SNPs associated with HHIP expression have differential effects on lung function in males and females

Katherine A. Fawcett; Ma’en Obeidat; Carl Melbourne; Nick R. G. Shrine; Anna L. Guyatt; Catherine John; Jian’an Luan; Anne Richmond; Marta Riise Moksnes; Raquel Granell; Stefan Weiß; Medea Imboden; Sebastian May-Wilson; Pirro G. Hysi; Thibaud 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 I Campbell

doi:10.12688/wellcomeopenres.15846.1

GeneticsWellcome Open ResearchJun 1, 2020

Peer-reviewed journal article

SNPs associated with HHIP expression have differential effects on lung function in males and females

Katherine A. Fawcett iD, Ma’en Obeidat iD, Carl Melbourne iD, Nick R. G. Shrine iD, Anna L. Guyatt iD, Catherine John iD, Jian’an Luan iD, Anne Richmond iD, Marta Riise Moksnes iD, Raquel Granell iD, Stefan Weiß iD, Medea Imboden iD, Sebastian May-Wilson iD, Pirro G. Hysi iD, Thibaud Boutin iD, Laura Portas iD, Claudia Flexeder iD, Sarah E. Harris iD, Carol A. Wang iD, Leo‐Pekka Lyytikäinen iD, Teemu Palviainen iD, Rachel E. Foong iD, Dirk Keidel iD, Cosetta Minelli iD, Claudia Langenberg iD, , Louise V. Wain iD

Abstract

Adult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males and females. Here, we present the first genome-wide genotype-by-sex interaction study on four lung function traits in 303,612 participants from the UK Biobank. We detected five SNPs showing genome-wide significant (P<5 x 10-8) interactions with sex on lung function, as well as 21 suggestively significant interactions (P<1 x 10-6). The strongest sex interaction signal came from rs7697189 at 4:145436894 on forced expiratory volume in 1 second (FEV1) (P = 3.15 x 10-15), and was replicated (P = 0.016) in 75,696 individuals in the SpiroMeta consortium. Sex-stratified analyses demonstrated that the minor (C) allele of rs7697189 increased lung function to a greater extent in males than females (untransformed FEV1 {beta} = 0.028 [SE 0.0022] litres in males vs {beta} = 0.009 [SE 0.0014] litres in females), and this effect was not accounted for by differential effects on height, smoking or age at puberty. This SNP resides upstream of the gene encoding hedgehog-interacting protein (HHIP) and has previously been reported for association with lung function and HHIP expression in lung tissue. In our analyses, while HHIP expression in lung tissue was significantly different between the sexes with females having higher expression (most significant probeset P=6.90 x 10-6) after adjusting for age and smoking, rs7697189 did not demonstrate sex differential effects on expression. 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, such as chronic obstructive pulmonary disease (COPD), in both sexes.

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