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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. Variants associated with HHIP expression have sex-differential effects on lung function

Author

Carl A. Melbourne, Caroline Hayward, Stefan Karrasch, Dirk Keidel, Katherine A. Fawcett, Susan M. Ring, Yohan Bossé, Carol A. Wang, Ben Michael Brumpton, Claudia Langenberg, Peter K. Joshi, Ke Hao, Igor Rudan, David J. Porteous, Don D. Sin, Raquel Granell, Blair H. Smith, Jian'an Luan, Kristian Hveem, Sarah E. Harris, Sandosh Padmanabhan, Archie Campbell, Sebastian May-Wilson, Veronique Vitart, Nicola Pirastu, Arnulf Langhammer, Craig E. Pennell, John M. Starr, Stefan Weiss, Karina Patasova, Nicholas J. Wareham, James F. Wilson, Deborah Jarvis, Tim D. Spector, Nick Shrine, David P. Strachan, Martin D. Tobin, Beate Stubbe, David M. Evans, Kirsi H. Pietiläinen, Mangino Massimo, Ian P. Hall, Graham L. Hall, Jaakko Kaprio, Ralf Ewert, Rachel E. Foong, Claudia Flexeder, Louise V. Wain, Ma'en Obeidat, Cristen J. Willer, Leo-Pekka Lyytikäinen, Olli T. Raitakari, John Henderson, Konstantin Strauch, Marta R Moksnes, Cosetta Minelli, Nicole Probst-Hensch, Pirro G. Hysi, Anna L. Guyatt, Henry Völzke, Thomas Meitinger, Peter D. Sly, Ozren Polasek, Anne Richmond, Mika Kähönen, Maarten van den Berge, Medea Imboden, Thibaud Boutin, Lucija Klaric, Laura Portas, Terho Lehtimäki, Ian J. Deary, Taina Rantanen, Catherine John, Teemu Palviainen, Fawcett, Katherine A [0000-0002-6675-2112], Obeidat, Ma'en [0000-0002-5443-2752], Shrine, Nick [0000-0003-3641-4371], Weiss, Stefan [0000-0002-3553-4315], May-Wilson, Sebastian [0000-0003-2668-5717], Boutin, Thibaud S [0000-0003-4754-1675], Portas, Laura [0000-0003-1789-1893], Harris, Sarah E [0000-0002-4941-5106], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Palviainen, Teemu [0000-0002-7847-8384], Keidel, Dirk [0000-0003-4706-5728], Minelli, Cosetta [0000-0001-9166-3958], Langenberg, Claudia [0000-0002-5017-7344], Bossé, Yohan [0000-0002-3067-3711], Van den Berge, Maarten [0000-0002-9336-7340], Sin, Don D [0000-0002-0756-6643], Campbell, Archie [0000-0003-0198-5078], Porteous, David [0000-0003-1249-6106], Padmanabhan, Sandosh [0000-0003-3869-5808], Smith, Blair H [0000-0002-5362-9430], Ring, Sue [0000-0003-3103-9330], Rantanen, Taina [0000-0002-1604-1945], Pennell, Craig E [0000-0002-0937-6165], Kaprio, Jaakko [0000-0002-3716-2455], Vitart, Veronique [0000-0002-4991-3797], Hayward, Caroline [0000-0002-9405-9550], Hall, Ian P [0000-0001-9933-3216], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Groningen Research Institute for Asthma and COPD (GRIAC), Technology Centre, University of Helsinki, Institute for Molecular Medicine Finland, Genetic Epidemiology, HUS Abdominal Center, Department of Medicine, Clinicum, CAMM - Research Program for Clinical and Molecular Metabolism, Department of Public Health, Research Programs Unit, Tampere University, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, and Department of Clinical Physiology and Nuclear Medicine

Subjects
0301 basic medicine, Spirometry, medicine.medical_specialty, HHIP, Medicine (miscellaneous), Expression, Genome-wide Interaction Study, Hhip, Lung Function, Sex, Single-nucleotide polymorphism, Biology, 3121 Internal medicine, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Genome-wide interaction study, Lung function, Internal medicine, expression, medicine, sex, Allele, Enhancer, Gene, Lung, genome-wide interaction study, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, lung function, ALSPAC, Differential effects, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030228 respiratory system, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine
Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P-8) interactions with sex on lung function, and 21 showed suggestive interactions (P-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

Published
2021

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