Wellcome Open Research (May 2021)
Variants associated with HHIP expression have sex-differential effects on lung function [version 2; peer review: 2 approved]
- 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
Affiliations
- Katherine A. Fawcett
- Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
- Ma'en Obeidat
- The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada
- Carl Melbourne
- Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
- Nick Shrine
- Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
- Anna L. Guyatt
- Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
- Catherine John
- Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
- Jian'an Luan
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK
- Anne Richmond
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
- Marta R. Moksnes
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Raquel Granell
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK
- Stefan Weiss
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany
- Medea Imboden
- Swiss Tropical and Public Health Institute, Basel, Switzerland
- Sebastian May-Wilson
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK
- Pirro Hysi
- The Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UK
- Thibaud S. Boutin
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
- Laura Portas
- Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK
- Claudia Flexeder
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany
- Sarah E. Harris
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Carol A. Wang
- School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Callaghan, Australia
- Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland
- Teemu Palviainen
- Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, FI-00014, Finland
- Rachel E. Foong
- School of Physiotherapy and Exercise Science, Faculty of Health Sciences, Curtin University, Perth, Australia
- Dirk Keidel
- Swiss Tropical and Public Health Institute, Basel, Switzerland
- Cosetta Minelli
- Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK
- Claudia Langenberg
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK
- Yohan Bossé
- Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada
- Maarten Van den Berge
- University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands
- Don D. Sin
- The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada
- Ke Hao
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
- Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK
- David Porteous
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK
- Sandosh Padmanabhan
- British 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, UK
- Blair H. Smith
- Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK
- David M. Evans
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK
- Sue Ring
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK
- Arnulf Langhammer
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Cristen Willer
- Department of Human Genetics, University of Michigan, Ann Arbor, USA
- Ralf Ewert
- Department of Internal Medicine B, Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, Greifswald, 17475, Germany
- Beate Stubbe
- Department of Internal Medicine B, Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, Greifswald, 17475, Germany
- Nicola Pirastu
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK
- Lucija Klaric
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
- Peter K. Joshi
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK
- Karina Patasova
- The Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UK
- Mangino Massimo
- The Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UK
- Ozren Polasek
- University of Split School of Medicine, Split, Croatia
- John M. Starr
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Stefan Karrasch
- Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, 81377, Germany
- Konstantin Strauch
- Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, 81377, Germany
- Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany
- Igor Rudan
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK
- Taina Rantanen
- Faculty of Sport and Health Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
- Kirsi Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, FI-00014, Finland
- Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland
- Olli T. Raitakari
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
- Graham L. Hall
- Telethon Kids Institute, Perth, Australia
- Peter D. Sly
- Children's Health and Environment Program, The University of Queensland, Brisbane, Australia
- Craig E. Pennell
- School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Callaghan, Australia
- Jaakko Kaprio
- Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, FI-00014, Finland
- Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland
- Veronique Vitart
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
- Ian J. Deary
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Debbie Jarvis
- MRC-PHE Centre for the Environment and Health, London, UK
- James F. Wilson
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
- Tim Spector
- The Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Campus, Lambeth Palace Road, London, UK
- Nicole Probst-Hensch
- Swiss Tropical and Public Health Institute, Basel, Switzerland
- Nicholas J. Wareham
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK
- Henry Völzke
- Intitute for Community Medicine, University Medicine Greifswald, Greifswald, 17487, Germany
- John Henderson
- Population Health Sciences Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK
- David P. Strachan
- Population Health Research Institute, St George's, University of London, London, SW17 0RE, UK
- Ben M. Brumpton
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
- Ian P. Hall
- Division of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- Martin D. Tobin
- Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
- Louise V. Wain
- National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK
- DOI
- https://doi.org/10.12688/wellcomeopenres.15846.2
- Journal volume & issue
-
Vol. 5
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<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.
