Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved]
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...
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| Language: | English |
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Wellcome
2021-05-01
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| Series: | Wellcome Open Research |
| Online Access: | https://wellcomeopenresearch.org/articles/5-111/v2 |
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| language |
English |
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Article |
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DOAJ |
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Katherine A. Fawcett Ma'en Obeidat Carl Melbourne Nick Shrine Anna L. Guyatt Catherine John Jian'an Luan Anne Richmond Marta R. Moksnes Raquel Granell Stefan Weiss Medea Imboden Sebastian May-Wilson Pirro Hysi Thibaud S. Boutin Laura Portas Claudia Flexeder Sarah E. Harris Carol A. Wang Leo-Pekka Lyytikäinen Teemu Palviainen Rachel E. Foong Dirk Keidel Cosetta Minelli Claudia Langenberg Yohan Bossé Maarten Van den Berge Don D. Sin Ke Hao Archie Campbell David Porteous Sandosh Padmanabhan Blair H. Smith David M. Evans Sue Ring Arnulf Langhammer Kristian Hveem Cristen Willer Ralf Ewert Beate Stubbe Nicola Pirastu Lucija Klaric Peter K. Joshi Karina Patasova Mangino Massimo Ozren Polasek John M. Starr Stefan Karrasch Konstantin Strauch Thomas Meitinger Igor Rudan Taina Rantanen Kirsi Pietiläinen Mika Kähönen Olli T. Raitakari Graham L. Hall Peter D. Sly Craig E. Pennell Jaakko Kaprio Terho Lehtimäki Veronique Vitart Ian J. Deary Debbie Jarvis James F. Wilson Tim Spector Nicole Probst-Hensch Nicholas J. Wareham Henry Völzke John Henderson David P. Strachan Ben M. Brumpton Caroline Hayward Ian P. Hall Martin D. Tobin Louise V. Wain |
| spellingShingle |
Katherine A. Fawcett Ma'en Obeidat Carl Melbourne Nick Shrine Anna L. Guyatt Catherine John Jian'an Luan Anne Richmond Marta R. Moksnes Raquel Granell Stefan Weiss Medea Imboden Sebastian May-Wilson Pirro Hysi Thibaud S. Boutin Laura Portas Claudia Flexeder Sarah E. Harris Carol A. Wang Leo-Pekka Lyytikäinen Teemu Palviainen Rachel E. Foong Dirk Keidel Cosetta Minelli Claudia Langenberg Yohan Bossé Maarten Van den Berge Don D. Sin Ke Hao Archie Campbell David Porteous Sandosh Padmanabhan Blair H. Smith David M. Evans Sue Ring Arnulf Langhammer Kristian Hveem Cristen Willer Ralf Ewert Beate Stubbe Nicola Pirastu Lucija Klaric Peter K. Joshi Karina Patasova Mangino Massimo Ozren Polasek John M. Starr Stefan Karrasch Konstantin Strauch Thomas Meitinger Igor Rudan Taina Rantanen Kirsi Pietiläinen Mika Kähönen Olli T. Raitakari Graham L. Hall Peter D. Sly Craig E. Pennell Jaakko Kaprio Terho Lehtimäki Veronique Vitart Ian J. Deary Debbie Jarvis James F. Wilson Tim Spector Nicole Probst-Hensch Nicholas J. Wareham Henry Völzke John Henderson David P. Strachan Ben M. Brumpton Caroline Hayward Ian P. Hall Martin D. Tobin Louise V. Wain Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved] Wellcome Open Research |
| author_facet |
Katherine A. Fawcett Ma'en Obeidat Carl Melbourne Nick Shrine Anna L. Guyatt Catherine John Jian'an Luan Anne Richmond Marta R. Moksnes Raquel Granell Stefan Weiss Medea Imboden Sebastian May-Wilson Pirro Hysi Thibaud S. Boutin Laura Portas Claudia Flexeder Sarah E. Harris Carol A. Wang Leo-Pekka Lyytikäinen Teemu Palviainen Rachel E. Foong Dirk Keidel Cosetta Minelli Claudia Langenberg Yohan Bossé Maarten Van den Berge Don D. Sin Ke Hao Archie Campbell David Porteous Sandosh Padmanabhan Blair H. Smith David M. Evans Sue Ring Arnulf Langhammer Kristian Hveem Cristen Willer Ralf Ewert Beate Stubbe Nicola Pirastu Lucija Klaric Peter K. Joshi Karina Patasova Mangino Massimo Ozren Polasek John M. Starr Stefan Karrasch Konstantin Strauch Thomas Meitinger Igor Rudan Taina Rantanen Kirsi Pietiläinen Mika Kähönen Olli T. Raitakari Graham L. Hall Peter D. Sly Craig E. Pennell Jaakko Kaprio Terho Lehtimäki Veronique Vitart Ian J. Deary Debbie Jarvis James F. Wilson Tim Spector Nicole Probst-Hensch Nicholas J. Wareham Henry Völzke John Henderson David P. Strachan Ben M. Brumpton Caroline Hayward Ian P. Hall Martin D. Tobin Louise V. Wain |
| author_sort |
Katherine A. Fawcett |
| title |
Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved] |
| title_short |
Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved] |
| title_full |
Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved] |
| title_fullStr |
Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved] |
| title_full_unstemmed |
Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved] |
| title_sort |
variants associated with hhip expression have sex-differential effects on lung function [version 2; peer review: 2 approved] |
| publisher |
Wellcome |
| series |
Wellcome Open Research |
| issn |
2398-502X |
| publishDate |
2021-05-01 |
| description |
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<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). 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. |
| url |
https://wellcomeopenresearch.org/articles/5-111/v2 |
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doaj-4b05913ad06e4e1882f53a780230d2ab2021-06-02T10:59:44ZengWellcomeWellcome Open Research2398-502X2021-05-01510.12688/wellcomeopenres.15846.218678Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved]Katherine A. Fawcett0Ma'en Obeidat1Carl Melbourne2Nick Shrine3Anna L. Guyatt4Catherine John5Jian'an Luan6Anne Richmond7Marta R. Moksnes8Raquel Granell9Stefan Weiss10Medea Imboden11Sebastian May-Wilson12Pirro Hysi13Thibaud S. Boutin14Laura Portas15Claudia Flexeder16Sarah E. Harris17Carol A. Wang18Leo-Pekka Lyytikäinen19Teemu Palviainen20Rachel E. Foong21Dirk Keidel22Cosetta Minelli23Claudia Langenberg24Yohan Bossé25Maarten Van den Berge26Don D. Sin27Ke Hao28Archie Campbell29David Porteous30Sandosh Padmanabhan31Blair H. Smith32David M. Evans33Sue Ring34Arnulf Langhammer35Kristian Hveem36Cristen Willer37Ralf Ewert38Beate Stubbe39Nicola Pirastu40Lucija Klaric41Peter K. Joshi42Karina Patasova43Mangino Massimo44Ozren Polasek45John M. Starr46Stefan Karrasch47Konstantin Strauch48Thomas Meitinger49Igor Rudan50Taina Rantanen51Kirsi Pietiläinen52Mika Kähönen53Olli T. Raitakari54Graham L. Hall55Peter D. Sly56Craig E. Pennell57Jaakko Kaprio58Terho Lehtimäki59Veronique Vitart60Ian J. Deary61Debbie Jarvis62James F. Wilson63Tim Spector64Nicole Probst-Hensch65Nicholas J. Wareham66Henry Völzke67John Henderson68David P. Strachan69Ben M. Brumpton70Caroline Hayward71Ian P. Hall72Martin D. Tobin73Louise V. Wain74Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UKThe University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, CanadaDepartment of Health Sciences, University of Leicester, Leicester, LE1 7RH, UKDepartment of Health Sciences, University of Leicester, Leicester, LE1 7RH, UKDepartment of Health Sciences, University of Leicester, Leicester, LE1 7RH, UKDepartment of Health Sciences, University of Leicester, Leicester, LE1 7RH, UKMRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UKK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, NorwayMedical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UKDepartment of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, GermanySwiss Tropical and Public Health Institute, Basel, SwitzerlandCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UKThe Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UKPopulation Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UKInstitute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, GermanyCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UKSchool of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Callaghan, AustraliaDepartment of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, FinlandInstitute for Molecular Medicine FIMM, University of Helsinki, Helsinki, FI-00014, FinlandSchool of Physiotherapy and Exercise Science, Faculty of Health Sciences, Curtin University, Perth, AustraliaSwiss Tropical and Public Health Institute, Basel, SwitzerlandPopulation Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UKMRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UKInstitut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, CanadaUniversity Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, The NetherlandsThe University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, CanadaDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USACentre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UKCentre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UKBritish Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UKDivision of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UKMedical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UKMedical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UKDepartment of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, NorwayK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, NorwayDepartment of Human Genetics, University of Michigan, Ann Arbor, USADepartment of Internal Medicine B, Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, Greifswald, 17475, GermanyDepartment of Internal Medicine B, Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, Greifswald, 17475, GermanyCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UKCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UKThe Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UKThe Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UKUniversity of Split School of Medicine, Split, CroatiaCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UKComprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, 81377, GermanyChair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, 81377, GermanyInstitute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, GermanyCentre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UKFaculty of Sport and Health Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, FinlandObesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, FI-00014, FinlandDepartment of Clinical Physiology, Tampere University Hospital, Tampere, 33521, FinlandDepartment of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, FinlandTelethon Kids Institute, Perth, AustraliaChildren's Health and Environment Program, The University of Queensland, Brisbane, AustraliaSchool of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Callaghan, AustraliaInstitute for Molecular Medicine FIMM, University of Helsinki, Helsinki, FI-00014, FinlandDepartment of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, FinlandMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UKCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UKMRC-PHE Centre for the Environment and Health, London, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UKThe Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UKSwiss Tropical and Public Health Institute, Basel, SwitzerlandMRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UKIntitute for Community Medicine, University Medicine Greifswald, Greifswald, 17487, GermanyPopulation Health Sciences Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UKPopulation Health Research Institute, St George's, University of London, London, SW17 0RE, UKMRC Integrative Epidemiology Unit, University of Bristol, Bristol, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UKDivision of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UKDepartment of Health Sciences, University of Leicester, Leicester, LE1 7RH, UKNational Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UKBackground: 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<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). 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.https://wellcomeopenresearch.org/articles/5-111/v2 |