{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T04:00:51Z","timestamp":1772164851338,"version":"3.50.1"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Genome-wide association studies have identified hundreds of loci associated with lipid levels. However, the genetic mechanisms underlying most of these loci are not well-understood. Recent work indicates that changes in the abundance of alternatively spliced transcripts contribute to complex trait variation. Consequently, identifying genetic loci that associate with alternative splicing in disease-relevant cell types and determining the degree to which these loci are informative for lipid biology is of broad interest.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We analyze gene splicing in 83 sample-matched induced pluripotent stem cell (iPSC) and hepatocyte-like cell lines (n=166), as well as in an independent collection of primary liver tissues (n=96) to perform discovery of splicing quantitative trait loci (sQTLs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>We observe that transcript splicing is highly cell type specific, and the genes that are differentially spliced between iPSCs and hepatocyte-like cells are enriched for metabolism pathway annotations. We identify 1384 hepatocyte-like cell sQTLs and 1455 iPSC sQTLs at a false discovery rate of &lt;5% and find that sQTLs are often shared across cell types. To evaluate the contribution of sQTLs to variation in lipid levels, we conduct colocalization analysis using lipid genome-wide association data. We identify 19 lipid-associated loci that colocalize either with an hepatocyte-like cell expression quantitative trait locus or sQTL. Only 2 loci colocalize with both a sQTL and expression quantitative trait locus, indicating that sQTLs contribute information about genome-wide association studies loci that cannot be obtained by analysis of steady-state gene expression alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>These results provide an important foundation for future efforts that use iPSC and iPSC-derived cells to evaluate genetic mechanisms influencing both cardiovascular disease risk and complex traits in general.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.120.003249","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T05:04:06Z","timestamp":1683781446000},"page":"248-257","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Evaluating the Contribution of Cell Type\u2013Specific Alternative Splicing to Variation in Lipid Levels"],"prefix":"10.1161","volume":"16","author":[{"given":"Katerina A.B.","family":"Gawronski","sequence":"first","affiliation":[{"name":"Cell and Molecular Biology Graduate Group (K.A.B.G., B.M.W.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9617-4624","authenticated-orcid":true,"given":"William P.","family":"Bone","sequence":"additional","affiliation":[{"name":"Genomics and Computational Biology Graduate Group (W.P.B., M.F.D.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0465-4744","authenticated-orcid":true,"given":"YoSon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Genetics (Y.P., E.E.P., D.J.R., K.M., B.F.V., C.D.B.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evanthia E.","family":"Pashos","sequence":"additional","affiliation":[{"name":"Department of Genetics (Y.P., E.E.P., D.J.R., K.M., B.F.V., C.D.B.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon M.","family":"Wenz","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Graduate Group (K.A.B.G., B.M.W.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8521-9543","authenticated-orcid":true,"given":"Max F.","family":"Dudek","sequence":"additional","affiliation":[{"name":"Genomics and Computational Biology Graduate Group (W.P.B., M.F.D.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7502-8292","authenticated-orcid":true,"given":"Xiao","family":"Wang","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute (X.W.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1873-2336","authenticated-orcid":true,"given":"Wenli","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute for Regenerative Medicine (W.Y.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9245-9876","authenticated-orcid":true,"given":"Daniel J.","family":"Rader","sequence":"additional","affiliation":[{"name":"Department of Genetics (Y.P., E.E.P., D.J.R., K.M., B.F.V., C.D.B.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"},{"name":"Department of Medicine (D.J.R., K.M.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"},{"name":"Division of Translational Medicine &amp; Human Genetics (D.J.R.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3298-0368","authenticated-orcid":true,"given":"Kiran","family":"Musunuru","sequence":"additional","affiliation":[{"name":"Department of Genetics (Y.P., E.E.P., D.J.R., K.M., B.F.V., C.D.B.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"},{"name":"Department of Medicine (D.J.R., K.M.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6205-9994","authenticated-orcid":true,"given":"Benjamin F.","family":"Voight","sequence":"additional","affiliation":[{"name":"Department of Genetics (Y.P., E.E.P., D.J.R., K.M., B.F.V., C.D.B.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"},{"name":"Department of Systems Pharmacology and Translational Therapeutics (B.F.V.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"},{"name":"Institute for Translational Medicine and Therapeutics (B.F.V.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher D.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Genetics (Y.P., E.E.P., D.J.R., K.M., B.F.V., C.D.B.), University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2797"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09266"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002998"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad9417"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14519"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1402665111"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw417"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.08.008"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4096"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw533"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-01994-1"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1841-z"},{"key":"e_1_3_3_14_2","volume-title":"Stembook","author":"Cai J","year":"2008","unstructured":"Cai, J, DeLaForest, A, Fisher, J, Urick, A, Wagner, T, Twaroski, K, Cayo, M, Nagaoka, M, Duncan, SA. 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