{"doi":"10.12688/wellcomeopenres.15846.2","title":"Variants associated with HHIP expression have sex-differential effects on lung function","abstract":"<ns4:p><ns4:bold>Background: </ns4:bold>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.</ns4:p><ns4:p> <ns4:bold>Methods:</ns4:bold> 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.</ns4:p><ns4:p> <ns4:bold>Results:</ns4:bold> Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P&lt;5x10<ns4:sup>-8</ns4:sup>) interactions with sex on lung function, and 21 showed suggestive interactions (P&lt;1x10<ns4:sup>-6</ns4:sup>). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV<ns4:sub>1</ns4:sub>) (P=3.15x10<ns4:sup>-15</ns4:sup>), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV<ns4:sub>1</ns4:sub> more in males (untransformed FEV<ns4:sub>1</ns4:sub> 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 (<ns4:italic>HHIP</ns4:italic>) gene and was previously associated with lung function and <ns4:italic>HHIP</ns4:italic> lung expression. We found <ns4:italic>HHIP</ns4:italic> expression was significantly different between the sexes (P=6.90x10<ns4:sup>-6</ns4:sup>), but we could not detect sex differential effects of rs7697189 on expression.</ns4:p><ns4:p> <ns4:bold>Conclusions:</ns4:bold> We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the <ns4:italic>HHIP</ns4:italic> gene. Establishing the mechanism by which <ns4:italic>HHIP</ns4:italic> 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.</ns4:p>","journal":"Wellcome Open Research","year":2021,"id":206418,"datarank":0.30605610906036634,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.03729218867615809,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.03729218867615809,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":3,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.12298736.v1"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":97188,"name":"Ma’en Obeidat","orcid":"0000-0002-5443-2752","position":1,"is_corresponding":false},{"id":323168,"name":"Carl Melbourne","orcid":"0000-0001-7216-4547","position":2,"is_corresponding":false},{"id":70431,"name":"Nick Shrine","orcid":"0000-0003-3641-4371","position":3,"is_corresponding":false},{"id":268130,"name":"Anna L. 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