, Missense, Ethnic group, POLYGENIC RISK SCORES, HUMAN HEMATOPOIESIS, Biology, BIOBANK, phenome-wide association study, Polymorphism, Single Nucleotide, DISEASE, White People, General Biochemistry, Genetics and Molecular Biology, Article, Blood cell, 03 medical and health sciences, SINGLE-CELL, selective sweeps, 0302 clinical medicine, Asian People, parasitic diseases, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, AFRICAN-AMERICANS, 0303 health sciences, interleukin-7, Interleukin-7, genetic architecture, Genetic architecture, TRAIT, HEK293 Cells, Phenotype, medicine.anatomical_structure, fine-mapping, polygenic trait score, lipids (amino acids, peptides, and proteins), FREQUENCY CODING VARIANTS, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
Published: 2020
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16. The association between charlson comorbidity index and mortality in acute coronary syndrome – the MADDEC study

Author: Shadi Mahdiani, Markus Hautamäki, Kari Antila, Leo-Pekka Lyytikäinen, Kjell Nikus, Markku Eskola, Jussi Hernesniemi, Niku Oksala, and Terho Lehtimäki
Subjects: Male, medicine.medical_specialty, Acute coronary syndrome, Time Factors, Health Status, Comorbidity, 030204 cardiovascular system & hematology, survival, Risk Assessment, Decision Support Techniques, 03 medical and health sciences, 0302 clinical medicine, GRACE, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Risk Factors, health services administration, Internal medicine, mental disorders, Humans, Medicine, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Finland, Aged, Retrospective Studies, Aged, 80 and over, business.industry, High mortality, Middle Aged, Prognosis, medicine.disease, mortality, nervous system diseases, myocardial infarction, Charlson comorbidity index, Female, prognosis, Cardiology and Cardiovascular Medicine, business
Abstract: Objectives. Acute coronary syndrome (ACS) is associated with high mortality. Charlson comorbidity index (CCI) was designed over 30 years ago to measure the impact of pre-existing comorbidities on long-term survival of the patient. We wanted to re-evaluate the performance of CCI and its components in modern setting. Design. This is a retrospective study of 1576 consecutive patients undergoing invasive evaluation and treated for ACS in single tertiary center between 2015–2016. Mortality was analyzed in timeframes of 1, 6 and 24 months. CCI-scores were retrieved from written medical records and complimented with data from electronic sources. The performance of CCI and its components was compared to the GRACE-score measuring patients’ status upon hospital admission. Results. Population mean age at baseline was 69.3 (SD 11.8) years and 69.1% of the patients were male (n = 1089). Most of the components of CCI associated significantly with mortality at all timeframes despite adjusting for age but only diabetes and congestive heart failure associated with mortality at all time points after adjusting for GRACE-score. CCI associated with mortality [GRACE adjusted HR-values of single unit increase of CCI after 1, 6 and 24-month follow-up: 1.12(95% CI:1.00–1.25), 1.17(1.07–1.29) and 1.24(1.16–1.33)]. CCI performed modestly with its AUC-values ranging between 0.755 and 0.784, with prognostic performance increasing with longer follow-up. Adding components of CCI did not significantly improve risk prediction over GRACE-score. Conclusions. In conclusion, CCI or its individual components measuring the impact of comorbidities on overall mortality does not provide any significant value compared to GRACE–score during up to 2 years of follow-up.
Published: 2019
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17. Combination of low blood pressure response, low exercise capacity and slow heart rate recovery during an exercise test significantly increases mortality risk

Author: Kjell Nikus, Mika Kähönen, Kalle Sipilä, Tuomo Nieminen, Jussi Hernesniemi, Atte Haarala, Jari Viik, Antti Tikkakoski, Terho Lehtimäki, Sanni Alanko, and Leo-Pekka Lyytikäinen
Subjects: Adult, Male, medicine.medical_specialty, Blood Pressure, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Heart Rate, Internal medicine, Heart rate, Humans, Medicine, 030212 general & internal medicine, Mortality, Aged, Cardiovascular mortality, Exercise Tolerance, business.industry, Original Articles, General Medicine, Middle Aged, Exercise capacity, Blood pressure, Exercise Test, Cardiology, Female, business, Follow-Up Studies
Abstract: Aims: We investigated the combination of low systolic blood pressure (SBP) response, low exercise capacity (EC) and slow heart rate recovery (HRR) during an exercise test in mortality prediction. Patients and methods: Our population consisted of 3456 patients from the Finnish Cardiovascular Study. A failure of SBP to increase >42 mmHg was defined as a low response. Low EC was defined as
Published: 2019
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18. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Author: Sina A. Gharib, Kenneth Rice, Donna K. Arnett, Tõnu Esko, Annemarie I. Luik, Niki Dimou, Dabeeru C. Rao, Pamela J. Schreiner, Melissa A. Richard, Reedik Mägi, Nicholette D. Palmer, Stefan Weiss, Han Chen, Solomon K. Musani, W. James Gauderman, Christian Gieger, Kari E. North, Salman M. Tajuddin, Diana van Heemst, Rainer Rauramaa, Stephen B. Kritchevsky, Henry Völzke, Minjung Kho, Michele K. Evans, Ruth J. F. Loos, Correa Adolfo, Pedro Marques-Vidal, Diane M. Becker, Claude Bouchard, José Haba-Rubio, Georg Homuth, Kurt Lohman, Nora Franceschini, Caizheng Yu, Peter Vollenweider, Ervin F. Fox, Thomas Meitinger, Karen Schwander, Heming Wang, Morris A. Swertz, Aldi T. Kraja, José Eduardo Krieger, Xiuqing Guo, Tangchun Wu, Raymond Noordam, Yongmei Liu, Michael R. Brown, Patrick C.N. Rensen, Annette Peters, Jingmin Liu, Tuomo Rankinen, Robert B. Wallance, Timo A. Lakka, Stephen S. Rich, Yun Ju Sung, Meian He, Till Roenneberg, Wanqing Wen, Dennis O. Mook-Kanamori, M. A. Province, Evangelos Evangelou, L. Adrienne Cupples, Maxime M Bos, Paul S. de Vries, Hans J. Grabe, Lisa R. Yanek, Jiwon Lee, Mario Sims, Bruce M. Psaty, Treva Rice, Tanika N. Kelly, Brenda W.J.H. Penninx, Brigitte Kühnel, Maria E. Graff, Alexandre C. Pereira, Daniel J. Gottlieb, Charles N. Rotimi, Lynne E. Wagenknecht, Ashley van der Spek, Lisa W. Martin, Jeffrey R. O'Connell, Changwei Li, James E. Hixson, Chuan Gao, Alisa K. Manning, Sharon L.R. Kardia, Stella Aslibekyan, Andres Metspalu, Sami Heikkinen, Maris Alver, Xiao-Ou Shu, Amy R. Bentley, Susan Redline, Konstantin Strauch, Tamara B. Harris, Yuri Milaneschi, L.F. Bielak, Marjan Ilkov, Myriam Fornage, Ilja M. Nolte, André G. Uitterlinden, Dina Vojinovic, Hugues Aschard, Paul Elliott, Kent D. Taylor, Najaf Amin, James M. Shikany, Yong-Bing Xiang, Jerome I. Rotter, Vilmundur Gudnason, Cornelia M. van Duijn, Ko Willems van Dijk, Andrea R. V. R. Horimoto, Jonathan Marten, Olli T. Raitakari, Vincent Laville, Pirjo Komulainen, Zhe Wang, Traci M. Bartz, Mary F. Feitosa, Mike A. Nalls, Eric Boerwinkle, Alanna C. Morrison, Melanie Waldenberger, Alexander P. Reiner, Christie M. Ballantyne, Wei Zheng, Raphael Heinzer, M. Arfan Ikram, Colleen M. Sitlani, Lisa de las Fuentes, Patricia B. Munroe, Patricia A. Peyser, Brian E. Cade, Tamar Sofer, Xiaofeng Zhu, Nienke R. Biermasz, Harold Snieder, Elise Lim, Tuomas O. Kilpeläinen, Ching-Ti Liu, Terho Lehtimäki, Thomas W. Winkler, Leo-Pekka Lyytikäinen, Gudny Eiriksdottir, Stephen Sidney, Alan B. Zonderman, Charles Kooperberg, Leiden University Medical Center (LUMC), Universiteit Leiden, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Universität Regensburg (UR), National Institutes of Health [Bethesda] (NIH), University of Copenhagen = Københavns Universitet (UCPH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), The University of Texas Health Science Center at Houston (UTHealth), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Massachusetts General Hospital [Boston], Harvard T.H. Chan School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Mississippi Medical Center (UMMC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Alabama at Birmingham [ Birmingham] (UAB), University of Washington [Seattle], Universidade de São Paulo Medical School (FMUSP), Icelandic Heart Association [Kopavogur, Iceland] (IHA), University of Michigan [Ann Arbor], University of Michigan System, University of Georgia [USA], School of Public Health [Boston], Boston University [Boston] (BU), Wake Forest University, Pennington Biomedical Research Center, Louisiana State University (LSU), University of Edinburgh, University of Tartu, Imperial College London, University of Ioannina, Huazhong University of Science and Technology [Wuhan] (HUST), Helmholtz Zentrum München = German Research Center for Environmental Health, Fimlab Laboratories [Tampere, Finland], University of Tampere [Finland], Lausanne University Hospital, University of Groningen [Groningen], This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338., European Project: 602757,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HUMAN(2013), Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, University of Copenhagen = Københavns Universitet (KU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), Van Duijn, CM, Wang, Heming [0000-0002-1486-7495], Bentley, Amy R [0000-0002-0827-9101], Schwander, Karen [0000-0002-0193-4134], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0002-7554-6783], Richard, Melissa [0000-0003-0129-9860], de Las Fuentes, Lisa [0000-0002-4689-325X], Feitosa, Mary [0000-0002-0933-2410], van der Spek, Ashley [0000-0001-7136-0159], Wang, Zhe [0000-0002-8046-4969], Marten, Jonathan [0000-0001-6916-2014], Laville, Vincent [0000-0003-4946-698X], Evangelou, Evangelos [0000-0002-5488-2999], He, Meian [0000-0002-2096-921X], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Marques-Vidal, Pedro [0000-0002-4548-8500], Nolte, Ilja M [0000-0001-5047-4077], Palmer, Nicholette D [0000-0001-8883-2511], Snieder, Harold [0000-0003-1949-2298], Weiss, Stefan [0000-0002-3553-4315], Yanek, Lisa R [0000-0001-7117-1075], Adolfo, Correa [0000-0002-9501-600X], Dimou, Niki [0000-0003-1678-9328], Heikkinen, Sami [0000-0002-6083-2402], Ikram, M Arfan [0000-0003-0372-8585], Krieger, Jose E [0000-0001-5464-1792], Lee, Jiwon [0000-0002-4079-7494], Liu, Jingmin [0000-0003-0001-6013], Martin, Lisa W [0000-0003-4352-0914], Metspalu, Andres [0000-0002-3718-796X], Rensen, Patrick CN [0000-0002-8455-4988], Rich, Stephen S [0000-0003-3872-7793], Rotter, Jerome I [0000-0001-7191-1723], Sofer, Tamar [0000-0001-8520-8860], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, André G [0000-0002-7276-3387], van Dijk, Ko Willems [0000-0002-2172-7394], Elliott, Paul [0000-0002-7511-5684], Esko, Tõnu [0000-0003-1982-6569], Grabe, Hans J [0000-0003-3684-4208], Zheng, Wei [0000-0003-1226-070X], Bouchard, Claude [0000-0002-0048-491X], Gudnason, Vilmundur [0000-0001-5696-0084], Loos, Ruth JF [0000-0002-8532-5087], Cupples, L Adrienne [0000-0003-0273-7965], Munroe, Patricia B [0000-0002-4176-2947], Liu, Ching-Ti [0000-0002-0703-0742], Apollo - University of Cambridge Repository, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), and UK DRI Ltd
Subjects: Male, 0301 basic medicine, Epidemiology, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Svefnrannsóknir, 0302 clinical medicine, MESH: Aged, 80 and over, Polymorphism (computer science), lcsh:Science, MESH: Phylogeny, Phylogeny, Aged, 80 and over, Genetics, MESH: Aged, [STAT.AP]Statistics [stat]/Applications [stat.AP], Multidisciplinary, MESH: Middle Aged, medicine.diagnostic_test, MESH: Polymorphism, Single Nucleotide, Chromosome Mapping, Middle Aged, Explained variation, Lipids, Sleep in non-human animals, Blóðfita, ddc, 3. Good health, MESH: Young Adult, Female, lipids (amino acids, peptides, and proteins), Erfðarannsóknir, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, Adolescent, MESH: Sleep, Science, Biology, Polymorphism, Single Nucleotide, MESH: Genetic Loci, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Phylogenetics, Svefn, medicine, Humans, SNP, Dyslipidaemias, Aged, MESH: Adolescent, MESH: Humans, Faraldsfræði, PCSK9, MESH: Adult, General Chemistry, MESH: Lipids, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Sleep, Lipid profile, MESH: Chromosome Mapping, MESH: Female, 030217 neurology & neurosurgery
Abstract: Publisher's version (útgefin grein)., Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles., This project was supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF–6110-00183) and the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848 and NNF15CC0018486). Diana van Heemst was supported by the European Commission funded project HUMAN (Health-2013-INNOVATION-1-602757). Susan Redline was supported in part by NIH R35HL135818 and HL11338. Study-specific acknowledgements can be found in the Supplementary Notes 2 and 4. The data on coronary artery disease have been contributed by the Myocardial Infarction Genetics and CARDIoGRAM investigators, and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.
Published: 2019
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19. Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

Author: Maria Carolina Borges, M. Geoffrey Hayes, Ke Hao, Carol A. Wang, Marjo-Riitta Järvelin, Niina Pitkänen, Ilkka Kalliala, Mariona Bustamante, Olli T. Raitakari, Bridget A. Knight, Robin N Beaumont, Matthew T. Weirauch, Line Skotte, Matthias Wielscher, Mark I. McCarthy, Klaus Bønnelykke, Vincent W. V. Jaddoe, Elina Hyppönen, Ole Mors, Tarunveer S. Ahluwalia, Thomas Werge, Frank Geller, Jonathan P. Bradfield, Vivek Appadurai, Kristin Skogstrand, Merete Nordentoft, Suzanne Vogelezang, Preben Bo Mortensen, Xueping Liu, Daniel Miller, Hakon Hakonarson, João Fadista, Pål R. Njølstad, Leah C. Kottyan, Wesley K. Thompson, Bruce Bedell, Katja Pahkala, Stefan Johansson, Dorte Helenius, Louis J. Muglia, Janine F. Felix, Rachel M. Freathy, Heather A. Boyd, Bjarke Feenstra, Ge Zhang, Anubha Mahajan, Alfonso Buil, Bo Jacobsson, Martine Vrijheid, Frederick T.J. Lin, William L. Lowe, Mads Melbye, Ron Nudel, Denise M. Scholtens, Julius Juodakis, Shouneng Peng, Christine Power, Andrew J. Schork, Jeffrey C. Murray, David M. Hougaard, Craig E. Pennell, Øyvind Helgeland, Struan F.A. Grant, Kelli K. Ryckman, Mary L. Marazita, Xiaoting Chen, Jonas Bacelis, Anders D. Børglum, Debbie A Lawlor, Hans Bisgaard, Robert M. Rossi, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Clinicum, Helsinki University Hospital Area, Epidemiology, Internal Medicine, Pediatrics, Erasmus MC other, Liu, Xueping, Helenius, Dorte, Skotte, Line, Beaumont, Robin N, Hyppönen, Elina, Feenstra, Bjarke, and UNIVERSITY OF OULU
Subjects: 0301 basic medicine, LD SCORE REGRESSION, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, Reproductive health and childbirth, Bioinformatics, Low Birth Weight and Health of the Newborn, Genome-wide association studies, 3123 Gynaecology and paediatrics, Pregnancy, Genotype, Infant Mortality, Genetics research, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, GWAS, FUNCTIONAL VARIATION, Aetiology, lcsh:Science, Pediatric, Multidisciplinary, Genome, Gestational age, Single Nucleotide, 021001 nanoscience & nanotechnology, 3. Good health, Multidisciplinary Sciences, Chromosomes, Human, Pair 2, Pair 2, Gestation, Science & Technology - Other Topics, Premature Birth, Cytokines, Female, 0210 nano-technology, Human, Reproductive signs and symptoms, EXPRESSION, PRETERM BIRTH, Science, Reproductive biology, Locus (genetics), Gestational Age, Biology, Polymorphism, Single Nucleotide, SEQUENCE, Article, General Biochemistry, Genetics and Molecular Biology, Chromosomes, 03 medical and health sciences, AGE, Fetus, Preterm, medicine, Genetics, SNP, Humans, Polymorphism, Science & Technology, Genome, Human, Human Genome, Infant, Newborn, Infant, General Chemistry, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, Newborn, 030104 developmental biology, Good Health and Well Being, lcsh:Q, WEIGHT, 3111 Biomedicine, HAPLOTYPES, Genome-Wide Association Study
Abstract: The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality., Gestational duration depends on both maternal and fetal genetic influences. Here, the authors perform a fetal genome-wide association meta-analysis and find that a locus on 2q13 is associated with pregnancy duration and further show that the lead SNP rs7594852 changes the binding properties of transcriptional repressor HIC1.
Published: 2019
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20. Eur Heart J

Author: Yoichiro Kamatani, Markus Scholz, Pin Huang, Marcus E. Kleber, Chang Liu, Aldons J. Lusis, Zhiheng Cai, Janet Gukasyan, Yi Han, Georgios J. Vlachojannis, W.H. Wilson Tang, Satoshi Koyama, Johan L.M. Björkegren, Margarete Mehrabian, David-Alexandre Trégouët, Hooman Allayee, Folkert W. Asselbergs, Peter Bazeley, Elizabeth R. Hauser, Casey E. Romanoski, Mohammad Daud Khan, Leo-Pekka Lyytikäinen, Riyaz S. Patel, Issei Komuro, Tuomo Nieminen, Stanley L. Hazen, Qiong Jia, Muredach P. Reilly, Redouane Aherrahrou, Xuling Chang, Jari Laurikka, James R. Hilser, Marion van Vugt, William E. Kraus, Clint L. Miller, Kaoru Ito, Jaana Hartiala, Marcus M. Seldin, Calvin Pan, Winfried März, Joachim Thiery, Jane F. Ferguson, Yan V. Sun, Chew-Kiat Heng, Pekka Kuukasjärvi, Mika Kähönen, Mete Civelek, Lindsey K. Stolze, S. Ram Kumar, Graciela E. Delgado, Nicholas L. Smith, Subarna Biswas, William S Schwartzman, Laurence J. Howe, Lijiang Ma, Rong Jiang, Adam W. Turner, Arshed A. Quyyumi, Terho Lehtimäki, Cardiology, Tampere University, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Bordeaux population health (BPH), and 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)
Subjects: Genetic factors, Smooth muscle cell migration, SLC44A3, Myocardial Infarction/genetics, Context (language use), Locus (genetics), Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, 3121 Internal medicine, Polymorphism, Single Nucleotide, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Japan, Risk Factors, Medicine, Humans, Genetic Predisposition to Disease, AcademicSubjects/MED00200, Myocardial infarction, Polymorphism, Coronary atherosclerosis, 030304 developmental biology, 0303 health sciences, business.industry, Coronary Artery Disease/genetics, Genetic Predisposition to Disease/genetics, Clnical Research, Endothelial Cells, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, Polymorphism, Single Nucleotide/genetics, 3. Good health, Coronary arteries, Meta-analysis, Editorial, medicine.anatomical_structure, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology and Cardiovascular Medicine, business, Single Nucleotide/genetics, Genome-Wide Association Study
Abstract: Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
Published: 2021
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21. Impedance plethysmography-based method in the assessment of subclinical atherosclerosis

Author: Mikko Peltokangas, Mira Haapala, Teemu Koivistoinen, Niku Oksala, Mika Kähönen, Antti Vehkaoja, Olli T. Raitakari, Leo-Pekka Lyytikäinen, Terho Lehtimäki, Matti Mäntysalo, Mika-Matti Laurila, Nina Hutri-Kähönen, Tampere University, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, BioMediTech, Kanta-Häme Central Hospital Hämeenlinna, Department of Clinical Physiology and Nuclear Medicine, Department of Paediatrics, Electrical Engineering, and Verisuoni- ja toimenpideradiologinen keskus
Subjects: 0301 basic medicine, Adult, medicine.medical_specialty, 030204 cardiovascular system & hematology, Pulse Wave Analysis, 3121 Internal medicine, Carotid Intima-Media Thickness, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine.artery, medicine, Plethysmograph, Pulse wave, Humans, Plethysmography, Impedance, cardiovascular diseases, Brachial artery, Carotid artery distensibility, Finland, Framingham Risk Score, business.industry, Pulse (signal processing), Atherosclerosis, 3126 Surgery, anesthesiology, intensive care, radiology, 030104 developmental biology, Intima-media thickness, Subclinical atherosclerosis, Cardiology, cardiovascular system, Cardiology and Cardiovascular Medicine, business, circulatory and respiratory physiology
Abstract: Background and aims The aim of this study was to examine an association of individual and combined pulse waveform parameters derived from bioimpedance measurements, that is pulse waves from a distal impedance plethysmographic (IPG), a whole-body impedance cardiographic (ICG) and transformed distal impedance plethysmographic (tIPG) signals, with markers of subclinical atherosclerosis, i.e. carotid intima-media thickness (cIMT), brachial artery flow-mediated dilation (FMD) and carotid artery distensibility (Cdist). The level of the association was also compared for arterial pulse wave velocity (PWV) and cIMT, FMD, and Cdist. Methods IPG, ICG, tIPG signals were measured from 1741 Finnish adults aged 30–45 years. The association between pulse wave parameters and cIMT, FMD and Cdist was studied using bootstrapped stepwise Akaike's Information Criterion method resulting in selection of parameters other than PWV, i.e. parameters having stronger association with cIMT, FMD and Cdist than PWV, in the model. Then risk scores were calculated from the selected pulse wave parameters and their association between cIMT, FMD and Cdist was studied with multivariable linear regression analysis. Results The risk score was found to be the third strongest predictor of subclinical atherosclerosis as indicated by cIMT measurement, the second strongest predictor of FMD and the strongest predictor of Cdist. These findings show that several individual pulse wave parameters were associated more strongly with cIMT, FMD, and Cdist than PWV when adjusted with clinical risk factors. Conclusions Impedance based pulse waveform analysis provides a useful tool for assessing cardiovascular risk and estimating presence of structural changes in the vasculature. publishedVersion
Published: 2021

22. The prognostic significance of T-wave inversion according to ECG lead group during long-term follow-up in the general population

Author: Markku Eskola, Mika Kähönen, Leo-Pekka Lyytikäinen, Ismo Anttila, Jussi Hernesniemi, Antti Jula, Harri Rissanen, Tiia Istolahti, Kjell Nikus, Heini Huhtala, Tuomo Nieminen, Terho Lehtimäki, Tampere University, Clinical Medicine, TAYS Heart Centre, Department of Clinical Chemistry, Health Sciences, Department of Clinical Physiology and Nuclear Medicine, Seinäjoen keskussairaala VA, HUS Internal Medicine and Rehabilitation, Päijät-Häme Welfare Consortium, and HYKS erva
Subjects: Male, Heart disease, CARDIOVASCULAR MORTALITY, Coronary Disease, 030204 cardiovascular system & hematology, Electrocardiography, 0302 clinical medicine, Interquartile range, Medicine, ST segment, 030212 general & internal medicine, PREDICTORS, Finland, RISK, education.field_of_study, population study, T wave, MEN, General Medicine, Middle Aged, Prognosis, 3142 Public health care science, environmental and occupational health, 3. Good health, PREVALENCE, ST-SEGMENT, Population study, Original Article, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Population, HEART-DISEASE, electrocardiogram, 3121 Internal medicine, 03 medical and health sciences, Physiology (medical), Internal medicine, Humans, coronary heart disease, education, business.industry, Proportional hazards model, Original Articles, medicine.disease, mortality, Confidence interval, 3121 General medicine, internal medicine and other clinical medicine, business, Follow-Up Studies
Abstract: Background Inverted T waves in the electrocardiogram (ECG) have been associated with coronary heart disease (CHD) and mortality. The pathophysiology and prognostic significance of T-wave inversion may differ between different anatomical lead groups, but scientific data related to this issue is scarce. Methods A representative sample of Finnish subjects (n = 6,354) aged over 30 years underwent a health examination including a 12-lead ECG in the Health 2000 survey. ECGs with T-wave inversions were divided into three anatomical lead groups (anterior, lateral, and inferior) and were compared to ECGs with no pathological T-wave inversions in multivariable-adjusted Fine-Gray and Cox regression hazard models using CHD and mortality as endpoints. Results The follow-up for both CHD and mortality lasted approximately fifteen years (median value with interquartile ranges between 14.9 and 15.3). In multivariate-adjusted models, anterior and lateral (but not inferior) T-wave inversions associated with increased risk of CHD (HR: 2.37 [95% confidence interval 1.20-4.68] and 1.65 [1.27-2.15], respectively). In multivariable analyses, only lateral T-wave inversions associated with increased risk of mortality in the entire study population (HR 1.51 [1.26-1.81]) as well as among individuals with no CHD at baseline (HR 1.59 [1.29-1.96]). Conclusions The prognostic information of inverted T waves differs between anatomical lead groups. T-wave inversion in the anterior and lateral lead groups is independently associated with the risk of CHD, and lateral T-wave inversion is also associated with increased risk of mortality. Inverted T wave in the inferior lead group proved to be a benign phenomenon.
Published: 2021

23. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author: Lukas Habegger, Charumathi Sabanayagam, Michael Preuss, Laura M. Raffield, Mary F. Feitosa, Bamidele O. Tayo, Kevin Ho, Leo-Pekka Lyytikäinen, Florian Kronenberg, Valencia Hui Xian Foo, Adrienne Tin, Michael Cantor, Nisha Bansal, Tarunveer S. Ahluwalia, Melanie Waldenberger, Sarah A. Pendergrass, Behrooz Z. Alizadeh, Wolfgang Koenig, Qiong Yang, Xiaodong Bai, Christoph Wanner, Ben Schöttker, Giovanni Coppola, A. R. Shuldiner, Leslie A. Lange, Piyush Gampawar, Markus Scholz, Tien Yin Wong, Mary L. Biggs, Morris Swertz, Alicia Hawes, Girish N. Nadkarni, Christina-Alexandra Schulz, Chiea Chuen Khor, Ricardo H. Ulloa, Jeffrey C. Staples, Miao-Li Chee, Laura M. Yerges-Armstrong, Andrew Blumenfeld, Karlhans Endlich, Bernhard Banas, Bruce H.R. Wolffenbuttel, Kai-Uwe Eckardt, Pavel Hamet, Carsten A. Böger, Harold Snieder, Marcus B. Jones, Judy Wang, Shih-Jen Hwang, Mathias Gorski, Anselm Hoppmann, Josyf C. Mychaleckyj, Bernd Holleczek, Pamela R. Matias-Garcia, Rainer Rettig, Karsten B. Sieber, Manasi Pradhan, Pashupati P. Mishra, Peter Rossing, Matthias Wuttke, Miao-Ling Chee, H. Marike Boezen, Yong Li, M. Arfan Ikram, Jeffrey G. Reid, Teresa Nutile, Maria Sotiropoulos Padilla, Lude Franke, Robert J. Carroll, Luca A. Lotta, Bernhard K. Krämer, Kjell Nikus, Jerome I. Rotter, Thomas Meitinger, Lars Wallentin, Cisca Wijmenga, Kent D. Taylor, Holly Kramer, Louis Widom, Olli T. Raitakari, Marcus E. Kleber, Man Li, Nina Hutri-Kähönen, Massimiliano Cocca, Reinhold Schmidt, John D. Overton, Cristian Pattaro, Michael Lattari, Sarah E. Wolf, Jin-Fang Chai, Karina Toledo, Brigitte Kühnel, Zhenhua Gu, Peter Almgren, Caitlin Forsythe, Yuri Milaneschi, Stephan J. L. Bakker, Layal Chaker, Dawn M. Waterworth, Silke Szymczak, James G. Wilson, Peter J. van der Most, Michelle L. O'Donoghue, William Salerno, Masayuki Yasuda, Sahar Ghasemi, Eric Boerwinkle, Josef Coresh, Ilja M. Nolte, Kia Manoochehri, Konstantin Strauch, Thomas D. Schleicher, Myriam Rheinberger, Audrey Y. Chu, Sanaz Sedaghat, Sandra Freitag-Wolf, Boting Ning, Matthias Nauck, Christina Beechert, Helena Schmidt, Harvey D. White, Nina Mononen, Johanne Tremblay, Navya Shilpa Josyula, Mika Kähönen, Katrin Horn, Andre Franke, Marianne Rots, Bettina Jung, Alexander R. Rosenkranz, Christian M. Shaffer, Mary Ann Lukas, Gerjan Navis, Christian Gieger, John Chalmers, Shareef Khalid, Uwe Völker, Marju Orho-Melander, Iris M. Heid, Brenda W.J.H. Penninx, A. Baras, Alexander Lopez, Evan Maxwell, Ruth J. F. Loos, Erin D. Fuller, Christa Meisinger, Gonçalo R. Abecasis, Suganthi Balasubramanian, Chris H. L. Thio, Martin H. de Borst, Stefan Coassin, Ching-Yu Cheng, Wolfgang Lieb, Kenneth Rice, Alexander Teumer, Mark Woodward, Gisu Eom, Hermann Brenner, Thomas W. Winkler, Anna Köttgen, Edith Hofer, Aris Economides, Ron T. Gansevoort, Pim van der Harst, Lyndon J. Mitnaul, Bruce M. Psaty, Erwin P. Bottinger, Olle Melander, Niek Verweij, Frauke Degenhardt, Yan Zhang, Mohsen Ghanbari, Veronika Wanner, Terho Lehtimäki, Leland Barnard, Tampere University, Primary Health Care, Department of Paediatrics, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Department of Marketing Management, Epidemiology, Internal Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health
Subjects: 0301 basic medicine, medicine.medical_specialty, Genome-wide association study, 030232 urology & nephrology, Protein Disulfide-Isomerases, Hasso-Plattner-Institut für Digital Engineering GmbH, Renal function, Locus (genetics), Biology, AMP-Activated Protein Kinases, Kidney, 3121 Internal medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, end-stage kidney disease, rapid eGFRcrea decline, Urologi och njurmedicin, medicine, Humans, Urology and Nephrology, ddc:610, Allele, Genetic association, Genetics, Creatinine, genome-wide association study, Acute kidney injury, acute kidney injury, medicine.disease, United Kingdom, ddc, 030104 developmental biology, chemistry, Nephrology, Medical genetics, 3111 Biomedicine, 610 Medizin und Gesundheit, Glomerular Filtration Rate
Abstract: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19
Published: 2021
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24. The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease

Author: Ilkka Seppälä, Aarno Palotie, Niina Pitkänen, Aki S. Havulinna, Nicholas J. Timpson, Marita Kalaoja, Leo-Pekka Lyytikäinen, Veikko Salomaa, Mika Kähönen, Sirpa Jalkanen, Laura J Corbin, Mikael Maksimow, Vanessa Y Tan, Markus Perola, Terho Lehtimäki, Johannes Kettunen, Samuli Ripatti, Emma Raitoharju, Ari Ahola-Olli, Kristiina Santalahti, Marko Salmi, Jorma S. A. Viikari, Olli T. Raitakari, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Research Programs Unit, and Aarno Palotie / Principal Investigator
Subjects: Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medicine (miscellaneous), Context (language use), Disease, 3121 Internal medicine, Proinflammatory cytokine, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Mendelian randomization, medicine, Humans, 030212 general & internal medicine, Obesity, 030304 developmental biology, Adiposity, 0303 health sciences, Nutrition and Dietetics, business.industry, Epidemiology/Genetics, Odds ratio, Original Articles, 3. Good health, Cytokine, 3121 General medicine, internal medicine and other clinical medicine, Immunology, Cytokines, Tumor necrosis factor alpha, Original Article, ICEP, 3111 Biomedicine, business, Body mass index
Abstract: ObjectiveThis study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.MethodsBMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI‐driven cytokines on risk of obesity‐related diseases.ResultsObservationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein‐1 (MCP‐1), and tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08‐1.19), 1.08 (95% CI: 1.04‐1.14), and 1.13 (95% CI: 1.04‐1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00‐1.06). There was inconsistent evidence for a protective role of MCP‐1 against inflammatory bowel diseases.ConclusionsObservational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI‐driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.
Published: 2021
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25. Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Author: Daniel I. Chasman, Torben Hansen, Rebecca S. Fine, Kari E. North, Harald Grallert, Jeffrey Haesser, Jie Yao, Arund D. Pradhan, Peter Kovacs, Mariaelisa Graff, Rebecca D. Jackson, Zoltán Kutalik, James G. Wilson, Neil Robertson, Mika Kähönen, Linda S. Adair, Jennifer Kriebel, Ruth J. F. Loos, Massimo Mangino, Jayne F. Martin Carli, Yiying Zhang, M. Arfan Ikram, Paraskevi Christofidou, Linda Broer, Paul M. Ridker, Barbara McKnight, Satu Männistö, Sophia Metz, Tea Skaaby, Jette Bork-Jensen, Craig E. Pennell, Sophie Molnos, Michael A. Province, Xiuqing Guo, Laura B. L. Wittemans, Stephen J. Lye, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Tim Kacprowski, America A. Sandoval-Zárate, Hermina Jakupović, Tuomas O. Kilpeläinen, Michael Preuss, Jaeyoung Hong, Cristina Venturini, Ying Wu, Germán D. Carrasquilla, Ivana Prokic, Mary F. Feitosa, Melissa E. Garcia, Paul L. Auer, Leslie A. Lange, Leo-Pekka Lyytikäinen, Kristin L. Young, Tugce Karaderi, Alexander P. Reiner, Tim D. Spector, Anubha Mahajan, Claudia Schurmann, Jerome I. Rotter, Rudolph L. Leibel, Georg Homuth, Claudia A. Doege, Hakon Hakonarson, Nicholas J. Wareham, Najaf Amin, Shuai Wang, Matthias Blüher, Ayse Demirkan, Andrew P. Morris, Charles A. LeDuc, Claudia Langenberg, Hanieh Yaghootkar, Mike A. Nalls, Erik Ingelsson, Dennis O. Mook-Kanamori, Jorge R. Kizer, Carolina Medina-Gomez, Timothy M. Frayling, Colleen M. Sitlani, David A. Mackey, Bruce M. Psaty, Matthias Nauck, Struan F.A. Grant, Konstantin Strauch, Olli T. Raitakari, Alexander Teumer, Mark Walker, Jonathan P. Bradfield, Judith B. Borja, Karen L. Mohlke, Lars Lind, André G. Uitterlinden, Renée de Mutsert, Ruifang Li-Gao, Cassandra N. Spracklen, Jin Li, Anne E. Justice, Cecilia M. Lindgren, Kaiying Guo, Terho Lehtimäki, Pekka Jousilahti, Yingchang Lu, Yii-Der Ida Chen, Sara M. Willems, Tamara B. Harris, Matthew A. Allison, Carol A. Wang, Niels Grarup, Lam Opal Huang, Veikko Salomaa, Jian'an Luan, Robert A. Scott, Kent D. Taylor, James B. Meigs, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Department of Organisation and Personnel Management, Health Services Management & Organisation (HSMO), Yaghootkar, Hanieh [0000-0001-9672-9477], Kilpeläinen, Tuomas O [0000-0002-8349-3028], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Leptin, Models, Molecular, medicine.medical_specialty, Genotype, Protein Conformation, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, KLF14, Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Missense mutation, Humans, Allele, Exome, Adiposity, 2. Zero hunger, Racial Groups, digestive, oral, and skin physiology, Gene Expression Regulation, Developmental, Genetic Variation, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, Obesity, 030104 developmental biology, Endocrinology, hormones, hormone substitutes, and hormone antagonists
Abstract: Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16, n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.
Published: 2020

26. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

Author: Inês Barroso, Peter D. Sly, Jose Ramon Bilbao, Nicholas J. Timpson, Johan G. Eriksson, Maria M. Groen-Blokhuis, Sijmen A. Reijneveld, Dariusz Gruszfeld, George Davey Smith, Christine Power, Eva Reischl, Mandy Vogel, Andrew T. Hattersley, Øyvind Helgeland, Niina Pitkänen, Akram Alyass, Jean-Paul Langhendries, Elina Hyppönen, Kathrin Landgraf, Loreto Santa-Marina, Frank Geller, Christopher D. Brown, Elvira Verduci, Katja Pahkala, Olli T. Raitakari, Joaquin Escribano, Torben Hansen, Hakon Hakonarson, Barbara Heude, Bridget A. Knight, Maties Torrent, Robin N Beaumont, Judith M. Vonk, Estelle Lowry, Patrick G. Holt, Harold Snieder, Carol A. Wang, Mark I. McCarthy, Christine Frithioff-Bøjsøe, Tanja G. M. Vrijkotte, Natalia Vilor-Tejedor, Lisbeth Carstensen, Catharina E. M. van Beijsterveldt, Ville Karhunen, Virpi Lindi, Marjo-Riitta Järvelin, Tarunveer S. Ahluwalia, Jordi Sunyer, Jaakko T. Leinonen, Clare S. Murray, Klaus Bønnelykke, Thorkild I. A. Sørensen, André G. Uitterlinden, Janine F. Felix, John A. Curtin, Mika Kähönen, Jorma Viikari, Leo-Pekka Lyytikäinen, Oluf Pedersen, Carmen Iñiguez, Harri Niinikoski, Wieland Kiess, Kim F. Michaelsen, Evie Stergiakouli, Anni Heiskala, Alessandra Chesi, Craig E. Pennell, Mohammed H Zafarmand, Peter Rzehak, Kook K Teo, Aihuali Li, Marie Standl, Veit Grote, Momoko Horikoshi, Ellen A. Nohr, Eleanor Wheeler, Rachel M. Freathy, Iryna O. Fedko, Gerard H. Koppelman, Elisabeth Widen, Jens-Christian Holm, Raimo Joro, David Meyre, Mustafa Atalay, Theresia M. Schnurr, Camilla Schmidt Morgen, Adnan Custovic, Niels Grarup, Trevor A. Mori, Terho Lehtimäki, Christian Theil Have, Angela Simpson, Mads Melbye, Bjarke Feenstra, Lawrence J. Beilin, Stefan Johansson, Ioanna Ntalla, Martine Vrijheid, Mariona Bustamante, George Dedoussis, Sylvain Sebert, Jonas Bacelis, Carolina Medina-Gomez, Elisabeth Thiering, Ken K. Ong, Eleftheria Zeggini, Berthold Koletzko, Karine Clément, Bo L. Chawes, Mette Hollensted, Babette S. Zemel, Markus Scholz, Holger Kirsten, Antje Körner, Albertine J. Oldehinkel, Barbera D. C. van Schaik, Philippe Froguel, Vincent W. V. Jaddoe, Dorret I. Boomsma, Struan F.A. Grant, Loic Yengo, Jonathan P. Bradfield, Tenna Ruest Haarmark Nielsen, Suzanne Vogelezang, Jakob Stokholm, Pål R. Njølstad, Bo Jacobsson, Marc Vaudel, Peter J. van der Most, Andreas Kühnapfel, Mads Vendelbo Lind, Timo A. Lakka, Saskia Selzam, Robert Plomin, Marie-Aline Charles, Jouke-Jan Hottenga, Kalliope Panoutsopoulou, Fernando Rivadeneira, Rebecca K. Vinding, Hans Bisgaard, I. S. Farooqi, Joachim Heinrich, Diana L. Cousminer, Ricardo Closa-Monasterolo, Claire Monnereau, European Commission, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, APH - Global Health, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, ARD - Amsterdam Reproduction and Development, APH - Methodology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Amsterdam Cardiovascular Sciences, Public and occupational health, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Children’s Hospital of Philadelphia (CHOP ), Herlev and Gentofte Hospital, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], University of Kuopio, University of Copenhagen = Københavns Universitet (KU), Universität Leipzig [Leipzig], University Medical Center Groningen [Groningen] (UMCG), University of Bristol [Bristol], Université d'Oulu, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Vrije Universiteit Brussel (VUB), CIBER de Epidemiología y Salud Pública (CIBERESP), Helmholtz-Zentrum München (HZM), University of Newcastle [Australia] (UoN), Turku University Hospital (TYKS), Statens Serum Institut [Copenhagen], Sahlgrenska Academy at University of Gothenburg [Göteborg], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Queen Mary University of London (QMUL), Norwegian Institute of Public Health [Oslo] (NIPH), King‘s College London, University of Groningen [Groningen], University of Amsterdam [Amsterdam] (UvA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Cambridge [UK] (CAM), McMaster University [Hamilton, Ontario], University of Exeter, Ludwig-Maximilians-Universität München (LMU), University of the Basque Country [Bizkaia] (UPV/EHU), The Wellcome Trust Sanger Institute [Cambridge], The University of Western Australia (UWA), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Universitat Rovira i Virgili, Imperial College London, University of Helsinki, Vrije Universiteit Amsterdam [Amsterdam] (VU), University College of London [London] (UCL), University of Bergen (UiB), University of Tampere [Finland], University of Oulu, Copenhagen University Hospital, University of Turku, University of Queensland [Brisbane], Haukeland University Hospital, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust University College London Wellcome 090532106130098381203141212259WT206194United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)U01DK105535National Institute for Health Research (NIHR)NF-SI-0617-10090Netherlands Organization for Health Research and DevelopmentTOP 40-00812-9811010American Diabetes Association1-17-PDF-077Daniel B. Burke Chair for Diabetes Research United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USAR01 HD058886Agencia de Gestio D'Ajuts Universitaris de Recerca Agaur (AGAUR)2017 FI_B 00636Generalitat de Catalunya -Fons Social Europeu European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG) 322605Oak Foundation Fellowship Wellcome TrustEuropean CommissionWT104150098497/Z/12/ZRoyal Society of LondonEuropean CommissionWT104150Wellcome Trust098395/Z/12/ZNatural Resources CanadaCanadian Forest ServiceCanada Research Chairs Finnish Cultural Foundation KNAW Academy Professor Award PAH/6635TARGET Danish Diabetes Academy Copenhagen Graduate School of Health and Medical Sciences Netherlands Organization for Health Research and Development (VIDI) 016.136.361European Research Council (ERC)European Commission648916European Research Council (ERC)European Commission UK Research & Innovation (UKRI)Medical Research Council UK (MRC)European CommissionMRC_MC_UU_12012/5MC_UU_00011/1National Institute for Health Research (NIHR) Botnar Foundation Bernard Wolfe Health Neuroscience Endowment European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO 279153University of Bristol UK Research & Innovation (UKRI)Medical Research Council UK (MRC)MC_UU_00011/1MC_UU_00011/3French National Agency of Research, F-CRIN/FORCE, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Genomics of Sex Differences, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University of Copenhagen = Københavns Universitet (UCPH), Universität Leipzig, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, University of Newcastle [Callaghan, Australia] (UoN), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Felix, Janine F [0000-0002-9801-5774], Apollo - University of Cambridge Repository, Biological Psychology, APH - Mental Health, Felix, Janine F. [0000-0002-9801-5774], Tampere University, Tampere University Hospital Catchment Area, Department of Clinical Physiology and Nuclear Medicine, Clinical Medicine, Department of Clinical Chemistry, Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Life Course Epidemiology (LCE), Vogelezang, Suzanne, Bradfield, Jonathan P, Ahluwalia, Tarunveer S, Curtin, John A, Hyppönen, Elina, Felix, JF, and Early Growth Genetics Consortium
Subjects: Male, Genetic-variation, Nedd4 Ubiquitin Protein Ligases, Pooled Analysis, Blood Pressure, 0302 clinical medicine, Human genetics, Mendelian Randomization, Young adult, Child, health care economics and organizations, Body mass index, Adiposity, Genetics & Heredity, 0303 health sciences, Statistics, 1184 Genetics, developmental biology, physiology, Genomics, adulto, 3. Good health, Cardiovascular Diseases, Child, Preschool, Physical Sciences, Menarche, genetic-variation, presión sanguínea, Monosaccharide Transport Proteins, Genetic loci, education, enfermedades cardiovasculares, Prostate-specific Antigen, Genetic correlation, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes Mellitus, Genetics, Humans, prostate-specific antigen, Statistical Methods, Molecular Biology, Ecology, Evolution, Behavior and Systematics, childhood, 0604 Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Early Growth Genetics Consortium, Biology and Life Sciences, Computational Biology, nutritional and metabolic diseases, Single nucleotide polymorphisms, Mendelian Randomization Analysis, Biological Tissue, Diabetes Mellitus, Type 2, estudio de asociación genómica completa, genetic factors, mendelian randomization, análisis de la aleatorización mendeliana, proteínas de transporte de monosacáridos, 030217 neurology & neurosurgery, Mathematics, Demography, Developmental Biology, Cardiovascular Risk, Cancer Research, obesity, Physiology, humanos, adolescente, Overweight, QH426-470, Genome-wide association studies, Waist–hip ratio, Mathematical and Statistical Techniques, Medicine and Health Sciences, body mass index (BMI), Genetics of disease, Genetics (clinical), 2. Zero hunger, adiposity, Metaanalysis, Physiological Parameters, Connective Tissue, Female, medicine.symptom, Anatomy, pooled analysis, Life Sciences & Biomedicine, Research Article, Adult, cardiovascular risk, Adolescent, Birth weight, menarquia, Adipose tissue, Biology, 3121 Internal medicine, Research and Analysis Methods, medicine, overweight, Genetic Predisposition to Disease, Obesity, 030304 developmental biology, Waist-Hip Ratio, índice de masa corporal, Body Weight, Cardiometabolic Risk Factors, predisposición genética a la enfermedad, Heritability, Genome Analysis, young-adults, Genome-wide Association, índice cintura-cadera, Young-adults, genome-wide association, Genome-Wide Association Study
Abstract: The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values, CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40-00812-9811010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya -Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG -no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku.dk), The Danish Diabetes Academy (http://danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO n degrees 279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.
Published: 2020
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27. Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

Author: Pekka Ellonen, Jukka T. Salonen, Mika Kähönen, Maija Lepistö, Ilkka Seppälä, Nina Hutri-Kähönen, Pashupati P. Mishra, Leo-Pekka Lyytikäinen, Emma Raitoharju, Olli T. Raitakari, Nina Mononen, Terho Lehtimäki, Jaakko Laaksonen, Markus Juonala, Henrikki Almusa, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Department of Paediatrics, Department of Clinical Physiology and Nuclear Medicine, Institute for Molecular Medicine Finland, University of Helsinki, and Department of Public Health
Subjects: 0301 basic medicine, Adult, Male, Mitochondrial DNA, Genotype, Science, Single-nucleotide polymorphism, Blood Pressure, 030204 cardiovascular system & hematology, Biology, 3121 Internal medicine, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Genome-wide association studies, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Mitochondrial genome, Risk Factors, SNP, Humans, Risk factor, Finland, Genetics, Multidisciplinary, Middle Aged, Pathogenicity, Peripheral blood, 3142 Public health care science, environmental and occupational health, 3. Good health, Mitochondria, 030104 developmental biology, Blood pressure, Phenotype, 3121 General medicine, internal medicine and other clinical medicine, Transfer RNA, Genome, Mitochondrial, Hypertension, Medicine, Female, 3111 Biomedicine, Genome-Wide Association Study
Abstract: High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.
Published: 2020

28. Relation of intraventricular conduction delay to risk of new-onset heart failure and structural heart disease in the general population

Author: Jussi Hernesniemi, Heini Huhtala, Terho Lehtimäki, Petri Haataja, Antti Jula, Markku Eskola, Leo-Pekka Lyytikäinen, Andrés Ricardo Pérez-Riera, Kjell Nikus, Jani Rankinen, Mika Kähönen, Teemu J. Niiranen, Tampere University, Clinical Medicine, TAYS Heart Centre, Department of Clinical Chemistry, Health Sciences, and Department of Clinical Physiology and Nuclear Medicine
Subjects: lcsh:Diseases of the circulatory (Cardiovascular) system, medicine.medical_specialty, Heart disease, Intraventricular conduction delay, Population, Heart failure, 030204 cardiovascular system & hematology, 3121 Internal medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, Structural heart disease, education, education.field_of_study, Bundle branch block, ECG, Left bundle branch block, business.industry, Hazard ratio, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, Confidence interval, 3. Good health, lcsh:RC666-701, Cardiology, Population study, Cardiology and Cardiovascular Medicine, business
Abstract: Background: Intraventricular conduction delays (IVCDs) are hallmarks of heart failure (HF) and structural heart disease (SHD) but their prognostic value for HF and SHD is unclear. Methods: Relation of eight IVCDs and the incidence of first-time HF or SHD was studied in a nationally representative random sample of 6080 Finnish subjects aged ≥ 30 years (mean age 52.1, SD 14.5 years) who participated in the health examination including 12-lead ECG. Results: During 16.5 years’ follow up, half of the subjects with left bundle branch block (LBBB) and one third of the subjects with non-specific IVCD developed HF. After controlling for known clinical risk factors the hazard ratio (HR) for new-onset HF for LBBB was 3.29 (95% confidence interval 1.93–5.63, P < 0.001) and 3.53 for non-specific IVCD (1.65–7.55, P = 0.001). In corresponding analysis, LBBB predicted SHD with HR 2.60 (1.21–5.62, P = 0.015). Excluding subjects with history of heart disease, including coronary heart disease, did not have impact on results. Right bundle branch block and other IVCDs displayed no relation to endpoints. Conclusion: LBBB and non-specific IVCD were associated with more than three-fold risk of new-onset HF. Furthermore, LBBB was associated with novel SHD. Their presence should alert clinician even in subjects free from any known heart disease. publishedVersion
Published: 2020

29. Long‐term outcome of intraventricular conduction delays in the general population

Author: Petri Haataja, Antti Jula, Mika Kähönen, Leo-Pekka Lyytikäinen, Harri Rissanen, Kjell Nikus, Jussi Hernesniemi, Jani Rankinen, Terho Lehtimäki, Markku Eskola, Heini Huhtala, Andrés Ricardo Pérez-Riera, Tampere University, TAYS Heart Centre, Clinical Medicine, Health Sciences, and Department of Clinical Chemistry
Subjects: Adult, Male, medicine.medical_specialty, electrocardiography, Population, Bundle-Branch Block, 030204 cardiovascular system & hematology, 3121 Internal medicine, 03 medical and health sciences, 0302 clinical medicine, Cardiac Conduction System Disease, Physiology (medical), Internal medicine, medicine, bundle branch block, Humans, 030212 general & internal medicine, education, Finland, Aged, Aged, 80 and over, education.field_of_study, Bundle branch block, population study, business.industry, Left bundle branch block, Hazard ratio, General Medicine, Original Articles, Right bundle branch block, Middle Aged, medicine.disease, Prognosis, Confidence interval, intraventricular conduction delay, Cardiology, Population study, Original Article, Female, 3111 Biomedicine, Left anterior fascicular block, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract: Background Previous population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD). Methods We studied long‐term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12‐lead ECG. For left bundle branch block (LBBB) and non‐specific IVCD (NSIVCD), two different definitions were used. Results During 16.5 years’ follow‐up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04–2.31, p = .032) and 1.27 (95% confidence interval 0.80–2.02, p = .308) for the Strauss’ definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R‐R’ pattern was not associated with any adverse outcome. Conclusions In a population study with long‐term follow‐up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder.
Published: 2020

30. Pre-Operative Masseter Area is an Independent Predictor of Long-Term Survival after Carotid Endarterectomy

Author: Niina Khan, Jussi Hernesniemi, Niku Oksala, Juha Pekka Pienimäki, Vesa J. Pihlajaniemi, Leo-Pekka Lyytikäinen, Iisa Lindström, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
Subjects: Male, medicine.medical_specialty, Computed Tomography Angiography, Intraclass correlation, medicine.medical_treatment, Kirurgia, anestesiologia, tehohoito, radiologia - Surgery, anesthesiology, intensive care, radiology, Kaplan-Meier Estimate, Carotid endarterectomy, 030204 cardiovascular system & hematology, 030230 surgery, Asymptomatic, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine.artery, medicine, Humans, Carotid Stenosis, Registries, Aged, Aged, 80 and over, Endarterectomy, Carotid, Biolääketieteet – Biomedicine, Masseter Muscle, Proportional hazards model, business.industry, Hazard ratio, Reproducibility of Results, Amaurosis fugax, Middle Aged, Survival Analysis, Treatment Outcome, Cardiology, Female, Surgery, medicine.symptom, Internal carotid artery, Cardiology and Cardiovascular Medicine, business
Abstract: Objective/Background Sarcopenia is a predictor of mortality in elderly patients. Masseter area (MA) reflects sarcopenia in trauma patients. It was hypothesised that MA and Masseter density (MD) could be evaluated reliably from pre-operative computed tomography angiography (CTA) scans and that they predict post-operative survival in carotid endarterectomy (CEA) patients. Methods This was an observational registry study. Patients (n = 242) were operated on for asymptomatic stenosis (n = 32; 13.2%), amaurosis fugax (n = 41; 16.9%), transient ischaemic attack (n = 85; 35.1%), or ischaemic stroke (n = 84; 34.7%). Internal carotid artery stenoses were graded angiographically. Intraclass correlation coefficient (ICC) was used to analyse measurement reliability by three independent observers. Cox regression analysis was used to study the effect of MA and MD on survival (hazard ratio [HR]). Results Median patient age was 71.0 years (interquartile range [IQR] 13.0) and follow up time was 68.5 months (range 3–163 months); at the end of follow up (1 October 2017), 104 (43.0%) patients had died according to the National Population Register. The average MA (MAavg, the mean of left and right MA [median 394.0 mm2; IQR 110.1 mm2]) and MD (MDavg, the mean of left and right MD [median 53.5 HU; IQR 16.5 HU]) could be measured with excellent reliability (ICC > 0.865, p Conclusion Average MA but not MD measured from the pre-operative CTA scan provides a reliable estimate of post-operative long-term survival in CEA patients independent of other risk factors, anthropometric measurements, and dental status.
Published: 2019
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31. Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium

Author: Panos Deloukas, Christina-Alexandra Schulz, Caren E. Smith, Lu Qi, Mary F. Feitosa, Melissa E. Garcia, Natalia Pervjakova, Denise K. Houston, Michael A. Province, Stavroula Kanoni, Torben Hansen, Jean Shin, Lynda M. Rose, Oscar H. Franco, Yongmei Liu, Trudy Voortman, Marie-Claude Vohl, Luigi Ferrucci, Chloé Sarnowski, Paul S. de Vries, Jose C. Florez, John C. Lieske, Louis Pérusse, Misa Graff, Jian'an Luan, Nicola M. McKeown, Felix R. Day, L. Adrienne Cupples, Qibin Qi, Frank J. A. van Rooij, Robert A. Scott, Josée Dupuis, Stephen S. Rich, Jorma Viikari, Tarunveer S. Ahluwalia, Leo-Pekka Lyytikäinen, Paul M. Ridker, Tomáš Paus, Stephen Turner, Harri Rissanen, Audrey Y. Chu, Albert Hofman, Olli T. Raitakari, Paul Knekt, Daniel I. Chasman, Nita G. Forouhi, Vera Mikkilä, Toshiko Tanaka, Mika Kähönen, George Dedoussis, Minjung Kho, Yun J. Sung, Anne E. Justice, Julius S. Ngwa, Ani Manichaikul, M. Carola Zillikens, Jordi Merino, Dena G. Hernandez, Rozenn N. Lemaitre, Tao Huang, Sharon L.R. Kardia, Jing Hua Zhao, Stefania Bandinelli, Veikko Salomaa, Arne Astrup, Wei Zhao, David S. Siscovick, John Blangero, Zdenka Pausova, Dabeeru C. Rao, Oluf Pedersen, Craig E. Pennell, Wendy H. Oddy, Jose M. Ordovas, Jessica C. Kiefte-de Jong, Marju Orho-Melander, Hassan S. Dashti, Satu Männistö, Tuomo Rankinen, Constantina Papoutsakis, Sherly X. Li, Antti Jula, Kari E. North, Thorkild I. A. Sørensen, André G. Uitterlinden, Alexis C. Frazier-Wood, Nicholas J. Wareham, Ulrika Ericson, Markus Perola, Ioanna P. Kalafati, Renée de Mutsert, Jinyan Huang, Ruifang Li-Gao, Claudia Langenberg, Mike A. Nalls, Olivia Li, Joanne E. Curran, Dennis O. Mook-Kanamori, Niina Eklund, Jerome I. Rotter, Angelo Tremblay, Claude Bouchard, Jennifer A. Smith, Terho Lehtimäki, Mary K. Wojczynski, Carol A. Wang, Epidemiology, Internal Medicine, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Day, Felix [0000-0003-3789-7651], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Forouhi, Nita [0000-0002-5041-248X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Aging, Calorie, Genotype, Heart Diseases, Receptors, Retinoic Acid, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Obesity, Molecular Biology, Aged, 2. Zero hunger, Genetics, Family aggregation, Membrane Proteins, Genomics, Nutrients, Middle Aged, medicine.disease, 3. Good health, Fibroblast Growth Factors, Psychiatry and Mental health, 030104 developmental biology, Genetic Loci, Meta-analysis, Medical genetics, Female, Energy Intake, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10(−6)) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
Published: 2019
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32. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author: Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
Subjects: Male, Epidemiology, Genome-wide association study, Cardiovascular, MESH: Genotype, Substance Misuse, Alcohol Use and Health, 0302 clinical medicine, Aetiology, triglycerides, 11 Medical and Health Sciences, Public, Environmental & Occupational Health, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Life Style, genome wide, gene-alcohol interaction, lipid levels, Lipid Measurement, Lifelines Cohort, DENSITY-LIPOPROTEIN CHOLESTEROL, MESH: Young Adult, 030220 oncology & carcinogenesis, Kexin, LOW-FREQUENCY, MESH: Cholesterol, HDL, MESH: Cholesterol, LDL, MESH: Triglycerides, HDL, Alcohol Drinking, Genotype, alcohol consumption, MESH: Phenotype, LDL, lipids, 03 medical and health sciences, Genetics, Humans, Life Style, METAANALYSIS, 01 Mathematical Sciences, Aged, MESH: Adolescent, HDL CHOLESTEROL, MESH: Humans, Science & Technology, Cholesterol, APOBEC1, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), MESH: Vascular Endothelial Growth Factor B, Racial Groups, cholesterol, The Netherlands, MESH: Adult, CONSUMPTION, chemistry, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Lipid profile, MESH: Female, MESH: Alcohol Drinking, MESH: Continental Population Groups, Vascular Endothelial Growth Factor B, Original Contributions, Blood lipids, VEGF-B, Medical and Health Sciences, Mathematical Sciences, BLOOD-LIPIDS, chemistry.chemical_compound, 2.1 Biological and endogenous factors, 030212 general & internal medicine, MESH: Aged, medicine.diagnostic_test, PLASMA, gene-environment interactions, Middle Aged, 3142 Public health care science, environmental and occupational health, Alcoholism, Phenotype, Female, gene-lifestyle interactions, genome-wide association studies, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, Groningen, Adult, Adolescent, Biology, Young Adult, medicine, CORONARY-HEART-DISEASE, Human Genome, Cholesterol, HDL, Lipid metabolism, Cholesterol, LDL, InterAct Consortium, MESH: Lipids, MESH: Male, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract: © The Author(s) 2019. A person'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 multiancestry 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 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of 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 stages 1 and 2, a total of 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 (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
Published: 2019
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33. A genome-wide association study identifies UGT1A1 as a regulator of serum cell-free DNA in young adults: The Cardiovascular Risk in Young Finns Study.

Author: Juulia Jylhävä, Leo-Pekka Lyytikäinen, Mika Kähönen, Nina Hutri-Kähönen, Johannes Kettunen, Jorma Viikari, Olli T Raitakari, Terho Lehtimäki, and Mikko Hurme
Subjects: Medicine, Science
Abstract: IntroductionCirculating cell-free DNA (cf-DNA) is a useful indicator of cell death, and it can also be used to predict outcomes in various clinical disorders. Several innate immune mechanisms are known to be involved in eliminating DNA and chromatin-related material as part of the inhibition of potentially harmful autoimmune responses. However, the exact molecular mechanism underlying the clearance of circulating cf-DNA is currently unclear.MethodsTo examine the mechanisms controlling serum levels of cf-DNA, we carried out a genome-wide association analysis (GWA) in a cohort of young adults (aged 24-39 years; n = 1841; 1018 women and 823 men) participating in the Cardiovascular Risk in Young Finns Study. Genotyping was performed with a custom-built Illumina Human 670 k BeadChip. The Quant-iT(TM) high sensitivity DNA assay was used to measure cf-DNA directly from serum.ResultsThe results revealed that 110 single nucleotide polymorphisms (SNPs) were associated with serum cf-DNA with genome-wide significance (pConclusionThe UGT1A1 enzyme catalyses the detoxification of several drugs and the turnover of many xenobiotic and endogenous compounds by glucuronidating its substrates. These data indicate that UGT1A1-associated processes are also involved in the regulation of serum cf-DNA concentrations.
Published: 2012
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34. Genetic profiling using genome-wide significant coronary artery disease risk variants does not improve the prediction of subclinical atherosclerosis: the Cardiovascular Risk in Young Finns Study, the Bogalusa Heart Study and the Health 2000 Survey--a meta-analysis of three independent studies.

Author: Jussi A Hernesniemi, Ilkka Seppälä, Leo-Pekka Lyytikäinen, Nina Mononen, Niku Oksala, Nina Hutri-Kähönen, Markus Juonala, Leena Taittonen, Erin N Smith, Nicholas J Schork, Wei Chen, Sathanur R Srinivasan, Gerald S Berenson, Sarah S Murray, Tomi Laitinen, Antti Jula, Johannes Kettunen, Samuli Ripatti, Reijo Laaksonen, Jorma Viikari, Mika Kähönen, Olli T Raitakari, and Terho Lehtimäki
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWASs) have identified a large number of variants (SNPs) associating with an increased risk of coronary artery disease (CAD). Recently, the CARDIoGRAM consortium published a GWAS based on the largest study population so far. They successfully replicated twelve already known associations and discovered thirteen new SNPs associating with CAD. We examined whether the genetic profiling of these variants improves prediction of subclinical atherosclerosis--i.e., carotid intima-media thickness (CIMT) and carotid artery elasticity (CAE)--beyond classical risk factors.We genotyped 24 variants found in a population of European ancestry and measured CIMT and CAE in 2001 and 2007 from 2,081, and 2,015 subjects (aged 30-45 years in 2007) respectively, participating in the Cardiovascular Risk in Young Finns Study (YFS). The Bogalusa Heart Study (BHS; n = 1179) was used as a replication cohort (mean age of 37.5). For additional replication, a sub-sample of 5 SNPs was genotyped for 1,291 individuals aged 46-76 years participating in the Health 2000 population survey. We tested the impact of genetic risk score (GRS(24SNP/CAD)) calculated as a weighted (by allelic odds ratios for CAD) sum of CAD risk alleles from the studied 24 variants on CIMT, CAE, the incidence of carotid atherosclerosis and the progression of CIMT and CAE during a 6-year follow-up.CIMT or CAE did not significantly associate with GRS(24SNP/CAD) before or after adjusting for classical CAD risk factors (p>0.05 for all) in YFS or in the BHS. CIMT and CAE associated with only one SNP each in the YFS. The findings were not replicated in the replication cohorts. In the meta-analysis CIMT or CAE did not associate with any of the SNPs.Genetic profiling, by using known CAD risk variants, should not improve risk stratification for subclinical atherosclerosis beyond conventional risk factors among healthy young adults.
Published: 2012
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35. Viridans streptococcal biofilm colonizes advanced and complicated atherosclerotic atheromas by evading immune system

Author: Niku Oksala, T. Ijas, C. Wang, V. Karhunen, Thanos Sioris, S. Horkko, N Astola, Tanja Pessi, Sirkka Goebeler, A. M. Louhelainen, Leo-Pekka Lyytikäinen, J. Lappetelainen, Heini Huhtala, Sari Tuomisto, Emma Raitoharju, Pekka J. Karhunen, M. Martiskainen, Reijo Laaksonen, T. Haapaniemi, Terho Lehtimäki, and Claudia Monaco
Subjects: Immune system, business.industry, Biofilm, Medicine, Cardiology and Cardiovascular Medicine, business, Microbiology
Published: 2021
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36. Pulse Wave Velocity Predicts the Progression of Blood Pressure and Development of Hypertension in Young Adults

Author: Jorma Viikari, Teemu Koivistoinen, Leo-Pekka Lyytikäinen, Heikki Aatola, Terho Lehtimäki, Tiina Luukkaala, Mika Kähönen, Olli T. Raitakari, Nina Hutri-Kähönen, and Markus Juonala
Subjects: Adult, Male, medicine.medical_specialty, Population, Diastole, Pulse Wave Analysis, 030204 cardiovascular system & hematology, Risk Assessment, Prehypertension, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Internal Medicine, Humans, Medicine, 030212 general & internal medicine, education, Pulse wave velocity, Finland, Retrospective Studies, education.field_of_study, Receiver operating characteristic, business.industry, Incidence, Age Factors, Blood Pressure Determination, Odds ratio, ta3121, Middle Aged, Confidence interval, Logistic Models, Blood pressure, Case-Control Studies, Hypertension, Multivariate Analysis, Disease Progression, Cardiology, Female, business, Follow-Up Studies
Abstract: The aim of the present study was to examine whether pulse wave velocity (PWV) predicts the progression of blood pressure and the development of hypertension in young adults. In addition, we studied whether PWV improves the risk prediction of incident hypertension beyond traditional cardiovascular risk factors. Systolic and diastolic blood pressures were measured in 2007 and 2011 for 1449 Finnish adults (aged 30–45 years). In addition, PWV and other cardiovascular risk factors were measured in 2007. The association between PWV (in 2007) and blood pressure (in 2011) was studied in the whole population (n=1449) and in a normotensive subpopulation (n=1183). The ability of PWV measured in 2007 to predict incident hypertension in 2011 was investigated in the subpopulation (n=1183). PWV measured in 2007 was directly and independently associated with systolic and diastolic blood pressures measured in 2011 ( P P P =0.040), and the continuous net reclassification improvement 59.4% ( P
Published: 2018
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37. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author: Jean-Claude Tardif, Kelly Cho, Adolfo Correa, Na Cai, Koichi Matsuda, Paul L. Auer, Ken Sin Lo, Jennifer A. Brody, Dragana Vuckovic, Oluf Pedersen, Eric Jorgenson, Cassandra N. Spracklen, Jennifer E. Huffman, Stefan Weiss, Tim Kacprowski, Nicholas A. Watkins, Yoichiro Kamatani, Michele K. Evans, John Danesh, Masahiro Kanai, Karyn Megy, Kumaraswamy Naidu Chitrala, Michael H. Guo, James S. Floyd, Savita Karthikeyan, Ani Manichaikul, Petra Schubert, Vijay G. Sankaran, Torben Hansen, Traci M. Bartz, Laura M. Raffield, Regina Manansala, Parsa Akbari, Scott C. Ritchie, Ruth J. F. Loos, Manuel Tardaguila, Willem H. Ouwehand, Peter W.F. Wilson, Emanuele Di Angelantonio, Abdou Mousas, Jeffrey Haessler, Yoav Ben-Shlomo, Benjamin Rodriguez, Karen L. Mohlke, Girish N. Nadkarni, Oliver Stegle, Paul Elliott, Erwin P. Bottinger, Nathan Pankratz, Hélène Choquet, Julian C. Knight, Niels Grarup, Niki Dimou, Leslie A. Lange, Stephan B. Felix, William J. Astle, Jerome I. Rotter, Frank J. A. van Rooij, Andreas Greinacher, Yongmei Liu, Tao Jiang, Michael Inouye, Ming-Huei Chen, Jingzhong Ding, Uwe Völker, Huijun Qian, Henry Völzke, Alan B. Zonderman, Evangelos Evangelou, Wei Huang, Jonathan D. Rosen, Christopher J. Penkett, Michel Georges, Kousik Kundu, Mohsen Ghanbari, Hannes Ponstingl, Adam S. Butterworth, Joanna M. M. Howson, Praveen Surendran, Terho Lehtimäki, Allan Linneberg, Emilie M. Wigdor, Michael Preuss, Olli T. Raitakari, Arden Moscati, Yukinori Okada, Yoshinori Murakami, Guillaume Lettre, Leo-Pekka Lyytikäinen, Hua Tang, Caleb A. Lareau, David J. Roberts, Saori Sakaue, Mika Kähönen, Alexander P. Reiner, VA Million Veteran Program, Fotis Koskeridis, Nina Mononen, Linda Broer, Kjell Nikus, Andrew D. Johnson, Patrick K. Albers, Stephen B. Watt, Erik L. Bao, Yun Li, Klaudia Walter, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Andrew D Beswick, Tõnu Esko, Jette Bork-Jensen, and Masato Akiyama
Subjects: Genetics, Gene regulatory network, Oxygen transport, Genome-wide association study, Biology, Genetic architecture, Blood cell, symbols.namesake, medicine.anatomical_structure, medicine, Mendelian inheritance, symbols, Allele, Allele frequency
Abstract: SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.
Published: 2020
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38. Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations

Author: Ming-Huei Chen, Laura M. Raffield, Abdou Mousas, Saori Sakaue, Jennifer E. Huffman, Tao Jiang, Parsa Akbari, Dragana Vuckovic, Erik L. Bao, Arden Moscati, Xue Zhong, Regina Manansala, Véronique Laplante, Minhui Chen, Ken Sin Lo, Huijun Qian, Caleb A. Lareau, Mélissa Beaudoin, Masato Akiyama, Traci M. Bartz, Yoav Ben-Shlomo, Andrew Beswick, Jette Bork-Jensen, Erwin P. Bottinger, Jennifer A. Brody, Frank J.A. van Rooij, Kumaraswamynaidu Chitrala, Kelly Cho, Hélène Choquet, Adolfo Correa, John Danesh, Emanuele Di Angelantonio, Niki Dimou, Jingzhong Ding, Paul Elliott, Tõnu Esko, Michele K. Evans, James S. Floyd, Linda Broer, Niels Grarup, Michael H. Guo, Andreas Greinacher, Jeff Haessler, Torben Hansen, Joanna M. M. Howson, Wei Huang, Eric Jorgenson, Tim Kacprowski, Mika Kähönen, Yoichiro Kamatani, Masahiro Kanai, Savita Karthikeyan, Fotis Koskeridis, Leslie A. Lange, Terho Lehtimäki, Markus M. Lerch, Allan Linneberg, Yongmei Liu, Leo-Pekka Lyytikäinen, Ani Manichaikul, Koichi Matsuda, Karen L. Mohlke, Nina Mononen, Yoshinori Murakami, Girish N. Nadkarni, Matthias Nauck, Kjell Nikus, Willem H. Ouwehand, Nathan Pankratz, Oluf Pedersen, Michael Preuss, Bruce M. Psaty, Olli T. Raitakari, David J. Roberts, Stephen S. Rich, Benjamin A.T. Rodriguez, Jonathan D. Rosen, Jerome I. Rotter, Petra Schubert, Cassandra N. Spracklen, Praveen Surendran, Hua Tang, Jean-Claude Tardif, Mohsen Ghanbari, Uwe Völker, Henry Völzke, Nicholas A. Watkins, Alan B. Zonderman, VA Million Veteran Program, Peter W.F. Wilson, Yun Li, Adam S. Butterworth, Jean-François Gauchat, Charleston W.K. Chiang, Bingshan Li, Ruth J.F. Loos, William J. Astle, Evangelos Evangelou, Vijay G. Sankaran, Yukinori Okada, Nicole Soranzo, Andrew D. Johnson, Alexander P. Reiner, Paul L. Auer, and Guillaume Lettre
Subjects: Blood cell, Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Ethnic group, Genome-wide association study, Biology, 030304 developmental biology
Abstract: SUMMARYMost loci identified by GWAS have been found in populations of European ancestry (EA). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EA individuals, we identified 5,552 trait-variant associations at P−9, including 71 novel loci not found in EA populations. We also identified novel ancestry-specific variants not found in EA, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional, and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EA-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations, and compared genetic architecture and the impact of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
Published: 2020
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39. Long-term prognostic significance of the ST level and ST slope in the 12-lead ECG in the general population

Author: Antti Jula, Tuomo Nieminen, Leo-Pekka Lyytikäinen, Mika Kähönen, Heini Huhtala, Harri Rissanen, Markku Eskola, Kjell Nikus, Jussi Hernesniemi, Tiia Istolahti, Terho Lehtimäki, Ismo Anttila, HYKS erva, Päijät-Häme Welfare Consortium, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Yhteiskuntatieteiden tiedekunta - Faculty of Social Sciences, and Tampere University
Subjects: Male, T-WAVE ABNORMALITIES, CARDIOVASCULAR MORTALITY, 12 lead ecg, Coronary Disease, 030204 cardiovascular system & hematology, Continuous variable, Electrocardiography, 0302 clinical medicine, Risk Factors, ST slope, 030212 general & internal medicine, Outcome, ST depression, RISK, education.field_of_study, Hazard ratio, Sisätaudit - Internal medicine, MEN, ASSOCIATION, Prognosis, 3. Good health, PREVALENCE, Cardiology, Population study, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Population, 03 medical and health sciences, Internal medicine, medicine, Humans, CORONARY-HEART-DISEASE, education, Aged, Proportional Hazards Models, business.industry, Proportional hazards model, ECG, SEGMENT, Arrhythmias, Cardiac, REPOLARIZATION, Confidence interval, ST level, 3121 General medicine, internal medicine and other clinical medicine, MALIGNANT FORM, business
Abstract: Background: Even minor ST depression in the electrocardiogram (ECG) is associated with cardiovascular disease and increased mortality. There is limited data on the prognostic significance of ST-level changes in the general population. Subjects and methods: A random sample of Finnish subjects (n = 6354) aged over 30 years (56.1% women) underwent a health examination including a 12-lead ECG in the Health 2000 survey. The effects of relative ST level as a continuous variable and ST slope (upsloping, horizontal, downsloping) in three different lead groups were analyzed using a multi-adjusted Cox proportional hazard model separately for men and women with total mortality as endpoint. Results: The follow-up lasted for 13.7 (SD 3.3) years for men and 13.9 (SD 3.1) years for women. Lower lateral ST levels were associated with all-cause mortality in multi-adjusted models in both genders (at.) + 80 ms hazard ratio [HR] 0.64 for a change of 1.0 mm [95% confidence interval 0.49-0.84, p = 0.002] for men and HR 0.61 [0.48-0.78, p
Published: 2020

40. The prevalence and prognostic significance of interatrial block in the general population

Author: Jussi Hernesniemi, Kjell Nikus, Antoni Bayés de Luna, Heini Huhtala, Ismo Anttila, Tiia Istolahti, Antti Jula, Markku Eskola, Antti Eranti, Leo-Pekka Lyytikäinen, Mika Kähönen, Terho Lehtimäki, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Yhteiskuntatieteiden tiedekunta - Faculty of Social Sciences, and Tampere University
Subjects: Adult, Male, medicine.medical_specialty, Population, 030204 cardiovascular system & hematology, Electrocardiography, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Atrial Fibrillation, Prevalence, medicine, Humans, Interatrial Block, atrial fibrillation, cardiovascular diseases, 030212 general & internal medicine, education, Stroke, Finland, Aged, interatrial block, education.field_of_study, population study, business.industry, ECG, Sisätaudit - Internal medicine, Atrial fibrillation, Original Articles, General Medicine, Middle Aged, medicine.disease, mortality, cardiovascular system, Cardiology, Population study, Female, business, Conduction delay
Abstract: Introduction: Partial and advanced interatrial block (IAB) in the electrocardiographic (ECG) represents inter-atrial conduction delay. IAB is associated with atrial fibrillation (AF) and stroke in the general population. Material and methods: A representative sample of Finnish subjects (n = 6354) aged over 30 years (mean: 52.2 years, standard deviation: 14.6) underwent a health examination including a 12-lead ECG. Five different IAB groups based on automatic measurements were compared to normal P waves using multivariate-adjusted Cox proportional hazard model. Follow-up lasted up to 15 years. Results: The prevalence of advanced and partial IAB was 1.0% and 9.7%, respectively. In the multivariate model, both advanced (hazard ratio (HR): 1.63 (95% confidence interval (CI): 1.00−2.65)) and partial IAB (HR: 1.39 (1.09−1.77)) were associated with increased risk of AF. Advanced IAB was associated with increased risk of stroke or transient ischaemic attack (TIA) independently of associated AF (HR: 2.22 (1.20−4.13)). Partial IAB was also associated with increased risk of being diagnosed with coronary heart disease (HR: 1.26 (1.01−1.58)). Discussion: KEY MESSAGES: Both partial and advanced interatrial block are associated with increased risk of atrial fibrillation in the general population. Advanced interatrial block is an independent risk factor for stroke and transient ischaemic attack. The clinical significance of interatrial block is dependent on the subtype classification.
Published: 2020

41. Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data

Author: Bakhtawar K. Mahmoodi, W.H. Wilson Tang, Frank Dudbridge, Marcus E. Kleber, Ify R. Mordi, Naveed Sattar, Chim C. Lang, Tabassome Simon, Ruth McPherson, Aroon D. Hingorani, Nilesh J. Samani, Imo E. Hoefer, Crystel M. Gijsberts, Winfried März, Michael V. Holmes, Frank L.J. Visseren, Panos Deloukas, Johannes Waltenberger, Claes Held, Alexandre F.R. Stewart, Jaana Hartiala, Anna P. Pilbrow, Kjell Nikus, Guillaume Paré, Ekaterina V Baranova, Nicolas Danchin, Wojciech Szczeklik, Vinicius Tragante, Andrej Teren, Jari Laurikka, Gerard Pasterkamp, Mahyar Heydarpour, Diederick E. Grobbee, Emil Hagström, Kenan Direk, Daniel Levin, Mika Kähönen, Riyaz S. Patel, Hooman Allayee, Yan Gong, A. Mark Richards, Simon C. Body, Michiel L. Bots, Graciela E. Delgado, Rhonda M. Cooper-DeHoff, Thomas O. Bergmeijer, John E. Deanfield, Ragnar O. Vilmundarson, Carl J. Pepine, Julie A. Johnson, Folkert W. Asselbergs, Markus Scholz, Ralph Burkhardt, Pekka Kuukasjärvi, Olaf H. Klungel, Anke H. Maitland-van der Zee, Jochen D. Muehlschlegel, Colin N. A. Palmer, Sander W. van der Laan, Christopher P. Nelson, G. Kees Hovingh, Joachim Thiery, Jessica van Setten, Stefan James, Raymond O McCubrey, Niclas Eriksson, Stanley L. Hazen, Laurence J. Howe, John A. Spertus, Terho Lehtimäki, Salma Kotti, Robert N. Doughty, Vicky A. Cameron, Axel Åkerblom, Marcin P. Kaczor, Peter S. Braund, Petra A. Lenzini, Sharon Cresci, Lars Wallentin, Marek Sanak, Adriaan O. Kraaijeveld, Jurriën M. ten Berg, Amand F. Schmidt, Leo-Pekka Lyytikäinen, Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Pulmonology, Paediatric Pulmonology, and APH - Personalized Medicine
Subjects: Risk, medicine.medical_specialty, Genotype, genetic association studies, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Single-nucleotide polymorphism, Coronary Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, single nucleotide polymorphism, Physiology (medical), Internal medicine, medicine, Factor V Leiden, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, Myocardial infarction, cardiovascular diseases, Polymorphism, Precision Medicine, Factor V/genetics, Secondary prevention, Clinical Trials as Topic, business.industry, Individual participant data, Coronary Disease/diagnosis, Factor V, Thrombosis/genetics, Thrombosis, Single Nucleotide, medicine.disease, Atherosclerosis, Prognosis, Coronary heart disease, 3. Good health, myocardial infarction, Cardiology, Cardiology and Cardiovascular Medicine, business, coronary artery disease, secondary prevention
Abstract: Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92–1.16]; I 2 =28%; P -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
Published: 2020

42. Influence of Genetic Variation in PDE3A on Endothelial Function and Stroke

Author: Matthew Traylor, Jaeyoon Chung, Christopher D. Anderson, Rainer Malik, Sandro Marini, Martin Dichgans, Leo-Pekka Lyytikäinen, Terho Lehtimäki, Mika Kähönen, Hugh S. Markus, Ali Amin Al Olama, Olli T. Raitakari, Markus, Hugh [0000-0002-9794-5996], Apollo - University of Cambridge Repository, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
Subjects: 0301 basic medicine, Adult, Male, Adolescent, Pregnancy Complications, Cardiovascular, Genome-wide association study, Bioinformatics, Polymorphism, Single Nucleotide, Brain Ischemia, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, Risk Factors, Genetic variation, Internal Medicine, Medicine, Humans, genetics, Genetic Predisposition to Disease, Child, Stroke, Retrospective Studies, genome-wide association study, business.industry, Sisätaudit - Internal medicine, Genetic data, Genetic Variation, Middle Aged, medicine.disease, stroke, Cyclic Nucleotide Phosphodiesterases, Type 3, 3. Good health, Vascular endothelium, Vasodilation, 030104 developmental biology, Ischemic stroke, Hypertension, Female, Endothelium, Vascular, business, cyclic nucleotide phosphodiesterases type 3, vascular endothelium, 030217 neurology & neurosurgery, Function (biology), Follow-Up Studies
Abstract: We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in PDE3A (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9–12 years of age; β[SE], 0.38 [0.070]; P =3.8×10 −8 ) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02–1.06]; P =5.2×10 −6 ). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24–27 years; β[SE], 0.47 [0.23]; P =0.047) but not in older adults (β[SE], −0.012 [0.13]; P =0.89). We conclude that a genetic variant in PDE3A influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.
Published: 2020
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43. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract: Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.
Published: 2020
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44. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author: Nicholas A. Watkins, Julian C. Knight, William J. Astle, Stephan B. Felix, Petra Schubert, Andreas Greinacher, Laura M. Raffield, Guillaume Lettre, Leslie A. Lange, Erwin P. Bottinger, Jonathan D. Rosen, Frank J. A. van Rooij, Tim Kacprowski, Hua Tang, Regina Manansala, Manuel Tardaguila, Mohsen Ghanbari, Tao Jiang, Torben Hansen, Abdou Mousas, Adam S. Butterworth, Yoav Ben-Shlomo, Praveen Surendran, Terho Lehtimäki, Peter W.F. Wilson, Parsa Akbari, Hélène Choquet, Niels Grarup, Girish N. Nadkarni, Jean-Claude Tardif, Jennifer E. Huffman, Dragana Vuckovic, Ruth J. F. Loos, Karyn Megy, Emilie M. Wigdor, Michael Preuss, Alan B. Zonderman, Yukinori Okada, Oluf Pedersen, Arden Moscati, Leo-Pekka Lyytikäinen, Masahiro Kanai, Wei Huang, Andrew D Beswick, Stephen B. Watt, Erik L. Bao, Allan Linneberg, Paul Elliott, Eric Jorgenson, Tõnu Esko, Michael H. Guo, VA Million Veteran Program, Saori Sakaue, Mika Kähönen, Olli T. Raitakari, Stefan Weiss, Traci M. Bartz, Nina Mononen, Jette Bork-Jensen, Willem H. Ouwehand, Linda Broer, John Danesh, Masato Akiyama, James S. Floyd, Scott C. Ritchie, Kjell Nikus, Paul L. Auer, Emanuele Di Angelantonio, Ken Sin Lo, Kelly Cho, Uwe Völker, Ming-Huei Chen, Evangelos Evangelou, David J. Roberts, Na Cai, Benjamin Rodriguez, Savita Karthikeyan, Yoichiro Kamatani, Michael Inouye, Yoshinori Murakami, Yongmei Liu, Alexander P. Reiner, Koichi Matsuda, Jingzhong Ding, Kumaraswamy Naidu Chitrala, Niki Dimou, Andrew D. Johnson, Nathan Pankratz, Jeffrey Haessler, Vijay G. Sankaran, Oliver Stegle, Qi Guo, Karen L. Mohlke, Jennifer A. Brody, Michele K. Evans, Fotios Koskeridis, Cassandra N. Spracklen, Jerome I. Rotter, Ani Manichaikul, Patrick K. Albers, Caleb A. Lareau, Michel Georges, Hannes Ponstingl, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Yun Li, Klaudia Walter, Huijun Qian, Henry Völzke, Christopher J. Penkett, J. M. M. Howson, Kousik Kundu, Epidemiology, and Internal Medicine
Subjects: Gene regulatory network, LOCI, EFFICIENT, Genome-wide association study, VARIANTS, Blood cell, 0302 clinical medicine, RARE, genetics, 11 Medical and Health Sciences, 0303 health sciences, rare diseases, Biobank, ddc, medicine.anatomical_structure, fine-mapping, VA Million Veteran Program, symbols, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, UK Biobank, polygenic risk, rare disease, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, GENETIC ARCHITECTURE, 03 medical and health sciences, symbols.namesake, splicing, blood, medicine, CELL, Allele, GENOME-WIDE ASSOCIATION, COMMON, 030304 developmental biology, Science & Technology, COMPLEX, Oxygen transport, Cell Biology, 06 Biological Sciences, Genetic architecture, hematopoiesis, INTERROGATION, Mendelian inheritance, chromatin, omnigenic, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Summary Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation., Graphical Abstract, Highlights • Largest genome-wide association study of blood cell traits to date • Empiric assessments of omnigenic and infinitesimal models of polygenic variation • Functional insights into how genetic variants impact human hematopoiesis • Assessment of the effect of polygenic trait scores upon blood diseases, Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.
Published: 2020
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45. RNA-sequencing reveals that STRN, ZNF484 and WNK1 add to the value of mitochondrial MT-COI and COX10 as markers of unstable coronary artery disease

Author: Karin R. Sipido, Stefan Janssens, Emma Raitoharju, Terho Lehtimäki, Stefano Cagnin, Christian Zinser, Roxane Menten, Paul Holvoet, Niku Oksala, Bernward Klocke, Leo-Pekka Lyytikäinen, Maarten Vanhaverbeke, Peter Sinnaeve, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
Subjects: 0301 basic medicine, Male, Molecular biology, Physiology, Gene Expression, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary Angiography, Vascular Medicine, Monocytes, Coronary artery disease, White Blood Cells, 0302 clinical medicine, Sequencing techniques, WNK Lysine-Deficient Protein Kinase 1, Animal Cells, Immune Physiology, Gene expression, Medicine and Health Sciences, Coronary Heart Disease, CAD, Prospective Studies, RNA-Seq, Innate Immune System, Multidisciplinary, Troponin T, Sisätaudit - Internal medicine, RNA sequencing, Middle Aged, Plaque, Atherosclerotic, Body Fluids, Mitochondria, Blood, Cholesterol, Cardiology, Medicine, Cytokines, Female, Cellular Types, Anatomy, Research Article, medicine.medical_specialty, Acute coronary syndrome, coronary artery diseas, CD14, Science, Immune Cells, Immunology, Macrophage polarization, RNA-sequencing, Nerve Tissue Proteins, Peripheral blood mononuclear cell, Diagnosis, Differential, Electron Transport Complex IV, 03 medical and health sciences, CAD, RNA-sequencing, atherosclerosis, coronary artery diseas, Internal medicine, medicine, Genetics, Humans, Acute Coronary Syndrome, Aged, Blood Cells, Alkyl and Aryl Transferases, business.industry, Macrophages, Biology and Life Sciences, Membrane Proteins, Cell Biology, Molecular Development, medicine.disease, Stable Coronary Artery Disease, Research and analysis methods, 030104 developmental biology, Molecular biology techniques, Immune System, Calmodulin-Binding Proteins, atherosclerosis, business, Biomarkers, Blood sampling, Developmental Biology, Follow-Up Studies
Abstract: Markers in monocytes, precursors of macrophages, which are related to CAD, are largely unknown. Therefore, we aimed to identify genes in monocytes predictive of a new ischemic event in patients with CAD and/or discriminate between stable CAD and acute coronary syndrome. We included 66 patients with stable CAD, of which 24 developed a new ischemic event, and 19 patients with ACS. Circulating CD14+ monocytes were isolated with magnetic beads. RNA sequencing analysis in monocytes of patients with (n = 13) versus without (n = 11) ischemic event at follow-up and in patients with ACS (n = 12) was validated with qPCR (n = 85). MT-COI, STRN and COX10 predicted new ischemic events in CAD patients (power for separation at 1% error rate of 0.97, 0.90 and 0.77 respectively). Low MT-COI and high STRN were also related to shorter time between blood sampling and event. COX10 and ZNF484 together with MT-COI, STRN and WNK1 separated ACS completely from stable CAD patients. RNA expressions in monocytes of MT-COI, COX10, STRN, WNK1 and ZNF484 were independent of cholesterol lowering and antiplatelet treatment. They were independent of troponin T, a marker of myocardial injury. But, COX10 and ZNF484 in human plaques correlated to plaque markers of M1 macrophage polarization, reflecting vascular injury. Expression of MT-COI, COX10, STRN and WNK1, but not that of ZNF484, PBMCs paired with that in monocytes. The prospective study of relation of MT-COI, COX10, STRN, WNK1 and ZNF484 with unstable CAD is warranted. ispartof: PLOS ONE vol:14 issue:12 ispartof: location:United States status: published
Published: 2019

46. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Author: Lorenz Risch, Igor Rudan, Hilma Holm, Christopher P. Nelson, Jan A. Kors, Stefanie Aeschbacher, Stefan Kääb, Peter W. Macfarlane, Lars Lind, Amanda A. Seyerle, Ozren Polasek, Daniel F. Gudbjartsson, Xiuqing Guo, Nilesh J. Samani, Bruce M. Psaty, Rosa B. Thorolfsdottir, Elsayed Z. Soliman, Yong Qian, Mary L. Biggs, Antti Jula, Vilmundur Gudnason, Paul L. Huang, Tamara B. Harris, Gianfranco Sinagra, Luisa Foco, Anubha Mahajan, Mika Kähönen, Lu-Chen Weng, Borbala Mifsud, Stefan van Duijvenboden, Terho Lehtimäki, Jennifer A. Brody, Paolo Gasparini, Kathleen A. Ryan, Marten E. van den Berg, James J. Cranley, Eric Boerwinkle, Cathy C. Laurie, Annette Peters, Joshua C. Bis, Raymond Noordam, Andrew P. Morris, Johan Sundström, Lenore J. Launer, Stefan Weiss, Rebecca D. Jackson, Alison D. Murray, Jeffrey R. O'Connell, Aki S. Havulinna, Dennis O. Mook-Kanamori, Sheila Ulivi, Renée de Mutsert, Eric A. Whitsel, Adrienne M. Stilp, James P. Cook, Nona Sotoodehnia, Antonio Luiz Pinho Ribeiro, Seung Hoan Choi, Mark J. Caulfield, Sébastien Thériault, Henry J. Lin, Dan M. Roden, J. Wouter Jukema, James F. Wilson, Veikko Salomaa, Honghuang Lin, Andrew A. Hicks, Christy L. Avery, Nina Mononen, Dan E. Arking, Ruth J. F. Loos, Yalda Jamshidi, André G. Uitterlinden, Nina Hutri-Kähönen, Andrew Tinker, Gudmar Thorleifsson, Daniel Levy, Martina Müller-Nurasyid, Alexander P. Reiner, Bruno H. Stricker, Caroline Hayward, Yordi J. van de Vegte, Ioanna Ntalla, Tim D. Spector, Niek Verweij, Michael R. Barnes, Martin Gögele, Nathan R. Tucker, Arie C. Maan, Eduardo Tarazona-Santos, Katri Sääksjärvi, Maria Pina Concas, Pim van der Harst, Georg Ehret, Cecilia M. Lindgren, David Conen, Cornelia M. van Duijn, Muhammad B. Riaz, Leo-Pekka Lyytikäinen, Amelia W. Hall, Peter P. Pramstaller, Maria Fernanda Lima-Costa, Vilmantas Giedraitis, Emelia J. Benjamin, M. Fabiola Del Greco, Thomas Meitinger, Erwin P. Bottinger, Francesco Cucca, Aaron Isaacs, Carolina Roselli, James H. Cartwright, Massimo Mangino, Adolfo Correa, Patrick Sulem, Thibaud Boutin, Michiel Rienstra, Stephan B. Felix, Julia Ramirez, Kathleen F. Kerr, Jonathan Marten, David J. Porteous, Kent D. Taylor, Patrick T. Ellinor, Michele Orini, Susan R. Heckbert, Olli T. Raitakari, Girish N. Nadkarni, Edward G. Lakatta, Anna F. Dominiczak, Jie Yao, Erik Ingelsson, Christopher Newton-Cheh, Katharina Schramm, Jerome I. Rotter, Michael J. Cutler, Pashupati P. Mishra, Diane Fatkin, Marcus Dörr, Ulrike Peters, Solmaz Assa, Christian Fuchsberger, M. Abdullah Said, Catriona L. K. Barnes, Peter K. Joshi, M. Yldau van der Ende, Alvaro Alonso, James G. Wilson, Jun Ding, Kathryn L. Lunetta, Kjell Nikus, Helen R. Warren, Charles Kooperberg, Moritz F. Sinner, Sandosh Padmanabhan, Patricia B. Munroe, Jeffrey Haessler, Albert V. Smith, Alan R. Shuldiner, Morten S. Olesen, Konstantin Strauch, Steven A. Lubitz, J. Gustav Smith, Renan P. Souza, Michael Preuss, Kirill V. Tarasov, M. Benjamin Shoemaker, Barry London, Melanie Waldenberger, Cristian Pattaro, David O. Arnar, Gardar Sveinbjornsson, Alessandro De Grandi, Ian Ford, Kenneth Rice, Mark Chaffin, Kari Stefansson, Hao Mei, Uwe Völker, Blair H. Smith, Nathalia M. Araujo, Harry Campbell, Pier D. Lambiase, Stephanie M. Gogarten, May E. Montasser, Unnur Thorsteinsdottir, Ivana Kolcic, and Stella Trompet
Subjects: 0303 health sciences, medicine.medical_specialty, education.field_of_study, business.industry, Population, Cardiomyopathy, Atrial fibrillation, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Endophenotype, Cardiac conduction, medicine, Cardiology, PR interval, business, education, 030304 developmental biology
Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
Published: 2019
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47. Whole blood microRNA levels associate with glycemic status and correlate with target mRNAs in pathways important to type 2 diabetes

Author: Pashupati P. Mishra, Niku Oksala, Melanie Waldenberger, Ilkka Seppälä, Jaana Leiviskä, Reijo Laaksonen, Mika Kähönen, Markus Juonala, Nina Mononen, Olli T. Raitakari, Leo-Pekka Lyytikäinen, Thomas Illig, Norman Klopp, Emma Raitoharju, Nina Hutri-Kähönen, Britt-Marie Loo, Terho Lehtimäki, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, Tampere University, HUSLAB, Department of Diagnostics and Therapeutics, and University of Helsinki
Subjects: 0301 basic medicine, Blood Glucose, endocrine system diseases, medicine.medical_treatment, lcsh:Medicine, Type 2 diabetes, DISEASE, GLUCOSE, MELLITUS, chemistry.chemical_compound, 0302 clinical medicine, Medicine, lcsh:Science, COMPLICATIONS, Multidisciplinary, PLASMA, biology, CARDIOVASCULAR RISK, miRNAs, Pre-diabetes, REGULATOR, medicine.medical_specialty, Biolääketieteet - Biomedicine, Article, DIFFERENTIAL EXPRESSION, 03 medical and health sciences, Insulin resistance, Diabetes mellitus, Internal medicine, Humans, RNA, Messenger, Glycemic, IDENTIFICATION, business.industry, Insulin, lcsh:R, medicine.disease, Impaired fasting glucose, Insulin receptor, MicroRNAs, 030104 developmental biology, Endocrinology, chemistry, Diabetes Mellitus, Type 2, POTENTIAL BIOMARKER, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, lcsh:Q, 3111 Biomedicine, Glycated hemoglobin, business, 030217 neurology & neurosurgery
Abstract: We analyzed the associations between whole blood microRNA profiles and the indices of glucose metabolism and impaired fasting glucose and examined whether the discovered microRNAs correlate with the expression of their mRNA targets. MicroRNA and gene expression profiling were performed for the Young Finns Study participants (n = 871). Glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured, the insulin resistance index (HOMA2-IR) was calculated, and the glycemic status (normoglycemic [n = 534]/impaired fasting glucose [IFG] [n = 252]/type 2 diabetes [T2D] [n = 24]) determined. Levels of hsa-miR-144-5p, -122-5p, -148a-3p, -589-5p, and hsa-let-7a-5p associated with glycemic status. hsa-miR-144-5p and -148a-3p associated with glucose levels, while hsa-miR-144-5p, -122-5p, -184, and -339-3p associated with insulin levels and HOMA2-IR, and hsa-miR-148a-3p, -15b-3p, -93-3p, -146b-5p, -221-3p, -18a-3p, -642a-5p, and -181-2-3p associated with HbA1c levels. The targets of hsa-miR-146b-5p that correlated with its levels were enriched in inflammatory pathways, and the targets of hsa-miR-221-3p were enriched in insulin signaling and T2D pathways. These pathways showed indications of co-regulation by HbA1c-associated miRNAs. There were significant differences in the microRNA profiles associated with glucose, insulin, or HOMA-IR compared to those associated with HbA1c. The HbA1c-associated miRNAs also correlated with the expression of target mRNAs in pathways important to the development of T2D.
Published: 2019

48. Left ventricular ejection fraction adds value over the GRACE score in prediction of 6-month mortality after ACS: the MADDEC study

Author: Shadi Mahdiani, Markku Eskola, Niku Oksala, Kari Antila, Markus Hautamäki, Jussi Hernesniemi, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Kjell Nikus, Nina Syyli, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University
Subjects: medicine.medical_specialty, Acute coronary syndrome, Scoring system, Coronary Artery Disease, 030204 cardiovascular system & hematology, acute coronary syndrome, 03 medical and health sciences, 0302 clinical medicine, Paired samples, Internal medicine, medicine, 030212 general & internal medicine, First episode, Framingham Risk Score, Ejection fraction, Proportional hazards model, business.industry, Sisätaudit - Internal medicine, left ventricular ejection fraction, prediction, medicine.disease, mortality, Cardiology, Cardiology and Cardiovascular Medicine, business, Clinical risk factor
Abstract: BackgroundReduced left ventricular ejection fraction (LVEF) is a risk marker for mortality after an acute coronary syndrome (ACS). Global Registry of Acute Coronary Events (GRACE) risk score, developed almost two decades ago, is the preferred scoring system for risk stratification in ACS. The aim of this study was to validate the GRACE score and evaluate whether LVEF has incremental predictive value over the GRACE in predicting 6-month mortality after ACS in a contemporary setting.MethodsA retrospective analysis of all 1576 consecutive patients who were admitted to Tays Heart Hospital and underwent coronary angiography for a first episode of ACS (2015–2016). Clinical risk factors were extensively recorded. Adjusted Cox regression analysis was used to analyse the associations between LVEF and the GRACE score with 6-month all-cause mortality. The incremental predictive value was assessed by the change in C-statistic by Delong’s method for paired samples and by index of discrimination improvement (IDI).ResultsIn univariable analysis, both LVEF and the GRACE were associated with 6-month mortality, and after applying both variables into the same model, the results remained significant (GRACE score: HR: 1.036, 95% CI 1.030 to 1.042; LVEF: HR: 0.965, 95% CI 0.948 to 0.982, both HRs corresponding to a one unit change in the exposure variable). The GRACE score demonstrated good discrimination for mortality (C-statistic: 0.833, 95% CI 0.795 to 0.871). Adding LVEF to the model with the GRACE score improved model performance significantly (C-statistic: 0.848, 95% CI 0.813 to 0.883, p=0.029 for the improvement and IDI 0.0171, 95% CI 0.0016 to 0.0327, p=0.031).ConclusionsAdding LVEF to the GRACE score significantly improves risk prediction of 6-month mortality after ACS.
Published: 2019
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49. A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity

Author: Jaakko T. Leinonen, Nicholas J. Timpson, Mohammad Hadi Zafarmand, Mette Hollensted, Anne E. Justice, Robert L. Hanson, Struan F.A. Grant, Frank D. Gilliland, Jesús Peralta-Romero, Diana L. Cousminer, Carol A. Wang, Jens-Christian Holm, Lindsay Fernández-Rhodes, Elina Hyppönen, Marc Vaudel, Marjo-Riitta Järvelin, Amélie Bonnefond, Esteban J. Parra, Robert I. Berkowitz, Koon K. Teo, Adnan Custovic, Christian Theil Have, Mariona Bustamante, Kari E. North, Stefan Johansson, Mustafa Atalay, Christine Frithioff-Bøjsøe, Estela Blanco, Adan Valladares-Salgado, Sylvain Sebert, Suzanne Vogelezang, Yujie Wang, Mark I. McCarthy, Timo A. Lakka, Christine Power, Raimo Joro, Oluf Pedersen, Heather M. Highland, Yik Ying Teo, Zhanghua Chen, Pål R. Njølstad, Momoko Horikoshi, William J. Gauderman, Øyvind Helgeland, Klaus Bønnelykke, Anke Hinney, Natalia Vilor-Tejedor, V. Saroja Voruganti, Niels Grarup, Sayuko Kobes, Shana E. McCormack, Christopher D. Brown, Alessandra Chesi, Nancy F. Butte, Triinu Peters, Miguel Cruz, Johan G. Eriksson, Torben Hansen, Babette S. Zemel, Terho Lehtimäki, Niina Pitkänen, Akram Alyass, Vincent W. V. Jaddoe, Elisabeth Thiering, Jonathan P. Bradfield, Eileen Tai-Hui Boh, Janine F. Felix, Olli T. Raitakari, Philippe Froguel, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Martine Vrijheid, Ville Karhunen, Mika Kähönen, Marie Standl, Angela Simpson, Seang-Mei Saw, David Meyre, Anthony G. Comuzzie, Mickaël Canouil, Tarunveer S. Ahluwalia, John A. Curtin, Barbera D. C. van Schaik, Johannes Hebebrand, Elisabeth Widen, Tanja G. M. Vrijkotte, Leslie J. Baier, Sheila Gahagan, Joachim Heinrich, Claire Monnereau, Jesús Vioque, Hans Bisgaard, Hakon Hakonarson, Estelle Lowry, Craig E. Pennell, Shelley A. Cole, Thorkild I. A. Sørensen, André G. Uitterlinden, Virpi Lindi, Genomics of Sex Differences, Institute for Molecular Medicine Finland, University of Helsinki, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Epidemiology, Erasmus MC other, Pediatrics, Internal Medicine, Bradfield, Jonathan P., Vogelezang, Suzanne, Felix, Janine F., Chesi, Alessandra, Hyppönen, Elina, Jaddoe, Vincent W.V., Early Growth Genetics Consortium, Epidemiology and Data Science, Public and occupational health, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, APH - Global Health, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, ARD - Amsterdam Reproduction and Development, APH - Methodology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, obesity, Pediatric Obesity, Medizin, IDENTIFIES 3, Genome-wide association study, VARIANTS, ethnic group, single nucleotide polymorphism, genetics, bayesian analysis, genes, Association Studies Article, Child, Genetics (clinical), 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, child, 0303 health sciences, adult, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Chromosome Mapping, General Medicine, 3. Good health, Female, body mass index procedure, childhood obesity, Life Sciences & Biomedicine, asian, Biochemistry & Molecular Biology, SUSCEPTIBILITY LOCI, DATABASE, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Wilms Tumor, Childhood obesity, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, MANAGEMENT, Humans, Genetic Predisposition to Disease, genome, Molecular Biology, 030304 developmental biology, genome-wide association study, Science & Technology, Early Growth Genetics Consortium, Case-control study, Bayes Theorem, 06 Biological Sciences, medicine.disease, Obesity, MC3R GENE, Genetic Loci, Case-Control Studies, 1182 Biochemistry, cell and molecular biology, Body mass index, Genome-Wide Association Study
Abstract: Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently
Published: 2019
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50. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author: David Torrents, Thorkild I. A. Sørensen, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Joachim Heinrich, Anna Murray, Nicholas J. Timpson, George Dedoussis, Beverley M. Shields, Timo A. Lakka, Lawrence J. Beilin, Carmen J. Marsit, Katharina E. Schraut, Marie Standl, Torben Hansen, James F. Wilson, Jonas Bacelis, Allan Vaag, Louis J. Muglia, Wei Ang, Josep M. Mercader, Ruifang Li-Gao, Ying Wu, Jessica Tyrrell, Pål R. Njølstad, Mohammad Hadi Zafarmand, Marie-France Hivert, Ioanna Ntalla, Debbie A Lawlor, Martina Müller-Nurasyid, Alana Cavadino, Natalia Vilor-Tejedor, Andrew R. Wood, Zoltán Kutalik, Jodie N. Painter, Tanja G. M. Vrijkotte, Kyle J. Gaulton, Xavier Estivill, George Davey Smith, Christine Power, Andrew T. Hattersley, Berthold Hocher, Gibran Hemani, Sheila J. Barton, Aino-Maija Eloranta, Kathryn L. Lunetta, Kim F. Michaelsen, Frank Geller, Bjarke Feenstra, Carol A. Wang, Peter Vollenweider, Wieland Kiess, Anubha Mahajan, Elina Hyppönen, Elisabeth M. van Leeuwen, Felix R. Day, Natalie R. van Zuydam, Leda Chatzi, Bo L. Chawes, Antje Körner, Dennis O. Mook-Kanamori, Ken K. Ong, Joanne M. Murabito, David M. Hougaard, Jian'an Luan, Letizia Marullo, Catharina E. M. van Beijsterveldt, Yik Ying Teo, Andrew P. Morris, Sarah E. Medland, Juan Fernández-Tajes, Jouke-Jan Hottenga, Frits R. Rosendaal, Inga Prokopenko, Katja Pahkala, Struan F.A. Grant, Sylvain Sebert, Judith B. Borja, Camilla Schmidt Morgen, Charlotta Pisinger, Jia Chen, Øyvind Helgeland, Christian Theil Have, Vincent W. V. Jaddoe, Marjolein N. Kooijman, Mika Kähönen, Timothy M. Frayling, Diana L. Cousminer, Bo Jacobsson, Antoine H. C. van Kampen, Eco J. C. de Geus, Manolis Kogevinas, Rico Rueedi, Grant W. Montgomery, Raimo Joro, Craig E. Pennell, Jonathan P. Bradfield, Janine F. Felix, Ge Zhang, Loreto Santa-Marina, Kalliope Panoutsopoulou, John R. B. Perry, Jeff Murray, Albert Hofman, Terho Lehtimäki, John W. Holloway, Barbera D. C. van Schaik, Pedro Marques-Vidal, Ronny Myhre, Haja N. Kadarmideen, Robert A. Scott, Frank D. Mentch, Katherine S. Ruth, Hans Bisgaard, Marjo-Riitta Järvelin, Catherine Allard, Rachel M. Freathy, Julie A. Marsh, Mariona Bustamante, Elisabeth Thiering, Cæcilie Trier, Marcus A. Tuke, William L. Lowe, Elisabeth Widen, Caroline L Relton, Christoph Reichetzeder, Penelope A. Lind, M. Geoffrey Hayes, Charles Laurin, Tarunveer S. Ahluwalia, Meike Bartels, Mads Melbye, Claudia Langenberg, Ke Hao, Shouneng Peng, Nicholas J. Wareham, Susan M. Ring, Hamdi Mbarek, Mario Murcia, Jing Hua Zhao, Michael Nodzenski, Cornelia M. van Duijn, Hakon Hakonarson, Hanieh Yaghootkar, Po-Ru Loh, Linda S. Adair, Sílvia Bonàs-Guarch, Eleftheria Zeggini, Sarah Metrustry, Shikta Das, Gonneke Willemsen, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Theresia M. Schnurr, Michael Stumvoll, David M. Evans, Bridget A. Knight, Luigi Bouchard, Robin N Beaumont, Mustafa Atalay, Zhen Qiao, Denise M. Scholtens, Klaus Bønnelykke, Samuel E. Jones, Peter K. Joshi, Oluf Pedersen, Jin-Fang Chai, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Hazel Inskip, Sara M. Willems, Cilius Esmann Fonvig, Momoko Horikoshi, Ellen A. Nohr, Jani Heikkinen, Emil V. R. Appel, Niels Grarup, Michael N. Weedon, Rebecca C Richmond, Peter Kovacs, Jorma Viikari, Amanda J. Bennett, Jens-Christian Holm, Carolina Medina-Gomez, Nicole M. Warrington, Anke Tönjes, Jakob Stokholm, Hugoline G. de Haan, Seang-Mei Saw, Ville Huikari, N. William Rayner, Johan G. Eriksson, Niina Pitkänen, Allan Linneberg, Gunn-Helen Moen, Olli T. Raitakari, Martine Vrijheid, Neil Robertson, Stefan Johansson, Tim D. Spector, Friman Sánchez, Mark I. McCarthy, Harri Niinikoski, Karen L. Mohlke, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Hypponen, E, Freathy, RM, EGG consortium, Medical and Clinical Psychology, University of Helsinki, Johan Eriksson / Principal Investigator, University of Helsinki, Institute for Molecular Medicine Finland, Warrington, Nicole M [0000-0003-4195-775X], Beaumont, Robin N [0000-0003-0750-8248], Day, Felix R [0000-0003-3789-7651], Helgeland, Øyvind [0000-0002-5612-2985], Laurin, Charles [0000-0003-2439-9004], Bacelis, Jonas [0000-0002-2450-732X], Feenstra, Bjarke [0000-0003-1478-649X], Mahajan, Anubha [0000-0001-5585-3420], Moen, Gunn-Helen [0000-0002-8768-0904], Schnurr, Theresia M [0000-0002-6573-4959], Grarup, Niels [0000-0001-5526-1070], Paternoster, Lavinia [0000-0003-2514-0889], Rueedi, Rico [0000-0002-6713-2214], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Metrustry, Sarah [0000-0003-2028-7486], Wang, Carol A [0000-0002-4301-3974], Joshi, Peter K [0000-0002-6361-5059], Pitkänen, Niina [0000-0001-7383-4987], Richmond, Rebecca C [0000-0003-0574-5071], Inskip, Hazel M [0000-0001-8897-1749], Holloway, John W [0000-0001-9998-0464], Estivill, Xavier [0000-0002-0723-2256], Hocher, Berthold [0000-0001-8143-0579], Lunetta, Kathryn L [0000-0002-9268-810X], Allard, Catherine [0000-0002-8829-4984], Muglia, Louis J [0000-0002-0301-8770], van Kampen, Antoine HC [0000-0003-1025-7232], van Schaik, Barbera DC [0000-0002-5568-8127], Langenberg, Claudia [0000-0002-5017-7344], Hemani, Gibran [0000-0003-0920-1055], Gaulton, Kyle J [0000-0003-1318-7161], Medina-Gomez, Carolina [0000-0001-7999-5538], Kutalik, Zoltán [0000-0001-8285-7523], Marques-Vidal, Pedro [0000-0002-4548-8500], Mbarek, Hamdi [0000-0002-1108-0371], Müller-Nurasyid, Martina [0000-0003-3793-5910], Appel, Emil VR [0000-0001-7704-6611], Fonvig, Cilius E [0000-0002-5031-0125], Hougaard, David M [0000-0001-5928-3517], Mercader, Josep M [0000-0001-8494-3660], Linneberg, Allan [0000-0002-0994-0184], Lind, Penelope A [0000-0002-3887-2598], Medland, Sarah E [0000-0003-1382-380X], Bartels, Meike [0000-0002-9667-7555], Stokholm, Jakob [0000-0003-4989-9769], Chawes, Bo L [0000-0001-6846-6243], Kovacs, Peter [0000-0002-0290-5423], Prokopenko, Inga [0000-0003-1624-7457], Tuke, Marcus A [0000-0003-0008-9263], Ruth, Katherine S [0000-0003-4966-9170], Jones, Samuel E [0000-0003-0153-922X], Zeggini, Eleftheria [0000-0003-4238-659X], Wilson, James F [0000-0001-5751-9178], Vrijkotte, Tanja GM [0000-0003-3641-4048], de Geus, Eco JCN [0000-0001-6022-2666], Kadarmideen, Haja N [0000-0001-6294-382X], Mohlke, Karen L [0000-0001-6721-153X], Sørensen, Thorkild IA [0000-0003-4821-430X], Bisgaard, Hans [0000-0003-4131-7592], Bønnelykke, Klaus [0000-0003-2003-1018], Melbye, Mads [0000-0001-8264-6785], Rivadeneira, Fernando [0000-0001-9435-9441], Felix, Janine F [0000-0002-9801-5774], Jaddoe, Vincent WV [0000-0003-2939-0041], Hansen, Torben [0000-0001-8748-3831], Hyppönen, Elina [0000-0003-3670-9399], Davey Smith, George [0000-0002-1407-8314], Morris, Andrew P [0000-0002-6805-6014], Hakonarson, Hakon [0000-0003-2814-7461], Grant, Struan FA [0000-0003-2025-5302], Lawlor, Debbie A [0000-0002-6793-2262], Njølstad, Pål R [0000-0003-0304-6728], Ong, Ken K [0000-0003-4689-7530], McCarthy, Mark I [0000-0002-4393-0510], Evans, David M [0000-0003-0663-4621], Freathy, Rachel M [0000-0003-4152-2238], Apollo - University of Cambridge Repository, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Neuroscience Center, Doctoral Programme Brain & Mind, Ecology and Evolutionary Biology, University of Helsinki, Research Groups, Department of General Practice and Primary Health Care, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Clinical Research, Doctoral Programme in Oral Sciences, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University Management, Epidemiology, Erasmus MC other, Internal Medicine, Pediatrics, Epidemiology and Data Science, APH - Global Health, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ARD - Amsterdam Reproduction and Development, Experimental Immunology, Public and occupational health, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Subjects: Male, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, DISEASE, Fetal Development, 0302 clinical medicine, Models, Pregnancy, Risk Factors, Genotype, Birth Weight, maternal genetic, 030212 general & internal medicine, Maternal-Fetal Exchange, 0303 health sciences, Body Height/genetics, 1184 Genetics, developmental biology, physiology, Heart Diseases/etiology, Single Nucleotide, ASSOCIATION, Metabolic Diseases/etiology, 3. Good health, Type 2/etiology, MENDELIAN RANDOMIZATION, GROWTH, Female, Maternal Inheritance, Maternal Inheritance/genetics, Adult, Blood Pressure/genetics, Heart Diseases, Offspring, Birth weight, cardio-metabolic health outcomes, Biology, Diabetes Mellitus, Type 2/etiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic, Metabolic Diseases, SDG 3 - Good Health and Well-being, Diabetes mellitus, Mendelian randomization, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Glycemic, Fetus, IDENTIFICATION, Models, Genetic, Infant, Newborn, Infant, birth weight, DIABETES-MELLITUS, medicine.disease, Newborn, Fetal Development/genetics, Body Height, Maternal-Fetal Exchange/genetics, LIFE, Blood pressure, Diabetes Mellitus, Type 2, ORIGINS, Institut für Ernährungswissenschaft, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.
Published: 2019
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