Variants associated with HHIP expression have sexdifferential effects on lung function

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Fawcett , K A , 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 , Wang , C A , Lyytikäinen , L P , Palviainen , T , Foong , R E , Keidel , D , Minelli , C , Langenberg , C , Bossé , Y , Berge , M V D , Sin , D D , Hao , K , Campbell , A , Porteous , D , Padmanabhan , S , Smith , B H , Evans , D M , Ring , S , Langhammer , A , Hveem , K , Willer , C , Ewert , R , Stubbe , B , Pirastu , N , Klaric , L , Joshi , P K , Patasova , K , Massimo , M , Polasek , O , Starr , J M , Karrasch , S , Strauch , K , Meitinger , T , Rudan , I , Rantanen , T , Pietiläinen , K , Kähönen , M , Raitakari , O T , Hall , G L , Sly , P D , Pennell , C E , Kaprio , J , Lehtimäki , T , Vitart , V , Deary , I J , Jarvis , D , Wilson , J F , Spector , T , Probst-Hensch , N , Wareham , N J , Völzke , H , Henderson , J , Strachan , D P , Brumpton , B M , Hayward , C , Hall , I P , Tobin , M D & Wain , L V 2021 , ' Variants associated with HHIP expression have sexdifferential effects on lung function ' , Wellcome open research , vol. 5 , 111 . https://doi.org/10.12688/WELLCOMEOPENRES.15846.2

Title: Variants associated with HHIP expression have sexdifferential effects on lung function
Author: Fawcett, Katherine A.; Obeidat, Ma'en; Melbourne, Carl; Shrine, Nick; Guyatt, Anna L.; John, Catherine; Luan, Jian'an; Richmond, Anne; Moksnes, Marta R.; Granell, Raquel; Weiss, Stefan; Imboden, Medea; May-Wilson, Sebastian; Hysi, Pirro; Boutin, Thibaud S.; Portas, Laura; Flexeder, Claudia; Harris, Sarah E.; Wang, Carol A.; Lyytikäinen, Leo Pekka; Palviainen, Teemu; Foong, Rachel E.; Keidel, Dirk; Minelli, Cosetta; Langenberg, Claudia; Bossé, Yohan; Berge, Maarten Van den; Sin, Don D.; Hao, Ke; Campbell, Archie; Porteous, David; Padmanabhan, Sandosh; Smith, Blair H.; Evans, David M.; Ring, Sue; Langhammer, Arnulf; Hveem, Kristian; Willer, Cristen; Ewert, Ralf; Stubbe, Beate; Pirastu, Nicola; Klaric, Lucija; Joshi, Peter K.; Patasova, Karina; Massimo, Mangino; Polasek, Ozren; Starr, John M.; Karrasch, Stefan; Strauch, Konstantin; Meitinger, Thomas; Rudan, Igor; Rantanen, Taina; Pietiläinen, Kirsi; Kähönen, Mika; Raitakari, Olli T.; Hall, Graham L.; Sly, Peter D.; Pennell, Craig E.; Kaprio, Jaakko; Lehtimäki, Terho; Vitart, Veronique; Deary, Ian J.; Jarvis, Debbie; Wilson, James F.; Spector, Tim; Probst-Hensch, Nicole; Wareham, Nicholas J.; Völzke, Henry; Henderson, John; Strachan, David P.; Brumpton, Ben M.; Hayward, Caroline; Hall, Ian P.; Tobin, Martin D.; Wain, Louise V.
Other contributor: University of Helsinki, University of Helsinki
University of Helsinki, HUS Abdominal Center
University of Helsinki, University of Helsinki








Date: 2021
Language: eng
Number of pages: 20
Belongs to series: Wellcome open research
ISSN: 2398-502X
DOI: https://doi.org/10.12688/WELLCOMEOPENRES.15846.2
URI: http://hdl.handle.net/10138/335905
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sexdifferential 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.
Subject: expression
genome-wide interaction study
HHIP
lung function
sex
1184 Genetics, developmental biology, physiology
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