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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 (+64 others)
2022

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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
more » ... 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.
doi:10.17863/cam.79909 fatcat:6fa4gs3ihvgsvnzftdvwggvz6i
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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 Wareham, Henry Völzke, John Henderson, David P Strachan, Ben M Brumpton, Caroline Hayward, Ian P Hall, Martin D Tobin, Louise V Wain, Apollo-University Of Cambridge Repository. "Variants associated with HHIP expression have sex-differential effects on lung function." (2022)