Variants associated with HHIP expression have sexdifferential effects on lung function

Abstract

<p><strong>Background:</strong> 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.<br><strong>Methods:</strong> 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.<br><strong>Results:</strong> 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 (<em>HHIP</em>) gene and was previously associated with lung function and HHIP lung expression. We found <em>HHIP</em> expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression.<br><strong>Conclusions:</strong> We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the <em>HHIP</em> gene. Establishing the mechanism by which <em>HHIP</em> 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.</p>