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3. Applying the Rome Proposal on Exacerbations of Chronic Obstructive Pulmonary Disease: Does Comorbid Chronic Heart Failure Matter?

Author

Jacobson PK, Lind L, and Persson HL

Subjects
chronic heart failure, telemonitoring, telemedicine, copd symptoms, Diseases of the respiratory system, RC705-779
Abstract

Petra Kristina Jacobson,1,2 Leili Lind,3,4 Hans L Persson1,2 1Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; 2Department of Respiratory Medicine in Linköping, Linköping University, Linköping, Sweden; 3Department of Biomedical Engineering/Health Informatics, Linköping University, Linköping, Sweden; 4Digital Systems Division, Unit Digital Health, RISE Research Institutes of Sweden, Linköping, SwedenCorrespondence: Petra Kristina Jacobson, Department of Respiratory Medicine in Linköping, Linköping University, Linköping, SE-581 85, Sweden, Tel +46 10 1031162, Email petra.jacobson@liu.seBackground: Chronic heart failure (CHF) is a common comorbidity among patients with chronic obstructive pulmonary disease (COPD). Both exacerbations of COPD (ECOPDs) and exacerbations of CHF (ECHFs) display worsening of breathlessness at rest (BaR) and breathlessness at physical activity (BaPA). Comorbid CHF may have an impact on the vital signs assessed, when the Rome proposal (adopted by GOLD 2023) is applied on ECOPDs. Thus, the aim of the present study was to investigate the impact of comorbid CHF on ECOPDs severity, particularly focusing on the influence of comorbid CHF on BaR and BaPA.Methods: We analysed data on COPD symptoms collected from the telehealth study The eHealth Diary. Patients with COPD (n = 43) and patients with CHF (n = 41) were asked to daily monitor BaR and BaPA, employing a digital pen and scales for BaR and BaPA (from 0 to 10). Twenty-eight patients of the COPD patients presented with comorbid CHF. Totally, 125 exacerbations were analysed.Results: Exacerbations in the group with COPD patients and comorbid CHF were compared to the group with COPD patients without comorbid CHF and the group with CHF patients. Compared with GOLD 2022, the GOLD 2023 (the Rome proposal) significantly downgraded the ECOPD severity. Comorbid CHF did not interfere significantly on the observed difference. Comorbid CHF did not worsen BaR scores, assessed at inclusion and at the symptom peak of the exacerbations.Conclusion: In the present study, we find no evidence that comorbid CHF would interfere significantly with the parameters included in the Rome proposal (GOLD 2023). We conclude that the Rome proposal can be safely applied even on COPD patients with very advanced comorbid CHF.Keywords: chronic heart failure, telemonitoring, telemedicine, COPD symptoms

Published
2023

4. The Exacerbation of Chronic Obstructive Pulmonary Disease: Which Symptom is Most Important to Monitor?

Author

Jacobson PK, Lind L, and Persson HL

Subjects
rome proposal, telemonitoring, telemedicine, copd management, copd symptoms, future exacerbations, Diseases of the respiratory system, RC705-779
Abstract

Petra Kristina Jacobson,1,2 Leili Lind,3,4 Hans Lennart Persson1,2 1Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; 2Department of Respiratory Medicine in Linköping, Linköping University, Linköping, Sweden; 3Department of Biomedical Engineering/Health Informatics, Linköping University, Linköping, Sweden; 4Digital Systems Division, Unit Digital Health, RISE Research Institutes of Sweden, Linköping, SwedenCorrespondence: Petra Kristina Jacobson, Department of Respiratory Medicine in Linköping, Linköping University, Linköping, SE-581 85, Sweden, Tel +46 0 10 1031162, Email petra.jacobson@liu.seBackground: GOLD 2023 defines an exacerbation of COPD (ECOPD) by a deterioration of breathlessness at rest (BaR), mucus and cough. The severity of an ECOPD is determined by the degree of BaR, ranging from 0 to 10. However, it is not known which symptom is the most important one to detect early of an ECOPD, and which symptom that predicts future ECOPDs best. Thus, the purpose of the present study was to find out which symptom is the most important one to monitor.Methods: We analysed data on COPD symptoms from the telehealth study The eHealth Diary. Frequent exacerbators (n = 27) were asked to daily monitor BaR and breathlessness at physical activity (BaPA), mucus and cough, employing a digital pen and symptom scales (0– 10). Twenty-seven patients with 105 ECOPDs were analysed. The association between symptom development and the occurrence of exacerbations was evaluated using the Andersen–Gill formulation of the Cox proportional hazards model for the analysis of recurrent time-to-event data with time-varying predictors.Results: According to the criteria proposed by GOLD 2023, 42% ECOPDs were mild, 48% were moderate and 5% were severe, while 6% were undefinable. Mucus and cough improved over study time, while BaR and BaPA deteriorated. Mucus appeared earliest, which was the most prominent feature of the average exacerbation, and worsening of mucus increased the risk for a future ECOPD. There was a 58% increase in the risk of exacerbation per unit increase in mucus score.Conclusion: This study suggests that mucus worsening is the most important COPD symptom to monitor to detect ECOPDs early and to predict future risk för ECOPDs. In the present study, we also noticed a pronounced difference between GOLD 2022 and 2023. Hence, GOLD 2023 defined the ECOPD severity much lower than GOLD 2022 did.Keywords: Rome proposal, telemonitoring, telemedicine, COPD management, COPD symptoms, future exacerbations

Published
2023

5. Unleashing the Power of Very Small Data to Predict Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Author

Jacobson PK, Lind L, and Persson HL

Subjects
machine learning, telehealth or digital health, cox proportional hazards, random survival forests, random forests, mhealth, Diseases of the respiratory system, RC705-779
Abstract

Petra Kristina Jacobson,1,2 Leili Lind,3,4 Hans Lennart Persson1,2 1Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; 2Department of Respiratory Medicine in Linköping, Linköping University, Linköping, Sweden; 3Department of Biomedical Engineering/Health Informatics, Linköping University, Linköping, Sweden; 4Digital Systems Division, Unit Digital Health, RISE Research Institutes of Sweden, Linköping, SwedenCorrespondence: Petra Kristina Jacobson, Department of Respiratory Medicine in Linköping, Linköping University, Linköping, SE-581 85, Sweden, Tel +46 10 1031162, Email petra.jacobson@liu.seIntroduction: In this article, we explore to what extent it is possible to leverage on very small data to build machine learning (ML) models that predict acute exacerbations of chronic obstructive pulmonary disease (AECOPD).Methods: We build ML models using the small data collected during the eHealth Diary telemonitoring study between 2013 and 2017 in Sweden. This data refers to a group of multimorbid patients, namely 18 patients with chronic obstructive pulmonary disease (COPD) as the major reason behind previous hospitalisations. The telemonitoring was supervised by a specialised hospital-based home care (HBHC) unit, which also was responsible for the medical actions needed.Results: We implement two different ML approaches, one based on time-dependent covariates and the other one based on time-independent covariates. We compare the first approach with standard COX Proportional Hazards (CPH). For the second one, we use different proportions of synthetic data to build models and then evaluate the best model against authentic data.Discussion: To the best of our knowledge, the present ML study shows for the first time that the most important variable for an increased risk of future AECOPDs is “maintenance medication changes by HBHC”. This finding is clinically relevant since a sub-optimal maintenance treatment, requiring medication changes, puts the patient in risk for future AECOPDs.Conclusion: The experiments return useful insights about the use of small data for ML.Keywords: machine learning, telehealth or digital health, COX proportional hazards, random survival forests, random forests, mHealth

Published
2023

6. Trapping of Bose-Einstein condensates in a three-dimensional dark focus generated by conical refraction

Author

Pfeiffer, D., Lind, L., Küber, J., Schmaltz, F., Turpin, A., Ahufinger, V., Mompart, J., and Birkl, G.

Subjects
Condensed Matter - Quantum Gases, Quantum Physics
Abstract

We present an efficient three-dimensional dark-focus optical trapping potential for neutral atoms and Bose-Einstein condensates. This "optical bottle" is created by a single blue-detuned light field exploiting the phenomenon of conical refraction occurring in biaxial crystals. The conversion of a Gaussian input beam to the bottle beam has an efficiency of close to 100 % and the optical setup requires the addition of the biaxial crystal and a circular polarizer only. Based on the conical-refraction theory, we derive the general form of the potential, the trapping frequencies, and the potential barrier heights. We present experiments on confining a $^{87}$Rb Bose-Einstein condensate in three dimensions. We determine the trap shape, the vibrational frequencies along the weak axis, as well as the lifetime of ultracold atoms in this type of potential.

Published
2017
Full Text
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7. The association between p,p′-DDE levels and left ventricular mass is mainly mediated by obesity

Author

La Merrill, MA, Lind, PM, Salihovic, S, van Bavel, B, and Lind, L

Subjects
Biological Sciences, Environmental Sciences, Chemical Sciences, Hypertension, Obesity, Nutrition, Cardiovascular, 2.1 Biological and endogenous factors, Adiposity, Aged, Aged, 80 and over, Blood Glucose, Cohort Studies, Dichlorodiphenyl Dichloroethylene, Environmental Pollutants, Female, Heart Ventricles, Humans, Hypertrophy, Left Ventricular, Insecticides, Male, Prevalence, Risk Factors, Sweden, P, p '-DDE, Left ventricular hypertrophy, Glucose, P, p′-DDE, Toxicology, Biological sciences, Chemical sciences, Environmental sciences
Abstract

Background and objectivesThe pesticide metabolite p,p'-DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p'-DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p'-DDE with LV mass.Methodsp,p'-DDE was measured in plasma from 70-year-old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70-, 75- and 80- years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques.ResultsWe found that p,p'-DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p'-DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%).ConclusionThe obesogenic effect of p,p'-DDE is a major determinant responsible for the association of p,p'-DDE with LV mass.

Published
2018

10. The Health Diary Telemonitoring and Hospital-Based Home Care Improve Quality of Life Among Elderly Multimorbid COPD and Chronic Heart Failure Subjects

Author

Persson HL, Lyth J, and Lind L

Subjects
digital pen, exacerbation, home care services, hospital-based, hospitalization, multimorbidity, telemedicine, qol, Diseases of the respiratory system, RC705-779
Abstract

Hans Lennart Persson,1,2 Johan Lyth,3,4 Leili Lind5,6 1Department of Respiratory Medicine in Linköping, Linköping University, Linköping SE-581 85, Sweden; 2Department of Biomedical and Clinical Sciences, Linköping University, Linköping SE-581 85, Sweden; 3Research and Development Unit in Region Östergötland, Linköping University, Linköping SE-581 85, Sweden; 4Department of Health, Medicine and Caring Sciences, Linköping University, Linköping SE-581 85, Sweden; 5Department of Biomedical Engineering/Health Informatics, Linköping University, Linköping SE-581 85, Sweden; 6Digital Systems Division, Department of Industrial Systems, RISE Research Institutes of Sweden, Linköping University, Linköping, S-581 83, SwedenCorrespondence: Hans Lennart PerssonDepartment of Respiratory Medicine in Linköping, Linköping University, Linköping SE-581 85, SwedenTel +46 13 10 1033621Email lennart.persson@liu.seBackground: Elderly, multimorbid patients with advanced chronic obstructive pulmonary disease (COPD) and/or chronic heart failure (CHF) exhibit poor health-related quality of life (HRQoL). Telemonitoring, based on digital pen technology, supported by hospital-based home care (HBHC) significantly reduces the number of hospitalizations. We hypothesized that the same intervention would prevent the deterioration of HRQoL that follows upon disease progression.Methods: Elderly computer-illiterate subjects with ≥ 2 hospitalizations the previous year were included. HRQoL was assessed at inclusion (baseline) and at 1, 6 and 12 months employing EuroQol-5 Dimensions (EQ-5D) and RAND-36 for general HRQoL, and Minnesota Living with Heart Failure Questionnaire (MLHFQ) and St. Georges Respiratory Questionnaire (SGRQ) for disease-specific HRQoL. Healthcare contacts, hospitalizations, as-needed medications, prescription changes and healthcare costs were registered.Results: Ninety-four patients were enrolled of which 53 subjects completed the 12-month study period. Compared to baseline, most domains of RAND-36 were improved significantly at 1 time-point or more. Only among COPD subjects, the disease-specific HRQoL was worsened at the 12 month evaluation. Measures of healthcare dependency were associated with poor HRQoL.Conclusion: The Health Diary system and HBHC together improve general HRQoL, and measures of healthcare dependency are associated with HRQoL variables.Keywords: digital pen, exacerbation, home care services, hospital-based, hospitalization, multimorbidity, telemedicine, QoL

Published
2020

14. Elderly patients with COPD require more health care than elderly heart failure patients do in a hospital-based home care setting

Author

Persson HL, Lyth J, Wiréhn AB, and Lind L

Subjects
home care services, hospital-based, telemedicine, digital pen, exacerbation, hospitalization, Diseases of the respiratory system, RC705-779
Abstract

Hans Lennart Persson,1 Johan Lyth,2 Ann-Britt Wiréhn,2 Leili Lind3,41Respiratory Medicine, Department of Medical and Health Sciences (IMH), Linköping University, Linköping, Sweden; 2Research and Development Unit in Region Östergötland and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; 3Department of Biomedical Engineering/Health Informatics, Linköping University, Linköping, Sweden; 4Rise Research Institutes of Sweden Ab/Division Ict Sics East, Linköping University, Linköping, SwedenBackground: Elderly patients with advanced stages of COPD or chronic heart failure (CHF) often require hospitalization due to exacerbations. We hypothesized that telemonitoring supported by hospital-based home care (HBHC) would detect exacerbations early, thus, reducing the number of hospitalization. We also speculated that patients with advanced COPD or CHF would present differences regarding exacerbation frequency and the need of HBHC.Methods: The Health Diary system, based on digital pen technology, was employed. Patients aged ≥65 years with ≥2 hospitalizations the previous year were included. Exacerbations were categorized and treated as either COPD or CHF exacerbation by an experienced physician. All HBHC contacts (home visits or telephone consultations) were registered.Results: Ninety-four patients with advanced diseases were enrolled (36 COPD and 58 CHF subjects) of which 53 subjects (19 COPD and 34 CHF subjects) completed the 1-year study period. Death was the major reason for not finalizing the study. Compared to the 1-year prior inclusion, the intervention significantly reduced hospitalization. Although COPD subjects were younger with less comorbidity, exacerbations and HBHC contacts were significantly greater in this group.Conclusions: COPD subjects exhibit exacerbations more frequently, mainly due to disease characteristics, thus, demanding much more HBHC.Keywords: home care services, hospital-based, telemedicine, digital pen, exacerbation, hospitalization

Published
2019

18. Genetic insights into resting heart rate and its role in cardiovascular disease.

Author

Vegte, Y.J. van de, Eppinga, R.N., Ende, M.Y. van der, Hagemeijer, Y.P., Mahendran, Y., Salfati, E., Smith, A.V., Tan, V.Y., Arking, D.E., Ntalla, I., Appel, E.V., Schurmann, C., Brody, J.A., Rueedi, R., Polasek, O., Sveinbjornsson, G., Lecoeur, C., Ladenvall, C., Zhao, J.H., Isaacs, A., Wang, L., Luan, Jian'an, Hwang, S.J., Mononen, N., Auro, K., Jackson, A.U., Bielak, L.F., Zeng, L., Shah, N., Nethander, M., Campbell, A., Rankinen, T., Pechlivanis, S., Qi, L., Zhao, Wei, Rizzi, F., Tanaka, T., Robino, A., Cocca, M., Lange, L., Müller-Nurasyid, M., Roselli, C., Zhang, W, Kleber, M.E., Guo, X., Lin, H.J., Pavani, F., Galesloot, T.E., Noordam, R., Milaneschi, Y., Schraut, K.E., Hoed, M. den, Degenhardt, F., Trompet, S., Berg, M.E. van den, Pistis, G., Tham, Y.C., Weiss, S., Sim, X.S., Li, H.L., Most, P.J. van der, Nolte, I.M., Lyytikäinen, L.P., Said, M.A., Witte, D.R., Iribarren, C., Launer, L., Ring, S.M., Vries, P.S. de, Sever, P., Linneberg, A., Bottinger, E.P., Padmanabhan, S., Psaty, B.M., Sotoodehnia, N., Kolcic, I., Arnar, D.O., Gudbjartsson, D.F., Holm, H., Balkau, B., Silva, C.T., Newton-Cheh, C.H., Nikus, K., Salo, P., Mohlke, K.L., Peyser, P.A., Schunkert, H., Lorentzon, M., Lahti, J., Rao, D.C., Cornelis, M.C., Faul, J.D., Smith, J.A., Stolarz-Skrzypek, K., Bandinelli, S., Concas, M.P., Sinagra, G., Meitinger, T., Waldenberger, M., Sinner, M.F., Strauch, K., Delgado, G.E., Taylor, K.D., Yao, J., Foco, L., Melander, O., Graaf, J. de, Mutsert, R. de, Geus, E.J.C. de, Johansson, Å., Joshi, P.K., Lind, L., Franke, A., Macfarlane, P.W., Tarasov, K.V., Tan, N., Felix, S.B., Tai, E.S., Quek, D.Q., Snieder, H., Ormel, J., Ingelsson, M., Lindgren, C., Morris, A.P., Raitakari, O.T., Hansen, T., Assimes, T., Gudnason, V., Timpson, N.J., Morrison, A.C., Munroe, P.B., Strachan, D.P., Grarup, N., Loos, R.J.F., Heckbert, S.R., Vollenweider, P., Hayward, C., Stefansson, K., Froguel, P., Groop, L., Wareham, N.J., Duijn, C.M. van, Feitosa, M.F., O'Donnell, C.J., Kähönen, M., Perola, M., Boehnke, M., Kardia, S.L.R., Erdmann, J., Palmer, C.N.A., Ohlsson, C., Porteous, D.J., Eriksson, J.G., Bouchard, C., Moebus, S., Kraft, P., Weir, D.R., Cusi, D., Ferrucci, L., Ulivi, S., Girotto, G., Correa, A., Kääb, S., Peters, A., Chambers, J.C., Kooner, J.S., März, W., Rotter, J.I., Hicks, A.A., Smith, J.G., Kiemeney, L.A.L.M., Mook-Kanamori, D.O., Penninx, B.W.J.H., Gyllensten, U., Wilson, J.F., Burgess, S., Sundström, J., Lieb, W., Jukema, J.W., Eijgelsheim, M., Lakatta, E.L.M., Cheng, C.Y., Dörr, M., Wong, T.Y., Sabanayagam, C., Oldehinkel, A.J., Riese, H., Lehtimäki, T., Verweij, N., Harst, P. van der, Vegte, Y.J. van de, Eppinga, R.N., Ende, M.Y. van der, Hagemeijer, Y.P., Mahendran, Y., Salfati, E., Smith, A.V., Tan, V.Y., Arking, D.E., Ntalla, I., Appel, E.V., Schurmann, C., Brody, J.A., Rueedi, R., Polasek, O., Sveinbjornsson, G., Lecoeur, C., Ladenvall, C., Zhao, J.H., Isaacs, A., Wang, L., Luan, Jian'an, Hwang, S.J., Mononen, N., Auro, K., Jackson, A.U., Bielak, L.F., Zeng, L., Shah, N., Nethander, M., Campbell, A., Rankinen, T., Pechlivanis, S., Qi, L., Zhao, Wei, Rizzi, F., Tanaka, T., Robino, A., Cocca, M., Lange, L., Müller-Nurasyid, M., Roselli, C., Zhang, W, Kleber, M.E., Guo, X., Lin, H.J., Pavani, F., Galesloot, T.E., Noordam, R., Milaneschi, Y., Schraut, K.E., Hoed, M. den, Degenhardt, F., Trompet, S., Berg, M.E. van den, Pistis, G., Tham, Y.C., Weiss, S., Sim, X.S., Li, H.L., Most, P.J. van der, Nolte, I.M., Lyytikäinen, L.P., Said, M.A., Witte, D.R., Iribarren, C., Launer, L., Ring, S.M., Vries, P.S. de, Sever, P., Linneberg, A., Bottinger, E.P., Padmanabhan, S., Psaty, B.M., Sotoodehnia, N., Kolcic, I., Arnar, D.O., Gudbjartsson, D.F., Holm, H., Balkau, B., Silva, C.T., Newton-Cheh, C.H., Nikus, K., Salo, P., Mohlke, K.L., Peyser, P.A., Schunkert, H., Lorentzon, M., Lahti, J., Rao, D.C., Cornelis, M.C., Faul, J.D., Smith, J.A., Stolarz-Skrzypek, K., Bandinelli, S., Concas, M.P., Sinagra, G., Meitinger, T., Waldenberger, M., Sinner, M.F., Strauch, K., Delgado, G.E., Taylor, K.D., Yao, J., Foco, L., Melander, O., Graaf, J. de, Mutsert, R. de, Geus, E.J.C. de, Johansson, Å., Joshi, P.K., Lind, L., Franke, A., Macfarlane, P.W., Tarasov, K.V., Tan, N., Felix, S.B., Tai, E.S., Quek, D.Q., Snieder, H., Ormel, J., Ingelsson, M., Lindgren, C., Morris, A.P., Raitakari, O.T., Hansen, T., Assimes, T., Gudnason, V., Timpson, N.J., Morrison, A.C., Munroe, P.B., Strachan, D.P., Grarup, N., Loos, R.J.F., Heckbert, S.R., Vollenweider, P., Hayward, C., Stefansson, K., Froguel, P., Groop, L., Wareham, N.J., Duijn, C.M. van, Feitosa, M.F., O'Donnell, C.J., Kähönen, M., Perola, M., Boehnke, M., Kardia, S.L.R., Erdmann, J., Palmer, C.N.A., Ohlsson, C., Porteous, D.J., Eriksson, J.G., Bouchard, C., Moebus, S., Kraft, P., Weir, D.R., Cusi, D., Ferrucci, L., Ulivi, S., Girotto, G., Correa, A., Kääb, S., Peters, A., Chambers, J.C., Kooner, J.S., März, W., Rotter, J.I., Hicks, A.A., Smith, J.G., Kiemeney, L.A.L.M., Mook-Kanamori, D.O., Penninx, B.W.J.H., Gyllensten, U., Wilson, J.F., Burgess, S., Sundström, J., Lieb, W., Jukema, J.W., Eijgelsheim, M., Lakatta, E.L.M., Cheng, C.Y., Dörr, M., Wong, T.Y., Sabanayagam, C., Oldehinkel, A.J., Riese, H., Lehtimäki, T., Verweij, N., and Harst, P. van der

Abstract

Contains fulltext : 296013.pdf (Publisher’s version ) (Open Access), Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Published
2023

19. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author

Broadaway, K. A. (K. Alaine), Yin, X. (Xianyong), Williamson, A. (Alice), Parsons, V. A. (Victoria A.), Wilson, E. P. (Emma P.), Moxley, A. H. (Anne H.), Vadlamudi, S. (Swarooparani), Varshney, A. (Arushi), Jackson, A. U. (Anne U.), Ahuja, V. (Vasudha), Bornstein, S. R. (Stefan R.), Corbin, L. J. (Laura J.), Delgado, G. E. (Graciela E.), Dwivedi, O. P. (Om P.), Silva, L. F. (Lilian Fernandes), Frayling, T. M. (Timothy M.), Grallert, H. (Harald), Gustafsson, S. (Stefan), Hakaste, L. (Liisa), Hammar, U. (Ulf), Herder, C. (Christian), Herrmann, S. (Sandra), Hojlund, K. (Kurt), Hughes, D. A. (David A.), Kleber, M. E. (Marcus E.), Lindgren, C. M. (Cecilia M.), Liu, C.-T. (Ching-Ti), Luan, J. (Jian'an), Malmberg, A. (Anni), Moissl, A. P. (Angela P.), Morris, A. P. (Andrew P.), Perakakis, N. (Nikolaos), Peters, A. (Annette), Petrie, J. R. (John R.), Roden, M. (Michael), Schwarz, P. E. (Peter E. H.), Sharma, S. (Sapna), Silveira, A. (Angela), Strawbridge, R. J. (Rona J.), Tuomi, T. (Tiinamaija), Wood, A. R. (Andrew R.), Wu, P. (Peitao), Zethelius, B. (Bjorn), Baldassarre, D. (Damiano), Eriksson, J. G. (Johan G.), Fall, T. (Tove), Florez, J. C. (Jose C.), Fritsche, A. (Andreas), Gigante, B. (Bruna), Hamsten, A. (Anders), Kajantie, E. (Eero), Laakso, M. (Markku), Lahti, J. (Jari), Lawlor, D. A. (Deborah A.), Lind, L. (Lars), Maerz, W. (Winfried), Meigs, J. B. (James B.), Sundstrom, J. (Johan), Timpson, N. J. (Nicholas J.), Wagner, R. (Robert), Walker, M. (Mark), Wareham, N. J. (Nicholas J.), Watkins, H. (Hugh), Barroso, I. (Ines), O'Rahilly, S. (Stephen), Grarup, N. (Niels), Parker, S. C. (Stephen CJ.), Boehnke, M. (Michael), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), Mohlke, K. L. (Karen L.), Broadaway, K. A. (K. Alaine), Yin, X. (Xianyong), Williamson, A. (Alice), Parsons, V. A. (Victoria A.), Wilson, E. P. (Emma P.), Moxley, A. H. (Anne H.), Vadlamudi, S. (Swarooparani), Varshney, A. (Arushi), Jackson, A. U. (Anne U.), Ahuja, V. (Vasudha), Bornstein, S. R. (Stefan R.), Corbin, L. J. (Laura J.), Delgado, G. E. (Graciela E.), Dwivedi, O. P. (Om P.), Silva, L. F. (Lilian Fernandes), Frayling, T. M. (Timothy M.), Grallert, H. (Harald), Gustafsson, S. (Stefan), Hakaste, L. (Liisa), Hammar, U. (Ulf), Herder, C. (Christian), Herrmann, S. (Sandra), Hojlund, K. (Kurt), Hughes, D. A. (David A.), Kleber, M. E. (Marcus E.), Lindgren, C. M. (Cecilia M.), Liu, C.-T. (Ching-Ti), Luan, J. (Jian'an), Malmberg, A. (Anni), Moissl, A. P. (Angela P.), Morris, A. P. (Andrew P.), Perakakis, N. (Nikolaos), Peters, A. (Annette), Petrie, J. R. (John R.), Roden, M. (Michael), Schwarz, P. E. (Peter E. H.), Sharma, S. (Sapna), Silveira, A. (Angela), Strawbridge, R. J. (Rona J.), Tuomi, T. (Tiinamaija), Wood, A. R. (Andrew R.), Wu, P. (Peitao), Zethelius, B. (Bjorn), Baldassarre, D. (Damiano), Eriksson, J. G. (Johan G.), Fall, T. (Tove), Florez, J. C. (Jose C.), Fritsche, A. (Andreas), Gigante, B. (Bruna), Hamsten, A. (Anders), Kajantie, E. (Eero), Laakso, M. (Markku), Lahti, J. (Jari), Lawlor, D. A. (Deborah A.), Lind, L. (Lars), Maerz, W. (Winfried), Meigs, J. B. (James B.), Sundstrom, J. (Johan), Timpson, N. J. (Nicholas J.), Wagner, R. (Robert), Walker, M. (Mark), Wareham, N. J. (Nicholas J.), Watkins, H. (Hugh), Barroso, I. (Ines), O'Rahilly, S. (Stephen), Grarup, N. (Niels), Parker, S. C. (Stephen CJ.), Boehnke, M. (Michael), Langenberg, C. (Claudia), Wheeler, E. (Eleanor), and Mohlke, K. L. (Karen L.)

Abstract

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value <5×10⁻⁸), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6‐3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6‐3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.

Published
2023

20. Two population-based studies showed that several environmental contaminants were related to diabetes

Author

Lind, M., Dunder, L., Lind, L., Salihovic, Samira, Lind, M., Dunder, L., Lind, L., and Salihovic, Samira

Abstract

Background and aims: In previous studies on environmental contaminants and diabetes only a limited number of contaminants have been evaluated. The aim with the present study is therefore to obtain a comprehensive picture of the relationships between a large number of environmental contaminants and prevalent diabetes. Materials and methods: In 10 examination cycles in The National Health and Nutrition Examination Survey (NHANES) (1999-2017) altogether 116 different environmental contaminants were evaluated in the circulation or urine in relation to prevalent diabetes. Similar analyses were also performed in the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) study (n=1016, all aged 70 years, 50% women, 42 contaminants). The logistic regression models were adjusted for age, sex, race, education, BMI, alcohol intake, smoking and lipids. Results: In a meta-analysis of the 10 NHANES examinations, thirty-six contaminants were significantly related to prevalent diabetes. Those contaminants represent a number of different classes, such as metals, PCBs, dioxins, furans, pesticides, PFAS, phthalates, and phenols. Some of these relationships were inverse, such as lead, cadmium, mercury, barium, cesium and strontium, some PFAS and furans, as well as benzo-phenone-3. In the smaller PIVUS study (119 prevalent diabetes cases), significant relationships similar to NHANES were seen for some PCBs, p,p´-DDE and lead. PFHxS and PFOA, showed inverse relationships also in PIVUS. The same was seen for mercury and cadmium. Conclusion: Many environmental contaminants were related to diabetes in the NHANES study. Some of these relationships, mainly some metals and PFAS, were negative. Many of these results were similar in the smaller PIVUS study. These findings need be evaluated in prospective studies.

Published
2023

21. Results from two population-based studies showed many environmental contaminants to be related to diabetes

Author

Lind, M., Dunder, L., Salihovic, S., Lind, L., Lind, M., Dunder, L., Salihovic, S., and Lind, L.

Abstract

Background and aim: In previous studies on environmental contaminants and diabetes only a limited number of contaminants have been evaluated. The aim with the present study is therefore to obtain a comprehensive picture of the relationships between a large number of environmental contaminants and prevalent diabetes. Methods: In 10 examination cycles in The National Health and Nutrition Examination Survey (NHANES) (1999–2017) altogether 116 different environmental contaminants were evaluated in the circulation or urine in relation to prevalent diabetes. Similar analyses were also performed in the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) study (n=1016, all aged 70 years, 50% women, 42 contaminants). The logistic regression models were adjusted for age, sex, race, education, BMI, alcohol intake, smoking and lipids. Results: In a meta-analysis of the 10 NHANES examinations, thirty-six contaminants were significantly related to prevalent diabetes. Those contaminants represent a number of different classes, such as metals, PCBs, dioxins, furans, pesticides, PFAS, phthalates, and phenols. Some of these relationships were inverse, such as lead, cadmium, mercury, barium, cesium and strontium, some PFAS and furans, as well as benzophenone-3. In the smaller PIVUS study (119 prevalent diabetes cases), significant relationships similar to NHANES were seen for some PCBs, p,p’-DDE and lead. PFHxS and PFOA, showed inverse relationships also in PIVUS. The same was seen for mercury and cadmium. Conclusions: Many environmental contaminants were related to diabetes in the NHANES study. Some of these relationships, mainly some metals and PFAS, were negative. Many of these results were similar in the smaller PIVUS study. These findings need be evaluated in prospective studies.

Published
2023

22. Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality

Author

Magnussen, C, Ojeda, F, Leong, D, Alegre-Diaz, J, Amouyel, P, Aviles-Santa, L, De Bacquer, D, Ballantyne, C, Bernabé-Ortiz, A, Bobak, M, Brenner, H, Carrillo-Larco, R, de Lemos, J, Dobson, A, Dörr, M, Donfrancesco, C, Drygas, W, Dullaart, R, Engström, G, Ferrario, M, Ferrières, J, de Gaetano, G, Goldbourt, U, Gonzalez, C, Grassi, G, Hodge, A, Hveem, K, Iacoviello, L, Ikram, M, Irazola, V, Jobe, M, Jousilahti, P, Kaleebu, P, Kavousi, M, Kee, F, Khalili, D, Koenig, W, Kontsevaya, A, Kuulasmaa, K, Lackner, K, Leistner, D, Lind, L, Linneberg, A, Lorenz, T, Lyngbakken, M, Malekzadeh, R, Malyutina, S, Mathiesen, E, Melander, O, Metspalu, A, Miranda, J, Moitry, M, Mugisha, J, Nalini, M, Nambi, V, Ninomiya, T, Oppermann, K, D'Orsi, E, Pająk, A, Palmieri, L, Panagiotakos, D, Perianayagam, A, Peters, A, Poustchi, H, Prentice, A, Prescott, E, Risérus, U, Salomaa, V, Sans, S, Sakata, S, Schöttker, B, Schutte, A, Sepanlou, S, Sharma, S, Shaw, J, Simons, L, Söderberg, S, Tamosiunas, A, Thorand, B, Tunstall-Pedoe, H, Twerenbold, R, Vanuzzo, D, Veronesi, G, Waibel, J, Wannamethee, S, Watanabe, M, Wild, P, Yao, Y, Zeng, Y, Ziegler, A, Blankenberg, S, Magnussen, Christina, Ojeda, Francisco M, Leong, Darryl P, Alegre-Diaz, Jesus, Amouyel, Philippe, Aviles-Santa, Larissa, De Bacquer, Dirk, Ballantyne, Christie M, Bernabé-Ortiz, Antonio, Bobak, Martin, Brenner, Hermann, Carrillo-Larco, Rodrigo M, de Lemos, James, Dobson, Annette, Dörr, Marcus, Donfrancesco, Chiara, Drygas, Wojciech, Dullaart, Robin P, Engström, Gunnar, Ferrario, Marco M, Ferrières, Jean, de Gaetano, Giovanni, Goldbourt, Uri, Gonzalez, Clicerio, Grassi, Guido, Hodge, Allison M, Hveem, Kristian, Iacoviello, Licia, Ikram, M Kamran, Irazola, Vilma, Jobe, Modou, Jousilahti, Pekka, Kaleebu, Pontiano, Kavousi, Maryam, Kee, Frank, Khalili, Davood, Koenig, Wolfgang, Kontsevaya, Anna, Kuulasmaa, Kari, Lackner, Karl J, Leistner, David M, Lind, Lars, Linneberg, Allan, Lorenz, Thiess, Lyngbakken, Magnus Nakrem, Malekzadeh, Reza, Malyutina, Sofia, Mathiesen, Ellisiv B, Melander, Olle, Metspalu, Andres, Miranda, J Jaime, Moitry, Marie, Mugisha, Joseph, Nalini, Mahdi, Nambi, Vijay, Ninomiya, Toshiharu, Oppermann, Karen, d'Orsi, Eleonora, Pająk, Andrzej, Palmieri, Luigi, Panagiotakos, Demosthenes, Perianayagam, Arokiasamy, Peters, Annette, Poustchi, Hossein, Prentice, Andrew M, Prescott, Eva, Risérus, Ulf, Salomaa, Veikko, Sans, Susana, Sakata, Satoko, Schöttker, Ben, Schutte, Aletta E, Sepanlou, Sadaf G, Sharma, Sanjib Kumar, Shaw, Jonathan E, Simons, Leon A, Söderberg, Stefan, Tamosiunas, Abdonas, Thorand, Barbara, Tunstall-Pedoe, Hugh, Twerenbold, Raphael, Vanuzzo, Diego, Veronesi, Giovanni, Waibel, Julia, Wannamethee, S Goya, Watanabe, Masafumi, Wild, Philipp S, Yao, Yao, Zeng, Yi, Ziegler, Andreas, Blankenberg, Stefan, Magnussen, C, Ojeda, F, Leong, D, Alegre-Diaz, J, Amouyel, P, Aviles-Santa, L, De Bacquer, D, Ballantyne, C, Bernabé-Ortiz, A, Bobak, M, Brenner, H, Carrillo-Larco, R, de Lemos, J, Dobson, A, Dörr, M, Donfrancesco, C, Drygas, W, Dullaart, R, Engström, G, Ferrario, M, Ferrières, J, de Gaetano, G, Goldbourt, U, Gonzalez, C, Grassi, G, Hodge, A, Hveem, K, Iacoviello, L, Ikram, M, Irazola, V, Jobe, M, Jousilahti, P, Kaleebu, P, Kavousi, M, Kee, F, Khalili, D, Koenig, W, Kontsevaya, A, Kuulasmaa, K, Lackner, K, Leistner, D, Lind, L, Linneberg, A, Lorenz, T, Lyngbakken, M, Malekzadeh, R, Malyutina, S, Mathiesen, E, Melander, O, Metspalu, A, Miranda, J, Moitry, M, Mugisha, J, Nalini, M, Nambi, V, Ninomiya, T, Oppermann, K, D'Orsi, E, Pająk, A, Palmieri, L, Panagiotakos, D, Perianayagam, A, Peters, A, Poustchi, H, Prentice, A, Prescott, E, Risérus, U, Salomaa, V, Sans, S, Sakata, S, Schöttker, B, Schutte, A, Sepanlou, S, Sharma, S, Shaw, J, Simons, L, Söderberg, S, Tamosiunas, A, Thorand, B, Tunstall-Pedoe, H, Twerenbold, R, Vanuzzo, D, Veronesi, G, Waibel, J, Wannamethee, S, Watanabe, M, Wild, P, Yao, Y, Zeng, Y, Ziegler, A, Blankenberg, S, Magnussen, Christina, Ojeda, Francisco M, Leong, Darryl P, Alegre-Diaz, Jesus, Amouyel, Philippe, Aviles-Santa, Larissa, De Bacquer, Dirk, Ballantyne, Christie M, Bernabé-Ortiz, Antonio, Bobak, Martin, Brenner, Hermann, Carrillo-Larco, Rodrigo M, de Lemos, James, Dobson, Annette, Dörr, Marcus, Donfrancesco, Chiara, Drygas, Wojciech, Dullaart, Robin P, Engström, Gunnar, Ferrario, Marco M, Ferrières, Jean, de Gaetano, Giovanni, Goldbourt, Uri, Gonzalez, Clicerio, Grassi, Guido, Hodge, Allison M, Hveem, Kristian, Iacoviello, Licia, Ikram, M Kamran, Irazola, Vilma, Jobe, Modou, Jousilahti, Pekka, Kaleebu, Pontiano, Kavousi, Maryam, Kee, Frank, Khalili, Davood, Koenig, Wolfgang, Kontsevaya, Anna, Kuulasmaa, Kari, Lackner, Karl J, Leistner, David M, Lind, Lars, Linneberg, Allan, Lorenz, Thiess, Lyngbakken, Magnus Nakrem, Malekzadeh, Reza, Malyutina, Sofia, Mathiesen, Ellisiv B, Melander, Olle, Metspalu, Andres, Miranda, J Jaime, Moitry, Marie, Mugisha, Joseph, Nalini, Mahdi, Nambi, Vijay, Ninomiya, Toshiharu, Oppermann, Karen, d'Orsi, Eleonora, Pająk, Andrzej, Palmieri, Luigi, Panagiotakos, Demosthenes, Perianayagam, Arokiasamy, Peters, Annette, Poustchi, Hossein, Prentice, Andrew M, Prescott, Eva, Risérus, Ulf, Salomaa, Veikko, Sans, Susana, Sakata, Satoko, Schöttker, Ben, Schutte, Aletta E, Sepanlou, Sadaf G, Sharma, Sanjib Kumar, Shaw, Jonathan E, Simons, Leon A, Söderberg, Stefan, Tamosiunas, Abdonas, Thorand, Barbara, Tunstall-Pedoe, Hugh, Twerenbold, Raphael, Vanuzzo, Diego, Veronesi, Giovanni, Waibel, Julia, Wannamethee, S Goya, Watanabe, Masafumi, Wild, Philipp S, Yao, Yao, Zeng, Yi, Ziegler, Andreas, and Blankenberg, Stefan

Abstract

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the

Published
2023

24. Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

Author

Fanelli, G, primary, Franke, B, additional, De Witte, W, additional, Ruisch, IH, additional, Haavik, J, additional, van Gils, V, additional, Jansen, WJ, additional, Vos, SJB, additional, Lind, L, additional, Buitelaar, JK, additional, Banaschewski, T, additional, Dalsgaard, S, additional, Serretti, A, additional, Mota, NR, additional, Poelmans, G, additional, and Bralten, J, additional

Published
2022
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26. Cardiovascular disease linked plasma proteins relate mainly to lung volumes

Author

Rydell, A, primary, Nerpin, E, additional, Zhou, X W, additional, Lind, L, additional, Lindberg, E, additional, Theorell Haglöw, J, additional, Fall, T, additional, Janson, C, additional, Lisspers, K, additional, Elmståhl, S, additional, Zaigham, S, additional, Melander, O, additional, Nilsson, P, additional, Orhu-Melander, M, additional, Ärnlöv, J, additional, and Malinovschi, A, additional

Published
2022
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33. Genetic landscape of the ACE2 coronavirus receptor

Author

Yang, Z, MacDonald-Dunlop, E, Chen, J, Zhai, R, Li, T, Richmond, A, Klaric, L, Pirastu, N, Ning, Z, Zheng, C, Wang, Y, Huang, T, He, Y, Guo, H, Ying, K, Gustafsson, S, Prins, B, Ramisch, A, Dermitzakis, ET, Png, G, Eriksson, N, Haessler, J, Hu, X, Zanetti, D, Boutin, T, Hwang, S-J, Wheeler, E, Pietzner, M, Raffield, LM, Kalnapenkis, A, Peters, JE, Viñuela, A, Gilly, A, Elmståhl, S, Dedoussis, G, Petrie, JR, Polašek, O, Folkersen, L, Chen, Y, Yao, C, Võsa, U, Pairo-Castineira, E, Clohisey, S, Bretherick, AD, Rawlik, K, Esko, T, Enroth, S, Johansson, Å, Gyllensten, U, Langenberg, C, Levy, D, Hayward, C, Assimes, TL, Kooperberg, C, Manichaikul, AW, Siegbahn, A, Wallentin, L, Lind, L, Zeggini, E, Schwenk, JM, Butterworth, AS, Michaëlsson, K, Pawitan, Y, Joshi, PK, Baillie, JK, Mälarstig, A, Reiner, AP, Wilson, JF, Shen, X, and GenOMICC Consortium and the IMI-DIRECT Consortium

Subjects
ANGIOTENSIN-CONVERTING ENZYME, Cardiac & Cardiovascular Systems, GenOMICC Consortium†, DATABASE, COVID, genetic, analysis, ALPHA-1-ANTITRYPSIN DEFICIENCY, 1117 Public Health and Health Services, angiotensin-converting enzyme 2, Physiology (medical), Humans, Cardiac and Cardiovascular Systems, 1102 Cardiorespiratory Medicine and Haematology, Medicinsk genetik, RISK, Kardiologi, Science & Technology, SARS-CoV-2, COVID-19, IMI-DIRECT Consortium†, 1103 Clinical Sciences, COVID-19/genetics, cardiovascular diseases, Angiotensin-Converting Enzyme 2/genetics, Cross-Sectional Studies, Peripheral Vascular Disease, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, TRIAL, Cardiology and Cardiovascular Medicine, Medical Genetics, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Genome-Wide Association Study, Receptors, Coronavirus
Abstract

Background: SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics–based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis–protein quantitative trait loci–based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10–2.42]; P =0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05–2.21]; P =0.03), and infection (odds ratio, 1.60 [95% CI, 1.08–2.37]; P =0.02). Tissue- and cell type–specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.

Published
2022
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34. Lake salinization drives consistent losses of zooplankton abundance and diversity across coordinated mesocosm experiments

Author

Hébert, MP, Hébert, MP, Symons, CC, Cañedo-Argüelles, M, Arnott, SE, Derry, AM, Fugère, V, Hintz, WD, Melles, SJ, Astorg, L, Baker, HK, Brentrup, JA, Downing, AL, Ersoy, Z, Espinosa, C, Franceschini, JM, Giorgio, AT, Göbeler, N, Gray, DK, Greco, D, Hassal, E, Huynh, M, Hylander, S, Jonasen, KL, Kirkwood, A, Langenheder, S, Langvall, O, Laudon, H, Lind, L, Lundgren, M, McClymont, A, Proia, L, Relyea, RA, Rusak, JA, Schuler, MS, Searle, CL, Shurin, JB, Steiner, CF, Striebel, M, Thibodeau, S, Urrutia Cordero, P, Vendrell-Puigmitja, L, Weyhenmeyer, GA, Beisner, BE, Hébert, MP, Hébert, MP, Symons, CC, Cañedo-Argüelles, M, Arnott, SE, Derry, AM, Fugère, V, Hintz, WD, Melles, SJ, Astorg, L, Baker, HK, Brentrup, JA, Downing, AL, Ersoy, Z, Espinosa, C, Franceschini, JM, Giorgio, AT, Göbeler, N, Gray, DK, Greco, D, Hassal, E, Huynh, M, Hylander, S, Jonasen, KL, Kirkwood, A, Langenheder, S, Langvall, O, Laudon, H, Lind, L, Lundgren, M, McClymont, A, Proia, L, Relyea, RA, Rusak, JA, Schuler, MS, Searle, CL, Shurin, JB, Steiner, CF, Striebel, M, Thibodeau, S, Urrutia Cordero, P, Vendrell-Puigmitja, L, Weyhenmeyer, GA, and Beisner, BE

Abstract

Human-induced salinization increasingly threatens inland waters; yet we know little about the multifaceted response of lake communities to salt contamination. By conducting a coordinated mesocosm experiment of lake salinization across 16 sites in North America and Europe, we quantified the response of zooplankton abundance and (taxonomic and functional) community structure to a broad gradient of environmentally relevant chloride concentrations, ranging from 4 to ca. 1400 mg Cl− L−1. We found that crustaceans were distinctly more sensitive to elevated chloride than rotifers; yet, rotifers did not show compensatory abundance increases in response to crustacean declines. For crustaceans, our among-site comparisons indicate: (1) highly consistent decreases in abundance and taxon richness with salinity; (2) widespread chloride sensitivity across major taxonomic groups (Cladocera, Cyclopoida, and Calanoida); and (3) weaker loss of functional than taxonomic diversity. Overall, our study demonstrates that aggregate properties of zooplankton communities can be adversely affected at chloride concentrations relevant to anthropogenic salinization in lakes.

Published
2022

35. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, Gravel, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, and Gravel, S

Abstract

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

36. A saturated map of common genetic variants associated with human height

Author

Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, 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Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, Hirschhorn, JN, Yengo, L, Vedantam, S, Marouli, E, Sidorenko, J, Bartell, E, Sakaue, S, Graff, M, Eliasen, AU, Jiang, Y, Raghavan, S, Miao, J, Arias, JD, Graham, SE, Mukamel, RE, Spracklen, CN, Yin, X, Chen, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, S, Sim, X, Vrieze, S, Ahluwalia, TS, Akiyama, M, Allison, MA, Alvarez, M, Andersen, MK, Ani, A, Appadurai, V, Arbeeva, L, Bhaskar, S, Bielak, LF, Bollepalli, S, Bonnycastle, LL, Bork-Jensen, J, Bradfield, JP, Bradford, Y, Braund, PS, Brody, JA, Burgdorf, KS, Cade, BE, Cai, H, Cai, Q, Campbell, A, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, Cocca, M, Concas, MP, Couture, C, Cuellar-Partida, G, Danning, R, Daw, EW, Degenhard, F, Delgado, GE, Delitala, A, Demirkan, A, Deng, X, Devineni, P, Dietl, A, Dimitriou, M, Dimitrov, L, Dorajoo, R, Ekici, AB, Engmann, JE, Fairhurst-Hunter, Z, Farmaki, A-E, Faul, JD, Fernandez-Lopez, J-C, Forer, L, Francescatto, M, Freitag-Wolf, S, Fuchsberger, C, Galesloot, TE, Gao, Y, Gao, Z, Geller, F, Giannakopoulou, O, Giulianini, F, Gjesing, AP, Goel, A, Gordon, SD, Gorski, M, Grove, J, Guo, X, Gustafsson, S, Haessler, J, Hansen, TF, Havulinna, AS, Haworth, SJ, He, J, Heard-Costa, N, Hebbar, P, Hindy, G, Ho, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, Mahajan, A, Mamakou, V, Mangino, M, Manichaikul, A, Marten, J, Mattheisen, M, Mavarani, L, McDaid, AF, Meidtner, K, Melendez, TL, Mercader, JM, Milaneschi, Y, Miller, JE, Millwood, IY, Mishra, PP, Mitchell, RE, Mollehave, LT, Morgan, A, Mucha, S, Munz, M, Nakatochi, M, Nelson, CP, Nethander, M, Nho, CW, Nielsen, AA, Nolte, IM, Nongmaithem, SS, Noordam, R, Ntalla, I, Nutile, T, Pandit, A, Christofidou, P, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, O, Poveda, A, Preuss, MH, Pyarajan, S, Raffield, LM, Rakugi, H, Ramirez, J, Rasheed, A, Raven, D, Rayner, NW, Riveros, C, Rohde, R, Ruggiero, D, Ruotsalainen, SE, Ryan, KA, Sabater-Lleal, M, Saxena, R, Scholz, M, Sendamarai, A, Shen, B, Shi, J, Shin, JH, Sidore, C, Sitlani, CM, Slieker, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, Taylor, KD, Tayo, BO, Tcheandjieu, C, Terzikhan, N, Tesolin, P, Teumer, A, Theusch, E, Thompson, DJ, Thorleifsson, G, Timmers, PRHJ, Trompet, S, Turman, C, Vaccargiu, S, van der Laan, SW, van der Most, PJ, van Klinken, JB, van Setten, J, Verma, SS, Verweij, N, Veturi, Y, Wang, CA, Wang, C, Wang, L, Wang, Z, Warren, HR, Wei, WB, Wickremasinghe, AR, Wielscher, M, Wiggins, KL, Winsvold, BS, Wong, A, Wu, Y, Wuttke, M, Xia, R, Xie, T, Yamamoto, K, Yang, J, Yao, J, Young, H, Yousri, NA, Yu, L, Zeng, L, Zhang, W, Zhang, X, Zhao, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, Christophersen, IE, Ciullo, M, Cole, JW, Collins, FS, Cooper, RS, Cruz, M, Cucca, F, Cupples, LA, Cutler, MJ, Damrauer, SM, Dantoft, TM, de Borst, GJ, de Groot, LCPGM, De Jager, PL, de Kleijn, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, Gasparini, P, Gieger, C, Girotto, G, Goddard, ME, Golightly, YM, Gonzalez-Villalpando, C, Gordon-Larsen, P, Grallert, H, Grant, SFA, Grarup, N, Griffiths, L, Gudnason, V, Haiman, C, Hakonarson, H, Hansen, T, Hartman, CA, Hattersley, AT, Hayward, C, Heckbert, SR, Heng, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, A, Kovacs, P, Kraaijeveld, A, Kraft, P, Krauss, RM, Kumari, M, Kutalik, Z, Laakso, M, Lange, LA, Langenberg, C, Launer, LJ, Le Marchand, L, Lee, H, Lee, NR, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, D, Metspalu, A, Mitchell, BD, Mitchell, P, Mook-Kanamori, DO, Morris, AD, Mucci, LA, Munroe, PB, Nalls, MA, Nazarian, S, Nelson, AE, Neville, MJ, Newton-Cheh, C, Nielsen, CS, Nothen, MM, Ohlsson, C, Oldehinkel, AJ, Orozco, L, Pahkala, K, Pajukanta, P, Palmer, CNA, Parra, EJ, Pattaro, C, Pedersen, O, Pennell, CE, Penninx, BWJH, Perusse, L, Peters, A, Peyser, PA, Porteous, DJ, Posthuma, D, Power, C, Pramstaller, PP, Province, MA, Qi, Q, Qu, J, Rader, DJ, Raitakari, OT, Ralhan, S, Rallidis, LS, Rao, DC, Redline, S, Reilly, DF, Reiner, AP, Rhee, SY, Ridker, PM, Rienstra, M, Ripatti, S, Ritchie, MD, Roden, DM, Rosendaal, FR, Rotter, J, Rudan, I, Rutters, F, Sabanayagam, C, Saleheen, D, Salomaa, V, Samani, NJ, Sanghera, DK, Sattar, N, Schmidt, B, Schmidt, H, Schmidt, R, Schulze, MB, Schunkert, H, Scott, LJ, Scott, RJ, Sever, P, Shiroma, EJ, Shoemaker, MB, Shu, X-O, Simonsick, EM, Sims, M, Singh, JR, Singleton, AB, Sinner, MF, Smith, JG, Snieder, H, Spector, TD, Stampfer, MJ, Stark, KJ, Strachan, DP, t' Hart, LM, Tabara, Y, Tang, H, Tardif, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, H, Wacher-Rodarte, NH, Walker, M, Wang, YX, Wareham, NJ, Watanabe, RM, Watkins, H, Weir, DR, Werge, TM, Widen, E, Wilkens, LR, Willemsen, G, Willett, WC, Wilson, JF, Wong, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, Tai, ES, Boehnke, M, Deloukas, P, Justice, AE, Lindgren, CM, Loos, RJF, Mohlke, KL, North, KE, Stefansson, K, Walters, RG, Winkler, TW, Young, KL, Loh, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, and Hirschhorn, JN

Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Published
2022

38. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Author

Cornelis, M C, Byrne, E M, Esko, T, Nalls, M A, Ganna, A, Paynter, N, Monda, K L, Amin, N, Fischer, K, Renstrom, F, Ngwa, J S, Huikari, V, Cavadino, A, Nolte, I M, Teumer, A, Yu, K, Marques-Vidal, P, Rawal, R, Manichaikul, A, Wojczynski, M K, Vink, J M, Zhao, J H, Burlutsky, G, Lahti, J, Mikkilä, V, Lemaitre, R N, Eriksson, J, Musani, S K, Tanaka, T, Geller, F, Luan, J, Hui, J, Mägi, R, Dimitriou, M, Garcia, M E, Ho, W-K, Wright, M J, Rose, L M, Magnusson, P K E, Pedersen, N L, Couper, D, Oostra, B A, Hofman, A, Ikram, M A, Tiemeier, H W, Uitterlinden, A G, van Rooij, F J A, Barroso, I, Johansson, I, Xue, L, Kaakinen, M, Milani, L, Power, C, Snieder, H, Stolk, R P, Baumeister, S E, Biffar, R, Gu, F, Bastardot, F, Kutalik, Z, Jacobs, Jr, D R, Forouhi, N G, Mihailov, E, Lind, L, Lindgren, C, Michaëlsson, K, Morris, A, Jensen, M, Khaw, K-T, Luben, R N, Wang, J J, Männistö, S, Perälä, M-M, Kähönen, M, Lehtimäki, T, Viikari, J, Mozaffarian, D, Mukamal, K, Psaty, B M, Döring, A, Heath, A C, Montgomery, G W, Dahmen, N, Carithers, T, Tucker, K L, Ferrucci, L, Boyd, H A, Melbye, M, Treur, J L, Mellström, D, Hottenga, J J, Prokopenko, I, Tönjes, A, Deloukas, P, Kanoni, S, Lorentzon, M, Houston, D K, Liu, Y, Danesh, J, Rasheed, A, Mason, M A, Zonderman, A B, Franke, L, Kristal, B S, Karjalainen, J, Reed, D R, Westra, H-J, Evans, M K, Saleheen, D, Harris, T B, Dedoussis, G, Curhan, G, Stumvoll, M, Beilby, J, Pasquale, L R, Feenstra, B, Bandinelli, S, Ordovas, J M, Chan, A T, Peters, U, Ohlsson, C, Gieger, C, Martin, N G, Waldenberger, M, Siscovick, D S, Raitakari, O, Eriksson, J G, Mitchell, P, Hunter, D J, Kraft, P, Rimm, E B, Boomsma, D I, Borecki, I B, Loos, R J F, Wareham, N J, Vollenweider, P, Caporaso, N, Grabe, H J, Neuhouser, M L, Wolffenbuttel, B H R, Hu, F B, Hyppönen, E, Järvelin, M-R, Cupples, L A, Franks, P W, Ridker, P M, van Duijn, C M, Heiss, G, Metspalu, A, North, K E, Ingelsson, E, Nettleton, J A, van Dam, R M, and Chasman, D I

Published
2015
Full Text
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42. Endotoxin-induced and vaccine-induced systemic inflammation both impair endothelium-dependent vasodilation, but not pulse wave reflection

Author

Lind L, Hulthe J, Johansson A, and Hedner E

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Lars Lind,1 Johannes Hulthe,2,3 Annika Johansson,3 Ewa Hedner31Department of Medicine, University Hospital, Uppsala, 2Sahlgrenska Hospital, Gothenburg, 3AstraZeneca Research and Development, Mölndal, SwedenBackground: Inflammation induced by either endotoxin or vaccination has previously been shown to impair endothelium-dependent vasodilation (EDV) in healthy young individuals. However, the vascular effects of these two mechanisms of inducing inflammation have not been compared in the same individuals.Methods: Twelve young healthy males were studied at the same time of the day on three occasions in a random order; on one occasion 4 hours following an endotoxin injection (Escherichia coli endotoxin, 20 IU/kg), on another occasion 8 hours following vaccination against Salmonella typhi, and on a third occasion 4 hours following a saline control injection. EDV and endothelium-independent vasodilation (EIDV) were evaluated by local infusions of acetylcholine and sodium nitroprusside in the brachial artery, and forearm blood flow was measured with venous occlusion plethysmography. The augmentation index was determined by pulse wave analysis as an index of pulse wave reflection.Results: Both endotoxin and vaccination impaired EDV to a similar degree compared with the saline control (P = 0.005 and P = 0.014, respectively). EIDV was not significantly affected by inflammation. Endotoxin, but not vaccination, increased body temperature and circulating levels of intracellular adhesion molecule-1 and interleukin-6. Augmentation index was not affected by the interventions.Conclusion: Despite the fact that endotoxin induced a more pronounced degree of inflammation than vaccination, both inflammatory challenges impaired EDV to a similar degree, supporting the view that different inflammatory stimuli could induce harmful effects on the vasculature.Keywords: endothelium, endotoxin, vaccination, vasodilation, inflammation

Published
2012

44. Ambulatory blood pressure monitoring for risk stratification in obese and non-obese subjects from 10 populations

Author

Hansen, T W, Thijs, L, Li, Y, Boggia, J, Liu, Y, Asayama, K, Kikuya, M, Björklund-Bodegård, K, Ohkubo, T, Jeppesen, J, Torp-Pedersen, C, Dolan, E, Kuznetsova, T, Stolarz-Skrzypek, K, Tikhonoff, V, Malyutina, S, Casiglia, E, Nikitin, Y, Lind, L, Sandoya, E, Kawecka-Jaszcz, K, Filipovský, J, Imai, Y, Wang, J, O'Brien, E, and Staessen, J A

Published
2014
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46. The Swedish CArdioPulmonary BioImage Study: objectives and design

Author

Bergström, G., Berglund, G., Blomberg, A., Brandberg, J., Engström, G., Engvall, J., Eriksson, M., de Faire, U., Flinck, A., Hansson, M. G., Hedblad, B., Hjelmgren, O., Janson, C., Jernberg, T., Johnsson, Å., Johansson, L., Lind, L., Löfdahl, C.-G., Melander, O., Östgren, C. J., Persson, A., Persson, M., Sandström, A., Schmidt, C., Söderberg, S., Sundström, J., Toren, K., Waldenström, A., Wedel, H., Vikgren, J., Fagerberg, B., and Rosengren, A.

Published
2015
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47. JL / LRL

Author

LIND, L. R.

Published
2002

49. Publisher Correction:Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author

Surendran, P, Feofanova, EV, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, AV, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Velez Edwards, DR, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, De Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, I, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, YV, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, AI, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Davey Smith, G, Boer, RAD, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, MI, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, JI, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, Van der Harst, P, Van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, DI, Levy, D, Newton-Cheh, C, Munroe, PB, Howson, JMM, and United Kingdom Research and Innovation

Subjects
Genetics & Heredity, Understanding Society Scientific Group, Science & Technology, business.industry, Published Erratum, Million Veteran Program, MEDLINE, Computational biology, 06 Biological Sciences, Biology, Blood pressure, Text mining, Meta-analysis, EPIC-InterAct, Genetics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business, Life Sciences & Biomedicine, EPIC-CVD, 11 Medical and Health Sciences, LifeLines Cohort Study, Developmental Biology
Abstract

In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article.

Published
2021
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