Variants associated withHHIP expression have sex-differential effects on lung function

Katherine A. Fawcett; Louise V. Wain; 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

doi:10.12688/wellcomeopenres.15846.1

Variants associated withHHIP expression have sex-differential effects on lung function

Katherine A. Fawcett^*, Louise V. Wain, 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. WangLeo 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Article number	111
Journal	Wellcome Open Research
Volume	5
DOIs	https://doi.org/10.12688/wellcomeopenres.15846.1
Publication status	Published - 2020

Keywords

Expression
Genome-wide interaction study
HHIP
Lung function
Sex

Access to Document

10.12688/wellcomeopenres.15846.1

Cite this

Fawcett, K. A., Wain, L. V., Obeidat, M., Melbourne, C., Shrine, N., Guyatt, A. L., John, C., Luan, J., Richmond, A., Moksnes, M. R., Granell, R., Weiss, S., Imboden, M., May-Wilson, S., Hysi, P., Boutin, T. S., Portas, L., Flexeder, C., Harris, S. E., ... Tobin, M. D. (2020). Variants associated withHHIP expression have sex-differential effects on lung function. Wellcome Open Research, 5, Article 111. https://doi.org/10.12688/wellcomeopenres.15846.1

@article{c39325d5d7ba46dfa5b58d3a20b8278d,

title = "Variants associated withHHIP expression have sex-differential effects on lung function",

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 = "Expression, Genome-wide interaction study, HHIP, Lung function, Sex",

author = "Fawcett, {Katherine A.} and Wain, {Louise V.} and Ma'en Obeidat and Carl Melbourne and Nick Shrine and Guyatt, {Anna L.} and Catherine John and Jian'an Luan and Anne Richmond and Moksnes, {Marta R.} and Raquel Granell and Stefan Weiss and Medea Imboden and Sebastian May-Wilson and Pirro Hysi and Boutin, {Thibaud S.} and Laura Portas and Claudia Flexeder and Harris, {Sarah E.} and Wang, {Carol A.} and Lyytik{\"a}inen, {Leo Pekka} and Teemu Palviainen and Foong, {Rachel E.} and Dirk Keidel and Cosetta Minelli and Claudia Langenberg and Yohan Boss{\'e} and {Van den Berge}, Maarten and Sin, {Don D.} and Ke Hao and Archie Campbell and David Porteous and Sandosh Padmanabhan and Smith, {Blair H.} and Evans, {David M.} and Sue Ring and Arnulf Langhammer and Kristian Hveem and Cristen Willer and Ralf Ewert and Beate Stubbe and Nicola Pirastu and Lucija Klaric and Joshi, {Peter K.} and Karina Patasova and Mangino Massimo and Ozren Polasek and Starr, {John M.} and Stefan Karrasch and Konstantin Strauch and Thomas Meitinger and Igor Rudan and Taina Rantanen and Kirsi Pietil{\"a}inen and Mika K{\"a}h{\"o}nen and Raitakari, {Olli T.} and Hall, {Graham L.} and Sly, {Peter D.} and Pennell, {Craig E.} and Jaakko Kaprio and Terho Lehtim{\"a}ki and Veronique Vitart and Deary, {Ian J.} and Debbie Jarvis and Wilson, {James F.} and Tim Spector and Nicole Probst-Hensch and Wareham, {Nicholas J.} and Henry V{\"o}lzke and John Henderson and Strachan, {David P.} and Brumpton, {Ben M.} and Caroline Hayward and Hall, {Ian P.} and Tobin, {Martin D.}",

note = "Funding Information: We gratefully acknowledge the contributions of co-authors Professor John M. Starr and Professor John Henderson, both of whom died prior to the publication of this manuscript. We thank UK Biobank and all the participants for generating this important health research resource. This study used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. The ALSPAC study team are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The ECRHS study would like to thank the participants, field workers and researchers who have participated in the ECRHS study for their time and cooperation. The EPIC-Norfolk study team are grateful to all the participants who have been part of the EPIC-Norfolk project and to the many members of the study teams at the University of Cambridge who have enabled this research. Generation Scotland is grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. The HUNT study team are grateful for the contributions from He Zhang and Hyun Min Kang and would also like to acknowledge the support given to them by the Genotyping core and Jin Chen. We thank the LBC1936 participants and team members who contributed to this study. The ORCADES study would like to acknowledge the invaluable contributions of the research nurses in Shetland, the administrative team in Edinburgh and the people of Shetland. The VIKING study would like to acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. The Viking Health Study - Shetland (VIKING) DNA extractions and genotyping were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. The Orkney Complex Disease Study (ORCADES) DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. The Raine study would like to acknowledge the continued contribution of Raine Study participants and their families, Raine Study team for cohort coordination and data collection, NHMRC for long term funding over last 30 years, The University of Western Australia, Curtin University, Women and Infants Research Foundation, Telethon Kids Institute, Edith Cowan University, Murdoch University, The University of Notre Dame Australia, and The Raine Medical Research Foundation for providing funding for Core Management of the Raine Study. The Raine study would also like to acknowledge The University of Western Australia (Division of Obstetrics and Gynaecology, King Edward Memorial Hospital and Medical School, Royal Perth Hospital), and Telethon Kids Institute for providing in-kind support for the storage and curation of biological samples, and Pawsey Supercomputing Centre with funding from Australian Government and the Government of Western Australia for providing computation resource to carry out analyses required. Publisher Copyright: {\textcopyright} 2020 Fawcett KA et al. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2020",

doi = "10.12688/wellcomeopenres.15846.1",

language = "English",

volume = "5",

journal = "Wellcome Open Research",

issn = "2398-502X",

publisher = "F1000 Research Ltd.",

}

Fawcett, KA, Wain, LV, Obeidat, M, Melbourne, C, Shrine, N, Guyatt, AL, John, C, Luan, J, Richmond, A, Moksnes, MR, Granell, R, Weiss, S, Imboden, M, May-Wilson, S, Hysi, P, Boutin, TS, Portas, L, Flexeder, C, Harris, SE, Wang, CA, Lyytikäinen, LP, Palviainen, T, Foong, RE, Keidel, D, Minelli, C, Langenberg, C, Bossé, Y, Van den Berge, M, Sin, DD, Hao, K, Campbell, A, Porteous, D, Padmanabhan, S, Smith, BH, Evans, DM, Ring, S, Langhammer, A, Hveem, K, Willer, C, Ewert, R, Stubbe, B, Pirastu, N, Klaric, L, Joshi, PK, Patasova, K, Massimo, M, Polasek, O, Starr, JM, Karrasch, S, Strauch, K, Meitinger, T, Rudan, I, Rantanen, T, Pietiläinen, K, Kähönen, M, Raitakari, OT, Hall, GL, Sly, PD, Pennell, CE, Kaprio, J, Lehtimäki, T, Vitart, V, Deary, IJ, Jarvis, D, Wilson, JF, Spector, T, Probst-Hensch, N, Wareham, NJ, Völzke, H, Henderson, J, Strachan, DP, Brumpton, BM, Hayward, C, Hall, IP & Tobin, MD 2020, 'Variants associated withHHIP expression have sex-differential effects on lung function', Wellcome Open Research, vol. 5, 111. https://doi.org/10.12688/wellcomeopenres.15846.1

TY - JOUR

T1 - Variants associated withHHIP expression have sex-differential effects on lung function

AU - Fawcett, Katherine A.

AU - Wain, Louise V.

AU - Obeidat, Ma'en

AU - Melbourne, Carl

AU - Shrine, Nick

AU - Guyatt, Anna L.

AU - John, Catherine

AU - Luan, Jian'an

AU - Richmond, Anne

AU - Moksnes, Marta R.

AU - Granell, Raquel

AU - Weiss, Stefan

AU - Imboden, Medea

AU - May-Wilson, Sebastian

AU - Hysi, Pirro

AU - Boutin, Thibaud S.

AU - Portas, Laura

AU - Flexeder, Claudia

AU - Harris, Sarah E.

AU - Wang, Carol A.

AU - Lyytikäinen, Leo Pekka

AU - Palviainen, Teemu

AU - Foong, Rachel E.

AU - Keidel, Dirk

AU - Minelli, Cosetta

AU - Langenberg, Claudia

AU - Bossé, Yohan

AU - Van den Berge, Maarten

AU - Sin, Don D.

AU - Hao, Ke

AU - Campbell, Archie

AU - Porteous, David

AU - Padmanabhan, Sandosh

AU - Smith, Blair H.

AU - Evans, David M.

AU - Ring, Sue

AU - Langhammer, Arnulf

AU - Hveem, Kristian

AU - Willer, Cristen

AU - Ewert, Ralf

AU - Stubbe, Beate

AU - Pirastu, Nicola

AU - Klaric, Lucija

AU - Joshi, Peter K.

AU - Patasova, Karina

AU - Massimo, Mangino

AU - Polasek, Ozren

AU - Starr, John M.

AU - Karrasch, Stefan

AU - Strauch, Konstantin

AU - Meitinger, Thomas

AU - Rudan, Igor

AU - Rantanen, Taina

AU - Pietiläinen, Kirsi

AU - Kähönen, Mika

AU - Raitakari, Olli T.

AU - Hall, Graham L.

AU - Sly, Peter D.

AU - Pennell, Craig E.

AU - Kaprio, Jaakko

AU - Lehtimäki, Terho

AU - Vitart, Veronique

AU - Deary, Ian J.

AU - Jarvis, Debbie

AU - Wilson, James F.

AU - Spector, Tim

AU - Probst-Hensch, Nicole

AU - Wareham, Nicholas J.

AU - Völzke, Henry

AU - Henderson, John

AU - Strachan, David P.

AU - Brumpton, Ben M.

AU - Hayward, Caroline

AU - Hall, Ian P.

AU - Tobin, Martin D.

N1 - Funding Information: We gratefully acknowledge the contributions of co-authors Professor John M. Starr and Professor John Henderson, both of whom died prior to the publication of this manuscript. We thank UK Biobank and all the participants for generating this important health research resource. This study used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. The ALSPAC study team are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The ECRHS study would like to thank the participants, field workers and researchers who have participated in the ECRHS study for their time and cooperation. The EPIC-Norfolk study team are grateful to all the participants who have been part of the EPIC-Norfolk project and to the many members of the study teams at the University of Cambridge who have enabled this research. Generation Scotland is grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. The HUNT study team are grateful for the contributions from He Zhang and Hyun Min Kang and would also like to acknowledge the support given to them by the Genotyping core and Jin Chen. We thank the LBC1936 participants and team members who contributed to this study. The ORCADES study would like to acknowledge the invaluable contributions of the research nurses in Shetland, the administrative team in Edinburgh and the people of Shetland. The VIKING study would like to acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. The Viking Health Study - Shetland (VIKING) DNA extractions and genotyping were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. The Orkney Complex Disease Study (ORCADES) DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. The Raine study would like to acknowledge the continued contribution of Raine Study participants and their families, Raine Study team for cohort coordination and data collection, NHMRC for long term funding over last 30 years, The University of Western Australia, Curtin University, Women and Infants Research Foundation, Telethon Kids Institute, Edith Cowan University, Murdoch University, The University of Notre Dame Australia, and The Raine Medical Research Foundation for providing funding for Core Management of the Raine Study. The Raine study would also like to acknowledge The University of Western Australia (Division of Obstetrics and Gynaecology, King Edward Memorial Hospital and Medical School, Royal Perth Hospital), and Telethon Kids Institute for providing in-kind support for the storage and curation of biological samples, and Pawsey Supercomputing Centre with funding from Australian Government and the Government of Western Australia for providing computation resource to carry out analyses required. Publisher Copyright: © 2020 Fawcett KA et al. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Expression

KW - Genome-wide interaction study

KW - HHIP

KW - Lung function

KW - Sex

UR - http://www.scopus.com/inward/record.url?scp=85102377799&partnerID=8YFLogxK

U2 - 10.12688/wellcomeopenres.15846.1

DO - 10.12688/wellcomeopenres.15846.1

M3 - Article

AN - SCOPUS:85102377799

SN - 2398-502X

VL - 5

JO - Wellcome Open Research

JF - Wellcome Open Research

M1 - 111

ER -

Variants associated withHHIP expression have sex-differential effects on lung function

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this