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COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome\u2010wide association study approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Participants with COPD (<jats:italic>N<\/jats:italic>\u00a0=\u00a04308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self\u2010reported unintentional weight loss\u00a0&gt;\u00a05% in the past year or low BMI (BMI\u00a0&lt;\u00a020\u00a0kg\/m<jats:sup>2<\/jats:sup>). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non\u2010Hispanic White (NHW) participants with COPD. Single variant and gene\u2010based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein\u2013protein interaction (PPI) data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At the single variant level, only the rs35368512 variant, intergenic to <jats:italic>GRXCR1<\/jats:italic> and <jats:italic>LINC02383<\/jats:italic>, was associated with weight loss (odds ratio\u00a0=\u00a03.6, 95% confidence interval\u00a0=\u00a02.3\u20135.6, <jats:italic>P<\/jats:italic>\u00a0=\u00a03.2\u00a0\u00d7\u00a010<jats:sup>\u22128<\/jats:sup>) among AA COPD participants in COPDGene. At the gene level in COPDGene, <jats:italic>EFNA2<\/jats:italic> and <jats:italic>BAIAP2<\/jats:italic> were significantly associated with weight loss in AA and NHW COPD participants, respectively. The <jats:italic>EFNA2<\/jats:italic> association replicated among AA from SPIROMICS (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0014), whereas the <jats:italic>BAIAP2<\/jats:italic> association replicated in NHW from ECLIPSE (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.025). The <jats:italic>EFNA2<\/jats:italic> gene encodes the membrane\u2010bound protein ephrin\u2010A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The <jats:italic>BAIAP2<\/jats:italic> gene encodes the insulin\u2010responsive protein of mass 53\u00a0kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene\u2010based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The <jats:italic>EFNA2<\/jats:italic> and <jats:italic>BAIAP2<\/jats:italic> genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12782","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T10:25:46Z","timestamp":1631701546000},"page":"1803-1817","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease"],"prefix":"10.1002","volume":"12","author":[{"given":"Preeti","family":"Lakshman Kumar","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ava C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham  Birmingham AL USA"},{"name":"Department of Epidemiology University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"Rocco","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham  Birmingham AL USA"},{"name":"Department of Epidemiology University of Alabama at Birmingham  Birmingham AL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael H.","family":"Cho","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine Brigham and Women's Hospital  Boston MA USA"},{"name":"Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Wan","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine Brigham and Women's Hospital  Boston MA USA"},{"name":"Veterans Affairs Boston Health Care System, Jamaica Plain  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian D.","family":"Hobbs","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine Brigham and Women's Hospital  Boston MA USA"},{"name":"Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George R.","family":"Washko","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor E.","family":"Ortega","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases Wake Forest School of Medicine  Winston\u2010Salem NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Christenson","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy, &amp; Sleep Medicine, Department of Medicine University of California San Francisco  San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingnan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Arizona College of Medicine  Tucson AZ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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