A1 Journal article (refereed)
Variants associated with HHIP expression have sex-differential effects on lung function [version 1; peer review: 2 approved] (2020)

Fawcett, K., Obeidat, M., Melbourne, C., Shrine, N., Guyatt, A., John, C., Luan, J., Richmond, A., Moksnes, M., Granell, R., Weiss, S., Imboden, M., May-Wilson, S., Hysi, P., Boutin, T., Portas, L., Flexeder, C., Harris, S., Wang, C., . . . Wain, L. (2020). Variants associated with HHIP expression have sex-differential effects on lung function [version 1; peer review: 2 approved]. Wellcome Open Research, 5, Article 111. https://doi.org/10.12688/wellcomeopenres.15846.1

JYU authors or editors

Publication details

All authors or editorsFawcett, KA; Obeidat, M; Melbourne, C; Shrine, N; Guyatt, AL; John, C; Luan, J; Richmond, A; Moksnes, MR; Granell, R; et al.

Journal or seriesWellcome Open Research


Publication year2020


Article number111

PublisherWellcome Trust

Publication countryUnited Kingdom

Publication languageEnglish


Publication open accessOpenly available

Publication channel open accessOpen Access channel

Publication is parallel published (JYX)https://jyx.jyu.fi/handle/123456789/71082


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.

Keywordsrespiratory organslungsfunctional capacitygenetic factorsgene expressiongenotypegender

Free keywordsgenome-wide interaction study; lung function; sex; HHIP; expression

Contributing organizations

Ministry reportingYes

Reporting Year2020

JUFO rating0

Last updated on 2024-22-04 at 23:32