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

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

doi:10.12688/wellcomeopenres.15846.2

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

Wellcome Open Res. 2021 May 24:5:111. doi: 10.12688/wellcomeopenres.15846.2. eCollection 2020.

Authors

Katherine A Fawcett¹, Ma'en Obeidat², Carl Melbourne¹, Nick Shrine¹, Anna L Guyatt¹, Catherine John¹, Jian'an Luan³, Anne Richmond⁴, Marta R Moksnes⁵, Raquel Granell⁶, Stefan Weiss⁷, Medea Imboden^{8

9}, Sebastian May-Wilson¹⁰, Pirro Hysi¹¹, Thibaud S Boutin⁴, Laura Portas¹², Claudia Flexeder¹³, Sarah E Harris^{14

15}, Carol A Wang¹⁶, Leo-Pekka Lyytikäinen^{17

18

19}, Teemu Palviainen²⁰, Rachel E Foong^{21

22}, Dirk Keidel^{8

9}, Cosetta Minelli¹², Claudia Langenberg³, Yohan Bossé²³, Maarten Van den Berge²⁴, Don D Sin^{2

25}, Ke Hao²⁶, Archie Campbell²⁷, David Porteous²⁷, Sandosh Padmanabhan²⁸, Blair H Smith²⁹, David M Evans^{6

30

31}, Sue Ring^{6

30}, Arnulf Langhammer³², Kristian Hveem⁵, Cristen Willer^{33

34

35}, Ralf Ewert³⁶, Beate Stubbe³⁶, Nicola Pirastu¹⁰, Lucija Klaric⁴, Peter K Joshi¹⁰, Karina Patasova¹¹, Mangino Massimo¹¹, Ozren Polasek³⁷, John M Starr^{14

38}, Stefan Karrasch^{39

13

40}, Konstantin Strauch^{41

42}, Thomas Meitinger^{43

44}, Igor Rudan¹⁰, Taina Rantanen⁴⁵, Kirsi Pietiläinen^{46

47}, Mika Kähönen^{48

49}, Olli T Raitakari^{50

51

52}, Graham L Hall^{21

22}, Peter D Sly⁵³, Craig E Pennell¹⁶, Jaakko Kaprio^{20

54}, Terho Lehtimäki^{17

18}, Veronique Vitart⁴, Ian J Deary^{14

15}, Debbie Jarvis^{12

55}, James F Wilson^{4

10}, Tim Spector¹¹, Nicole Probst-Hensch^{8

9}, Nicholas J Wareham³, Henry Völzke⁵⁶, John Henderson³⁰, David P Strachan⁵⁷, Ben M Brumpton^{5

58

59}, Caroline Hayward⁴, Ian P Hall⁶⁰, Martin D Tobin^{1

61}, Louise V Wain^{1

61}

Affiliations

¹ Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
² The University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
³ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
⁴ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
⁵ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁶ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
⁷ Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany.
⁸ Swiss Tropical and Public Health Institute, Basel, Switzerland.
⁹ University of Basel, Basel, Switzerland.
¹⁰ Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK.
¹¹ The Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Campus, Lambeth Palace Road, London, UK.
¹² Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK.
¹³ Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, 85764, Germany.
¹⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
¹⁵ Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
¹⁶ School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Callaghan, Australia.
¹⁷ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
¹⁸ Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
¹⁹ Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, 33521, Finland.
²⁰ Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, FI-00014, Finland.
²¹ Telethon Kids Institute, Perth, Australia.
²² School of Physiotherapy and Exercise Science, Faculty of Health Sciences, Curtin University, Perth, Australia.
²³ Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada.
²⁴ University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands.
²⁵ Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
²⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA.
²⁷ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.
²⁸ 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.
²⁹ Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK.
³⁰ Population Health Sciences Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
³¹ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4072, Australia.
³² Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
³³ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, USA.
³⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
³⁵ Department of Human Genetics, University of Michigan, Ann Arbor, USA.
³⁶ Department of Internal Medicine B, Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
³⁷ University of Split School of Medicine, Split, Croatia.
³⁸ Alzheimer Scotland Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
³⁹ Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, 80336, Germany.
⁴⁰ Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, 81377, Germany.
⁴¹ Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁴² Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, 81377, Germany.
⁴³ Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁴⁴ Institute of Human Genetics, Klinikum rechts der Isar der TU Muenchen, Muenchen, 81675, Germany.
⁴⁵ Faculty of Sport and Health Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland.
⁴⁶ Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, FI-00014, Finland.
⁴⁷ Obesity Centre, Abdominal Centre, Helsinki University Hospital and University of Helsinki, Helsinki, FI-00029, Finland.
⁴⁸ Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland.
⁴⁹ Department of Clinical Physiology, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
⁵⁰ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁵¹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁵² Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁵³ Children's Health and Environment Program, The University of Queensland, Brisbane, Australia.
⁵⁴ Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland.
⁵⁵ MRC-PHE Centre for the Environment and Health, London, UK.
⁵⁶ Intitute for Community Medicine, University Medicine Greifswald, Greifswald, 17487, Germany.
⁵⁷ Population Health Research Institute, St George's, University of London, London, SW17 0RE, UK.
⁵⁸ Clinic of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁵⁹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁶⁰ Division of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK.
⁶¹ National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.

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 (FEV ₁) (P=3.15x10 ^-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV ₁ more in males (untransformed FEV ₁ 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.

Keywords: HHIP; expression; genome-wide interaction study; lung function; sex.

Associated data

figshare/10.6084/m9.figshare.12298736.v1

Abstract

Associated data

Grants and funding