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1. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G, Chen, Jing, Packer, Richard, Hall, Robert J, Guyatt, Anna L, Batini, Chiara, Thompson, Rebecca J, Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D, Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A, John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y, Chen, Zhengming, Li, Liming, China Kadoorie Biobank Collaborative Group, Wijnant, Sara RA, Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G, Manichaikul, Ani, Oelsner, Elizabeth C, Rich, Stephen S, Barr, R Graham, Kerr, Shona M, Vitart, Veronique, Brown, Michael R, Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M, Gharib, Sina A, Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E, Meyers, Deborah A, Bleecker, Eugene R, Gabriel, Stacey B, Gupta, Namrata, Smith, Albert Vernon, Luan, Jian'an, Zhao, Jing-Hua, Hansen, Ailin F, Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H, Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L, Yu, Bing, Lim, Elise, Xu, Hanfei, O'Connor, George T, Thareja, Gaurav, Albagha, Omar ME, Qatar Genome Program Research (QGPR) Consortium, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O, Hiemstra, Pieter S, Slats, Annelies M, Mullin, Benjamin H, Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T, Wyss, Annah B, Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A, Joshi, Peter K, Timmers, Paul RHJ, Williams, Alexander T, Free, Robert C, Wang, Xueyang, Morrison, John L, Gilliland, Frank D, Chen, Zhanghua, Wang, Carol A, Foong, Rachel E, Harris, Sarah E, Taylor, Adele, Redmond, Paul, Cook, James P, Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T, Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H, Cox, Simon R, Pennell, Craig E, Hall, Graham L, Gauderman, W James, Brightling, Chris, Wilson, James F, Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O, Timpson, Nicholas J, Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C, Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L, Dudbridge, Frank, Silverman, Edwin K, Strachan, David P, Walters, Robin G, Morris, Andrew P, London, Stephanie J, Cho, Michael H, Wain, Louise V, Hall, Ian P, Tobin, Martin D, Shrine, Nick [0000-0003-3641-4371], Chen, Jing [0000-0003-1287-1930], Guyatt, Anna L. [0000-0003-1860-6337], Hobbs, Brian D. [0000-0001-9564-0745], Kim, Wonji [0000-0002-1249-797X], Coley, Kayesha [0000-0003-4951-6799], Chen, Zhengming [0000-0001-6423-105X], Li, Liming [0000-0001-5873-7089], Lahousse, Lies [0000-0002-3494-4363], Uitterlinden, Andre G. [0000-0002-7276-3387], Oelsner, Elizabeth C. [0000-0002-7481-9671], Rich, Stephen S. [0000-0003-3872-7793], Kerr, Shona M. [0000-0002-4137-1495], Vitart, Veronique [0000-0002-4991-3797], Jeong, Ayoung [0000-0003-1542-0756], Gharib, Sina A. [0000-0002-2480-4367], Gieger, Christian [0000-0001-6986-9554], Peters, Annette [0000-0001-6645-0985], Hu, Xiaowei [0000-0001-7804-7392], Smith, Albert Vernon [0000-0003-1942-5845], Luan, Jian’an [0000-0003-3137-6337], Langhammer, Arnulf [0000-0001-5296-6673], Willer, Cristen [0000-0001-5645-4966], Porteous, David [0000-0003-1249-6106], Smith, Blair H. [0000-0002-5362-9430], Campbell, Archie [0000-0003-0198-5078], Sofer, Tamar [0000-0001-8520-8860], Lee, Jiwon [0000-0002-4079-7494], Lim, Elise [0000-0001-8967-8464], Thareja, Gaurav [0000-0003-2277-6400], Albagha, Omar M. E. [0000-0001-5916-5983], Suhre, Karsten [0000-0001-9638-3912], Granell, Raquel [0000-0002-4890-4012], Faquih, Tariq O. [0000-0001-8026-2251], Hiemstra, Pieter S. [0000-0002-0238-5982], Hysi, Pirro [0000-0001-5752-2510], Koskela, Jukka T. [0000-0002-0154-7222], Jin, Jianping [0000-0002-3774-1609], Sikdar, Sinjini [0000-0003-1230-5162], Lee, Mikyeong [0000-0002-3036-3684], May-Wilson, Sebastian [0000-0003-2668-5717], Joshi, Peter K. [0000-0002-6361-5059], Timmers, Paul R. H. J. [0000-0002-5197-1267], Gilliland, Frank D. [0000-0002-9033-7269], Wang, Carol A. [0000-0002-4301-3974], Harris, Sarah E. [0000-0002-4941-5106], Mahajan, Anubha [0000-0001-5585-3420], Palviainen, Teemu [0000-0002-7847-8384], Kaprio, Jaakko [0000-0002-3716-2455], Pietiläinen, Kirsi H. [0000-0002-8522-1288], Cox, Simon R. [0000-0003-4036-3642], Pennell, Craig E. [0000-0002-0937-6165], Wilson, James F. [0000-0001-5751-9178], Vasankari, Tuula [0000-0002-1413-8970], Salomaa, Veikko [0000-0001-7563-5324], Timpson, Nicholas J. [0000-0002-7141-9189], Dupuis, Josée [0000-0003-2871-3603], Brumpton, Ben [0000-0002-3058-1059], Langenberg, Claudia [0000-0002-5017-7344], Weiss, Stefan [0000-0002-3553-4315], Homuth, Georg [0000-0001-6839-0605], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Morrison, Alanna C. [0000-0001-6381-4296], Rudan, Igor [0000-0001-6993-6884], Lee, Joo-Hyeon [0000-0002-7364-6422], Sayers, Ian [0000-0001-5601-5410], Rawlins, Emma L. [0000-0001-7426-3792], Dudbridge, Frank [0000-0002-8817-8908], Strachan, David P. [0000-0001-7854-1366], Walters, Robin G. [0000-0002-9179-0321], Morris, Andrew P. [0000-0002-6805-6014], London, Stephanie J. [0000-0003-4911-5290], Cho, Michael H. [0000-0002-4907-1657], Wain, Louise V. [0000-0003-4951-1867], Hall, Ian P. [0000-0001-9933-3216], Tobin, Martin D. [0000-0002-3596-7874], Apollo - University of Cambridge Repository, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of General Administration, Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Uitterlinden, Andre G [0000-0002-7276-3387], Oelsner, Elizabeth C [0000-0002-7481-9671], Rich, Stephen S [0000-0003-3872-7793], Kerr, Shona M [0000-0002-4137-1495], Gharib, Sina A [0000-0002-2480-4367], Luan, Jian'an [0000-0003-3137-6337], Smith, Blair H [0000-0002-5362-9430], Albagha, Omar ME [0000-0001-5916-5983], Faquih, Tariq O [0000-0001-8026-2251], Hiemstra, Pieter S [0000-0002-0238-5982], Koskela, Jukka T [0000-0002-0154-7222], Joshi, Peter K [0000-0002-6361-5059], Timmers, Paul RHJ [0000-0002-5197-1267], Gilliland, Frank D [0000-0002-9033-7269], Wang, Carol A [0000-0002-4301-3974], Harris, Sarah E [0000-0002-4941-5106], Pietiläinen, Kirsi H [0000-0002-8522-1288], Cox, Simon R [0000-0003-4036-3642], Pennell, Craig E [0000-0002-0937-6165], Wilson, James F [0000-0001-5751-9178], Timpson, Nicholas J [0000-0002-7141-9189], Morrison, Alanna C [0000-0001-6381-4296], Rawlins, Emma L [0000-0001-7426-3792], Strachan, David P [0000-0001-7854-1366], Walters, Robin G [0000-0002-9179-0321], Morris, Andrew P [0000-0002-6805-6014], London, Stephanie J [0000-0003-4911-5290], Cho, Michael H [0000-0002-4907-1657], Wain, Louise V [0000-0003-4951-1867], Hall, Ian P [0000-0001-9933-3216], Tobin, Martin D [0000-0002-3596-7874], Epidemiology, and Internal Medicine

Subjects
Smoking, 631/208/205/2138, 45/43, article, 692/699/1785, Polymorphism, Single Nucleotide, 3142 Public health care science, environmental and occupational health, Pulmonary Disease, Chronic Obstructive, Genetics, Humans, 1182 Biochemistry, cell and molecular biology, Genetic Predisposition to Disease, Lung, Genome-Wide Association Study
Abstract

Funder: British Lung Foundation, Funder: National Institute for Health Research (NIHR), Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Published
2023

2. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G, Chen, Jing, Packer, Richard, Hall, Robert J, Guyatt, Anna L, Batini, Chiara, Thompson, Rebecca J, Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D, Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A, John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y, Chen, Zhengming, Li, Liming, Wijnant, Sara RA, Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G, Manichaikul, Ani, Oelsner, Elizabeth C, Rich, Stephen S, Barr, R Graham, Kerr, Shona M, Vitart, Veronique, Brown, Michael R, Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M, Gharib, Sina A, Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E, Meyers, Deborah A, Bleecker, Eugene R, Gabriel, Stacey B, Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F, Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H, Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L, Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T, Thareja, Gaurav, Albagha, Omar ME, Ismail, Said I, Al-Muftah, Wadha, Badji, Radja, Mbarek, Hamdi, Darwish, Dima, Fadl, Tasnim, Yasin, Heba, Ennaifar, Maryem, Abdellatif, Rania, Alkuwari, Fatima, Alvi, Muhammad, Al-Sarraj, Yasser, Saad, Chadi, Althani, Asmaa, Fethnou, Eleni, Qafoud, Fatima, Alkhayat, Eiman, Afifi, Nahla, Tomei, Sara, Liu, Wei, Lorenz, Stephan, Syed, Najeeb, Almabrazi, Hakeem, Vempalli, Fazulur Rehaman, Temanni, Ramzi, Saqri, Tariq Abu, Khatib, Mohammedhusen, Hamza, Mehshad, Zaid, Tariq Abu, El Khouly, Ahmed, Pathare, Tushar, Poolat, Shafeeq, Al-Ali, Rashid, Al-Khodor, Souhaila, Alshafai, Mashael, Badii, Ramin, Chouchane, Lotfi, Estivill, Xavier, Fakhro, Khalid, Mokrab, Younes, Puthen, Jithesh V, Tatari, Zohreh, Suhre, Karsten, Granell, Raquel, Faquih, Tariq O, Hiemstra, Pieter S, Slats, Annelies M, Mullin, Benjamin H, Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T, Wyss, Annah B, Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A, Joshi, Peter K, Timmers, Paul RHJ, Williams, Alexander T, Free, Robert C, Wang, Xueyang, Morrison, John L, Gilliland, Frank D, Chen, Zhanghua, Wang, Carol A, Foong, Rachel E, Harris, Sarah E, Taylor, Adele, Redmond, Paul, Cook, James P, Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T, Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H, Cox, Simon R, Pennell, Craig E, Hall, Graham L, Gauderman, W James, Brightling, Chris, Wilson, James F, Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O, Timpson, Nicholas J, Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C, Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L, Dudbridge, Frank, Silverman, Edwin K, Strachan, David P, Walters, Robin G, Morris, Andrew P, London, Stephanie J, Cho, Michael H, Wain, Louise V, Hall, Ian P, Tobin, Martin D, Shrine, Nick [0000-0003-3641-4371], Chen, Jing [0000-0003-1287-1930], Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Kim, Wonji [0000-0002-1249-797X], Coley, Kayesha [0000-0003-4951-6799], Chen, Zhengming [0000-0001-6423-105X], Li, Liming [0000-0001-5873-7089], Lahousse, Lies [0000-0002-3494-4363], Uitterlinden, Andre G [0000-0002-7276-3387], Oelsner, Elizabeth C [0000-0002-7481-9671], Rich, Stephen S [0000-0003-3872-7793], Kerr, Shona M [0000-0002-4137-1495], Vitart, Veronique [0000-0002-4991-3797], Jeong, Ayoung [0000-0003-1542-0756], Gharib, Sina A [0000-0002-2480-4367], Gieger, Christian [0000-0001-6986-9554], Peters, Annette [0000-0001-6645-0985], Hu, Xiaowei [0000-0001-7804-7392], Smith, Albert Vernon [0000-0003-1942-5845], Luan, Jian’an [0000-0003-3137-6337], Langhammer, Arnulf [0000-0001-5296-6673], Willer, Cristen [0000-0001-5645-4966], Porteous, David [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Campbell, Archie [0000-0003-0198-5078], Sofer, Tamar [0000-0001-8520-8860], Lee, Jiwon [0000-0002-4079-7494], Lim, Elise [0000-0001-8967-8464], Thareja, Gaurav [0000-0003-2277-6400], Albagha, Omar ME [0000-0001-5916-5983], Suhre, Karsten [0000-0001-9638-3912], Granell, Raquel [0000-0002-4890-4012], Faquih, Tariq O [0000-0001-8026-2251], Hiemstra, Pieter S [0000-0002-0238-5982], Hysi, Pirro [0000-0001-5752-2510], Koskela, Jukka T [0000-0002-0154-7222], Jin, Jianping [0000-0002-3774-1609], Sikdar, Sinjini [0000-0003-1230-5162], Lee, Mikyeong [0000-0002-3036-3684], May-Wilson, Sebastian [0000-0003-2668-5717], Joshi, Peter K [0000-0002-6361-5059], Timmers, Paul RHJ [0000-0002-5197-1267], Gilliland, Frank D [0000-0002-9033-7269], Wang, Carol A [0000-0002-4301-3974], Harris, Sarah E [0000-0002-4941-5106], Mahajan, Anubha [0000-0001-5585-3420], Palviainen, Teemu [0000-0002-7847-8384], Kaprio, Jaakko [0000-0002-3716-2455], Pietiläinen, Kirsi H [0000-0002-8522-1288], Cox, Simon R [0000-0003-4036-3642], Pennell, Craig E [0000-0002-0937-6165], Wilson, James F [0000-0001-5751-9178], Vasankari, Tuula [0000-0002-1413-8970], Salomaa, Veikko [0000-0001-7563-5324], Timpson, Nicholas J [0000-0002-7141-9189], Dupuis, Josée [0000-0003-2871-3603], Brumpton, Ben [0000-0002-3058-1059], Langenberg, Claudia [0000-0002-5017-7344], Weiss, Stefan [0000-0002-3553-4315], Homuth, Georg [0000-0001-6839-0605], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Morrison, Alanna C [0000-0001-6381-4296], Rudan, Igor [0000-0001-6993-6884], Lee, Joo-Hyeon [0000-0002-7364-6422], Sayers, Ian [0000-0001-5601-5410], Rawlins, Emma L [0000-0001-7426-3792], Dudbridge, Frank [0000-0002-8817-8908], Strachan, David P [0000-0001-7854-1366], Walters, Robin G [0000-0002-9179-0321], Morris, Andrew P [0000-0002-6805-6014], London, Stephanie J [0000-0003-4911-5290], Cho, Michael H [0000-0002-4907-1657], Wain, Louise V [0000-0003-4951-1867], Hall, Ian P [0000-0001-9933-3216], Tobin, Martin D [0000-0002-3596-7874], and Apollo - University of Cambridge Repository

Subjects
hengityselimet, genome-wide association studies, perimä, 631/208/205/2138, 45/43, article, keuhkosairaudet, hengityselinten taudit, riskitekijät, 692/699/1785, keuhkot, perinnöllisyys, respiratory tract diseases
Abstract

Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Published
2023

3. Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses

Author

Adam S. Butterworth, Scott C. Ritchie, Nilesh J. Samani, Steven Bell, Stephen Kaptoge, Matthew Arnold, Michael Inouye, Qi Guo, Frank Dudbridge, Christopher P. Nelson, Lisa Pennells, Emanuele Di Angelantonio, John R. Thompson, Angela M. Wood, Eleni Sofianopoulou, John Danesh, David Stevens, Stephen Burgess, Gad Abraham, Luanluan Sun, Thomas A. W. Bolton, Pennells, Lisa [0000-0002-8594-3061], Nelson, Christopher P. [0000-0001-8025-2897], Ritchie, Scott C. [0000-0002-8454-9548], Arnold, Matthew [0000-0001-6339-1115], Bell, Steven [0000-0001-6774-3149], Burgess, Stephen [0000-0001-5365-8760], Dudbridge, Frank [0000-0002-8817-8908], Stevens, David [0000-0001-8874-7122], Thompson, John R. [0000-0003-4819-1611], Wood, Angela [0000-0002-7937-304X], Samani, Nilesh J. [0000-0002-3286-8133], Inouye, Michael [0000-0001-9413-6520], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Nelson, Christopher P [0000-0001-8025-2897], Ritchie, Scott C [0000-0002-8454-9548], Thompson, John R [0000-0003-4819-1611], and Samani, Nilesh J [0000-0002-3286-8133]

Subjects
Male, Epidemiology, 030204 cardiovascular system & hematology, Cardiovascular Medicine, Biochemistry, Vascular Medicine, Cohort Studies, Welsh, 0302 clinical medicine, Medical Conditions, Endocrinology, Agency (sociology), Coronary Heart Disease, 030212 general & internal medicine, Incidence, General Medicine, Middle Aged, Medical research, C-Reactive Proteins, Lipids, Social research, Stroke, Cholesterol, Neurology, Cardiovascular Diseases, language, Medicine, Female, Cohort study, Research Article, Adult, medicine.medical_specialty, Endocrine Disorders, Cerebrovascular Diseases, Cardiology, Library science, Risk Assessment, 03 medical and health sciences, Political science, medicine, Diabetes Mellitus, Humans, Ischemic Stroke, Aged, Medicine and health sciences, Government, Biology and life sciences, Public health, Proteins, Cardiovascular Disease Risk, language.human_language, United Kingdom, Heart Disease Risk Factors, Medical Risk Factors, Metabolic Disorders, Polygenic risk score, Biomarkers
Abstract

Background Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD. Methods and findings Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703–0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009–0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40–75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to, Luanluan Sun and colleagues investigate whether adding polygenic risk scores to conventional risk factors of cardiovascular disease helps predict disease risk., Author summary Why was this study done? Application of polygenic risk scores (PRSs) has opened opportunities to enhance risk stratification and prevention for common diseases. The clinical utility of PRSs in cardiovascular disease (CVD) risk prediction is, however, uncertain. Previous analyses have generally focused only on coronary heart disease (CHD) rather than the composite outcome of CHD and stroke, and have often lacked modelling of clinical implications of initiating guideline-recommended interventions (e.g., statin therapy). What did the researchers do and find? We quantified the incremental predictive gain with PRSs on top of conventional risk factors using data on 306,654 individuals from UK Biobank. We modelled the population health implications of initiating statin therapy as recommended by current guidelines using data from 2.1 million individuals from the Clinical Practice Research Datalink. Addition of information on PRSs to a conventional risk prediction model increased the C-index (a measure of risk discrimination) and improved risk classification of cases and non-cases. We estimated that targeted assessment of PRSs among people at intermediate (i.e., 5% to

Published
2021

4. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Steinthorsdottir, Valgerdur, McGinnis, Ralph, Williams, Nicholas O., Stefansdottir, Lilja, Thorleifsson, Gudmar, Shooter, Scott, Fadista, João, Sigurdsson, Jon K., Auro, Kirsi M., Berezina, Galina, Borges, Maria-Carolina, Bumpstead, Suzannah, Bybjerg-Grauholm, Jonas, Colgiu, Irina, Dolby, Vivien A., Dudbridge, Frank, Engel, Stephanie M., Franklin, Christopher S., Frigge, Michael L., Frisbaek, Yr, Geirsson, Reynir T., Geller, Frank, Gretarsdottir, Solveig, Gudbjartsson, Daniel F., Harmon, Quaker, Hougaard, David Michael, Hegay, Tatyana, Helgadottir, Anna, Hjartardottir, Sigrun, Jääskeläinen, Tiina, Johannsdottir, Hrefna, Jonsdottir, Ingileif, Juliusdottir, Thorhildur, Kalsheker, Noor, Kasimov, Abdumadjit, Kemp, John P., Klungsøyr, Kari, Lee, Wai K., Melbye, Mads, Miedzybrodska, Zosia, Moffett, Ashley, Najmutdinova, Dilbar, Nishanova, Firuza, Olafsdottir, Thorunn, Perola, Markus, Poston, Lucilla, Prescott, Gordon, Saevarsdottir, Saedis, Salimbayeva, Damilya, Scaife, Paula Juliet, Skotte, Line, Staines-Urias, Eleonora, Stefansson, Olafur A., Sørensen, Karina Meden, Thomsen, Liv Cecilie Vestrheim, Tragante, Vinicius, Trogstad, Lill, Simpson, Nigel A. B., Aripova, Tamara, Casas, Juan P., Thorsteinsdottir, Unnur, Iversen, Ann-Charlotte, Feenstra, Bjarke, Lawlor, Deborah A., Boyd, Heather Allison, Magnus, Per, Zakhidova, Nodira, Svyatova, Gulnara, Stefansson, Kari, Laivuori, Hannele, Heinonen, Seppo, Kajantie, Eero, Kere, Juha, Kivinen, Katja, Pouta, Anneli, Morgan, Linda, Pipkin, Fiona Broughton, Walker, James J., Macphail, Sheila, Kilby, Mark, Habiba, Marwan, Williamson, Catherine, O’Shaughnessy, Kevin, O’Brien, Shaughn, Cameron, Alan, Redman, Christopher W. G., Farrall, Martin, Caulfield, Mark, Dominiczak, Anna F., Steinthorsdottir, Valgerdur [0000-0003-1846-6274], McGinnis, Ralph [0000-0003-4540-9857], Williams, Nicholas O. [0000-0003-3989-9167], Berezina, Galina [0000-0002-5442-4461], Bybjerg-Grauholm, Jonas [0000-0003-1705-4008], Dudbridge, Frank [0000-0002-8817-8908], Franklin, Christopher S. [0000-0003-3893-0759], Geller, Frank [0000-0002-9238-3269], Gudbjartsson, Daniel F. [0000-0002-5222-9857], Hougaard, David Michael [0000-0001-5928-3517], Helgadottir, Anna [0000-0002-1806-2467], Jääskeläinen, Tiina [0000-0002-1202-0936], Jonsdottir, Ingileif [0000-0001-8339-150X], Kemp, John P. [0000-0002-9105-2249], Kivinen, Katja [0000-0002-1135-7625], Melbye, Mads [0000-0001-8264-6785], Moffett, Ashley [0000-0002-8388-9073], Pipkin, Fiona Broughton [0000-0002-6209-5987], Prescott, Gordon [0000-0002-9156-2361], Saevarsdottir, Saedis [0000-0001-9392-6184], Skotte, Line [0000-0002-7398-1271], Stefansson, Olafur A. [0000-0002-9663-3018], Simpson, Nigel A. B. [0000-0002-0758-7583], Dominiczak, Anna F. [0000-0003-4913-3608], Walker, James J. [0000-0002-8922-083X], Iversen, Ann-Charlotte [0000-0001-7726-7684], Feenstra, Bjarke [0000-0003-1478-649X], Lawlor, Deborah A. [0000-0002-6793-2262], Boyd, Heather Allison [0000-0001-6849-9985], Laivuori, Hannele [0000-0003-3212-7826], Svyatova, Gulnara [0000-0001-5092-3143], Stefansson, Kari [0000-0003-1676-864X], Morgan, Linda [0000-0002-2995-4081], and Apollo - University of Cambridge Repository

Subjects
45, 692/699/75/243, 631/208/205/2138, 45/43, article, 692/699/2732
Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

Published
2020

5. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Dilbar Najmutdinova, Firuza Nishanova, Tatyana Hegay, John P. Kemp, Anna Helgadottir, Lucilla Poston, Saedis Saevarsdottir, Ralph McGinnis, Lilja Stefansdottir, Yr Frisbaek, Hrefna Johannsdottir, Olafur A. Stefansson, Thorunn A. Olafsdottir, Markus Perola, Scott Shooter, Frank Geller, Mads Melbye, Reynir Tómas Geirsson, Lill Trogstad, Thorhildur Juliusdottir, Kari Stefansson, Jonas Bybjerg-Grauholm, Eleonora Staines-Urias, Nodira Zakhidova, Daniel F. Gudbjartsson, Vinicius Tragante, João Fadista, Galina Berezina, Damilya Salimbayeva, Zosia Miedzybrodska, Katja Kivinen, James J. Walker, Kari Klungsøyr, Anna F. Dominiczak, Maria Carolina Borges, Fiona Broughton Pipkin, Nigel Simpson, Quaker E. Harmon, Per Magnus, Ashley Moffett, Tamara Aripova, Gordon Prescott, Sigrun Hjartardottir, Noor Kalsheker, Karina Meden Sørensen, Nicholas Williams, Hannele Laivuori, David M. Hougaard, Gulnara Svyatova, Debbie A Lawlor, Stephanie M. Engel, Gudmar Thorleifsson, Wai K. Lee, Paula J. Scaife, Christopher S. Franklin, Bjarke Feenstra, Irina Colgiu, Ann-Charlotte Iversen, Abdumadjit Kasimov, Jon K. Sigurdsson, Liv Cecilie Vestrheim Thomsen, Unnur Thorsteinsdottir, Line Skotte, Linda Morgan, Juan P Casas, Michael L. Frigge, Vivien A. Dolby, Frank Dudbridge, Valgerdur Steinthorsdottir, Suzannah Bumpstead, Kirsi M Auro, Ingileif Jonsdottir, Tiina Jääskeläinen, Heather A. Boyd, Solveig Gretarsdottir, Pregnancy and Genes, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki University Hospital Area, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, HUS Children and Adolescents, Lastentautien yksikkö, Clinicum, Children's Hospital, STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Tampere University, Department of Gynaecology and Obstetrics, Clinical Medicine, University of Helsinki, Research Programs Unit, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, HUS Gynecology and Obstetrics, University of Helsinki, HUS Children and Adolescents, University of Helsinki, STEMM - Stem Cells and Metabolism Research Program, Steinthorsdottir, Valgerdur [0000-0003-1846-6274], McGinnis, Ralph [0000-0003-4540-9857], Williams, Nicholas O [0000-0003-3989-9167], Berezina, Galina [0000-0002-5442-4461], Bybjerg-Grauholm, Jonas [0000-0003-1705-4008], Dudbridge, Frank [0000-0002-8817-8908], Franklin, Christopher S [0000-0003-3893-0759], Geller, Frank [0000-0002-9238-3269], Gudbjartsson, Daniel F [0000-0002-5222-9857], Hougaard, David Michael [0000-0001-5928-3517], Helgadottir, Anna [0000-0002-1806-2467], Jääskeläinen, Tiina [0000-0002-1202-0936], Jonsdottir, Ingileif [0000-0001-8339-150X], Kemp, John P [0000-0002-9105-2249], Kivinen, Katja [0000-0002-1135-7625], Melbye, Mads [0000-0001-8264-6785], Moffett, Ashley [0000-0002-8388-9073], Pipkin, Fiona Broughton [0000-0002-6209-5987], Prescott, Gordon [0000-0002-9156-2361], Saevarsdottir, Saedis [0000-0001-9392-6184], Skotte, Line [0000-0002-7398-1271], Stefansson, Olafur A [0000-0002-9663-3018], Simpson, Nigel AB [0000-0002-0758-7583], Dominiczak, Anna F [0000-0003-4913-3608], Walker, James J [0000-0002-8922-083X], Iversen, Ann-Charlotte [0000-0001-7726-7684], Feenstra, Bjarke [0000-0003-1478-649X], Lawlor, Deborah A [0000-0002-6793-2262], Boyd, Heather Allison [0000-0001-6849-9985], Laivuori, Hannele [0000-0003-3212-7826], Svyatova, Gulnara [0000-0001-5092-3143], Stefansson, Kari [0000-0003-1676-864X], Morgan, Linda [0000-0002-2995-4081], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Gestational hypertension, Multifactorial Inheritance, Reproductive disorders, A990, Datasets as Topic, General Physics and Astronomy, Blood Pressure, Genome-wide association study, VARIANTS, Genome-wide association studies, 0302 clinical medicine, Pre-Eclampsia, 3123 Gynaecology and paediatrics, Medicine, Prospective Studies, 030212 general & internal medicine, reproductive and urinary physiology, 2. Zero hunger, RISK, Multidisciplinary, biology, Obstetrics, Middle Aged, MEDICAL BIRTH REGISTRY, female genital diseases and pregnancy complications, 3. Good health, Europe, PREGNANCY, CARDIOVASCULAR-DISEASE, Hypertension, embryonic structures, Asia, Central, Female, Adult, medicine.medical_specialty, Fibroblast Growth Factor 5, Science, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Article, General Biochemistry, Genetics and Molecular Biology, Preeclampsia, 03 medical and health sciences, Fibroblast growth factor-5, Genetic predisposition, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, FETAL, METAANALYSIS, Adaptor Proteins, Signal Transducing, Aged, Pregnancy, business.industry, Case-control study, Hypertension, Pregnancy-Induced, General Chemistry, medicine.disease, MDS1 and EVI1 Complex Locus Protein, BODY-MASS INDEX, 030104 developmental biology, Genetic Loci, Case-Control Studies, COHORT PROFILE, biology.gene, business, Body mass index, Genome-Wide Association Study
Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia., Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020

6. A flexible and parallelizable approach to genome-wide polygenic risk scores

Author

Christopher P. Nelson, Paul J. Newcombe, Frank Dudbridge, Nilesh J. Samani, Newcombe, Paul J [0000-0002-5611-6702], Dudbridge, Frank [0000-0002-8817-8908], and Apollo - University of Cambridge Repository

Subjects
Linkage disequilibrium, Multifactorial Inheritance, Epidemiology, Computer science, Inference, Coronary Artery Disease, Machine learning, computer.software_genre, Genome, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, risk prediction, Risk Factors, Computer cluster, Humans, Genetic Predisposition to Disease, summary statistics, Genetics (clinical), 030304 developmental biology, Block (data storage), Bayesian variable selection, 0303 health sciences, Parallelizable manifold, meta-GWAS, Models, Genetic, business.industry, 030305 genetics & heredity, Heritability, polygenic risk scores, Diabetes Mellitus, Type 1, ROC Curve, Area Under Curve, Case-Control Studies, Schizophrenia, Polygenic risk score, Artificial intelligence, business, computer, Genome-Wide Association Study
Abstract

The heritability of most complex traits is driven by variants throughout the genome. Consequently, polygenic risk scores, which combine information on multiple variants genome‐wide, have demonstrated improved accuracy in genetic risk prediction. We present a new two‐step approach to constructing genome‐wide polygenic risk scores from meta‐GWAS summary statistics. Local linkage disequilibrium (LD) is adjusted for in Step 1, followed by, uniquely, long‐range LD in Step 2. Our algorithm is highly parallelizable since block‐wise analyses in Step 1 can be distributed across a high‐performance computing cluster, and flexible, since sparsity and heritability are estimated within each block. Inference is obtained through a formal Bayesian variable selection framework, meaning final risk predictions are averaged over competing models. We compared our method to two alternative approaches: LDPred and lassosum using all seven traits in the Welcome Trust Case Control Consortium as well as meta‐GWAS summaries for type 1 diabetes (T1D), coronary artery disease, and schizophrenia. Performance was generally similar across methods, although our framework provided more accurate predictions for T1D, for which there are multiple heterogeneous signals in regions of both short‐ and long‐range LD. With sufficient compute resources, our method also allows the fastest runtimes.

Published
2019

7. Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention

Author

Inouye, Michael, Abraham, Gad, Nelson, Christopher, Wood, Angela, Sweeting, Michael, Dudbridge, Frank, Lai, Florence, Kaptoge, Stephen, Brozynska, Marta, Wang, Tingting, Ye, Shu, Webb, Thomas, Rutter, Martin, Tzoulaki, Ioanna, Patel, Riyaz, Loos, Ruth JF, Keavney, Bernard, Hemingway, Harry, Thompson, John, Watkins, Hugh, Deloukas, Panos, Angelantonio, Emanuele Di, Butterworth, Adam, Danesh, John, Samani, Nilesh, for The UK Biobank CardioMetabolic Consortium CHD Working Group, Inouye, Michael [0000-0001-9413-6520], Nelson, Christopher [0000-0001-8025-2897], Sweeting, Michael [0000-0003-0980-8965], Dudbridge, Frank [0000-0002-8817-8908], Rutter, Martin [0000-0001-6380-539X], Hemingway, Harry [0000-0003-2279-0624], Samani, Nilesh [0000-0002-3286-8133], and Apollo - University of Cambridge Repository

Subjects
for The UK Biobank CardioMetabolic Consortium CHD Working Group
Abstract

Background Coronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention. Methods Using a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank. Findings In UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution. Interpretation Recent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification. Funding National Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.

Published
2018

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