{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:30:44Z","timestamp":1768570244673,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,28]]},"group-title":"Respiratory Medicine","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Rationale<\/jats:title>\n                  <jats:p>Variations in age-related lung function decline are associated with genetic and environmental factors. The genetic variants contributing to this decline remain largely unknown, limiting the understanding of individual susceptibility and potential interventions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>This study aims to uncover the genetic factors associated with lung function decline, using the Lifelines cohort study.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Longitudinal data covering 3 visits and approximately 15 years follow up from 165,138 individuals were available. Genotyping and longitudinal spirometry data were present for 24,749 subjects aged 25 or older at baseline. A three-step approach was used. First, lung function change over time was estimated using a linear-mixed effect model. Second, a genome-wide association study for the estimated change was conducted, adjusting for age, sex, smoking load and the first 10 principal components. Third, single nucleotide polymorphisms (SNPs) with p-value&lt;1\u00d710\n                    <jats:sup>\u22125<\/jats:sup>\n                    were analysed using a linear-mixed effect model. Selected SNPs were tested in two independent cohorts (N=1,376 and N=27,249), followed by meta-analysis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Measurements and Main Results<\/jats:title>\n                  <jats:p>\n                    Among the included individuals, 19,722 had spirometry at two timepoints and 5,027 at three, with median [IQR] follow-up of 8.1 [4.4, 10.4] and 12.1 [11, 13.6] years, respectively. We identified 67 variants suggestively associated with lung function decline (p&lt;1\u00d710\n                    <jats:sup>?5<\/jats:sup>\n                    ). Rs150094594, was significant (P=0.007) in a replication cohort with consistent effect direction. This intergenic variant, not previously reported, reached genome-wide significance in the meta-analysis (rs150094594:T, \u03b2(SE): 15.9(2.7) ml\/year, p-value=3.9\u00d710\n                    <jats:sup>\u22129<\/jats:sup>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study shows a role of genetics in lung function decline, emphasizing the importance of exploring the interplay between genetic and environmental factors.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.26.25338838","type":"posted-content","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T23:35:17Z","timestamp":1761694517000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic variants underpinning lung function decline in the Lifelines general population cohort study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0699-335X","authenticated-orcid":false,"given":"Rui","family":"Mar\u00e7alo","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8911-3658","authenticated-orcid":false,"given":"Corry-Anke","family":"Brandsma","sequence":"additional","affiliation":[]},{"given":"Peter J.","family":"van der Most","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4980-6200","authenticated-orcid":false,"given":"Alda","family":"Marques","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2243-6123","authenticated-orcid":false,"given":"Gabriela R.","family":"Moura","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9336-7340","authenticated-orcid":false,"given":"Maarten","family":"van den Berge","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7531-4547","authenticated-orcid":false,"given":"Judith M","family":"Vonk","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7210-8174","authenticated-orcid":false,"given":"Maaike","family":"de Vries","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2025103006550473000_2025.10.26.25338838v1.1","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S2213-2600(18)30529-0","article-title":"Lung function trajectories in health and disease","volume":"7","year":"2019","journal-title":"Lancet Respir Med"},{"key":"2025103006550473000_2025.10.26.25338838v1.2","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1016\/S0140-6736(24)00016-3","article-title":"Lung-function trajectories: relevance and implementation in clinical practice","volume":"403","year":"2024","journal-title":"The Lancet"},{"key":"2025103006550473000_2025.10.26.25338838v1.3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S2213-2600(23)00461-7","article-title":"GOLD COPD report: 2024 update","volume":"12","year":"2024","journal-title":"The Lancet. 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