Variants associated with HHIP expression have sex-differential effects on lung function
Fawcett, Katherine A.; Wain, Louise V.; 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; Van den Berge, Maarten; 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. (2021)
Fawcett, Katherine A.
Wain, Louise V.
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
Van den Berge, Maarten
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.
2021
111
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202106085768
https://urn.fi/URN:NBN:fi:tuni-202106085768
Kuvaus
Peer reviewed
Tiivistelmä
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.
Kokoelmat
- TUNICRIS-julkaisut [16944]