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. 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

Medicine and Health

University of Leicester
Glenfield Hospital
The University of British Columbia Centre for Heart Lung Innovation
University of Cambridge School of Clinical Medicine
University of Edinburgh
Norwegian University of Science and Technology
University of Bristol
University Medicine Greifswald
Swiss Tropical and Public Health Institute (Swiss TPH)
University of Basel
The University of Edinburgh Medical School
King's College London
National Heart and Lung Institute
Helmholtz Zentrum München German Research Center for Environmental Health
School of Medicine and Public Health
Fimlab Laboratories
Tampere University
Tampere University Hospital
University of Helsinki
University of Western Australia
Curtin University
Université Laval
University Medical Center Groningen
University of British Columbia
Mount Sinai School of Medicine
Western General Hospital
University of Glasgow
Ninewells Hospital and Medical School
Bristol Medical School
University of Queensland
University of Michigan, Ann Arbor
University of Michigan Medical School
University of Split Medical School
Ludwig-Maximilians-Universität München
Member of the German Center for Lung Research (DZL)
University of Munich
University of Jyväskylä
Helsinki University Central Hospital
University of Turku and Turku University Hospital
University of Turku
Turku University Hospital
Imperial College London
St. George's University of London
St. Olavs Hospital
University of Nottingham

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

3 Scopus citations

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
State	Published - 2020

Keywords

Expression
Genome-wide interaction study
HHIP
Lung function
Sex

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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{9aca6b344cd646d39937d78e3949407f,

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 = "Publisher Copyright: {\textcopyright} 2020 Fawcett KA et al.",

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.

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 - https://www.scopus.com/pages/publications/85102377799

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

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