{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:46:22Z","timestamp":1789173982125,"version":"build-2803163510"},"posted":{"date-parts":[[2026,7,3]]},"group-title":"Genetics","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NHGRI","award":["R01HG013371"],"award-info":[{"award-number":["R01HG013371"]}]},{"name":"NIH\/NHGRI","award":["U41HG010972"],"award-info":[{"award-number":["U41HG010972"]}]},{"name":"NIH\/NHGRI","award":["R01HG011649"],"award-info":[{"award-number":["R01HG011649"]}]},{"name":"NIH\/NHGRI","award":["U01HG010973"],"award-info":[{"award-number":["U01HG010973"]}]},{"name":"NIH\/NHGRI","award":["U01HG013748"],"award-info":[{"award-number":["U01HG013748"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The Human Pangenome Reference Consortium has generated 462 open-access reference genomes and a variation graph that represents differences among them, providing a substrate for pangenome-based analysis methods that overcome the longstanding limitation of comparing all genomic data to a single linear reference. A key unresolved question is the extent to which these approaches can improve trait mapping. We investigate this using the genetics of gene expression variation as a model. We developed a graph-based method (EdgeDepth) for associating sequence variation with traits using short-read genome sequencing data, and show that it captures complex forms of genetic variation missed by other methods. We evaluated trait mapping performance using 430 samples with deep RNA-seq data, and found that pangenomic methods enable the detection of expression quantitative trait loci involving multiallelic indels and structural variants, leading to increased power at a subset of genes. These include 812 genes (7.9% of total) with \u226520% improvement in statistical significance relative to the 1000 Genomes Project callset, and 185 (1.8%) with a 50% improvement, 10 of which are candidates to explain prior GWAS results. Notably, these analyses implicate\n                  <jats:italic>GBAP1<\/jats:italic>\n                  pseudogene copy number as a causal factor in Crohn\u2019s disease, likely via miRNA-mediated regulation of\n                  <jats:italic>GBA1<\/jats:italic>\n                  , which explains prior GWAS results based on flanking SNPs. The inclusion of pangenome-specific variation also improved the performance of gene expression prediction models, with median variance explained increasing from 10.1% to 12.5%, and 14.6% of genes showing significant improvement (\u0394r\n                  <jats:sup>2<\/jats:sup>\n                  &gt;0.05). Taken together, these results suggest that integration of pangenomic methods into human genetic studies will improve trait association and genomic prediction at a meaningful subset of genes.\n                <\/jats:p>","DOI":"10.64898\/2026.07.01.735728","type":"posted-content","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T20:30:27Z","timestamp":1783110627000},"source":"Crossref","is-referenced-by-count":1,"title":["Pangenome-based human genome analysis improves trait association and genomic prediction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-6902","authenticated-orcid":false,"given":"Shuangjia","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, CT, USA"},{"name":"Center for Genomic Health, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8183-213X","authenticated-orcid":false,"given":"Wen-Wei","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, CT, USA"},{"name":"Center for Genomic Health, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7592-752X","authenticated-orcid":false,"given":"Marianne K.","family":"DeGorter","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Page C.","family":"Goddard","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-3702","authenticated-orcid":false,"given":"Jana","family":"Ebler","sequence":"additional","affiliation":[{"name":"Center for Digital Medicine, Heinrich Heine University, D\u00fcsseldorf, Germany"},{"name":"Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7110-3937","authenticated-orcid":false,"given":"Tsung-Yu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Human Pangenome Reference Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5395-1457","authenticated-orcid":false,"given":"Mark J. P.","family":"Chaisson","sequence":"additional","affiliation":[{"name":"Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA"},{"name":"Norris Cancer Center, University of Southern California, Los Angeles CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-1030","authenticated-orcid":false,"given":"Tobias","family":"Marschall","sequence":"additional","affiliation":[{"name":"Center for Digital Medicine, Heinrich Heine University, D\u00fcsseldorf, Germany"},{"name":"Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital D\u00fcsseldorf, Heinrich Heine University, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-3903","authenticated-orcid":false,"given":"Stephen B.","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA"},{"name":"Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA"},{"name":"Department of Biomedical Data Science, Stanford University School of Medicine, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4963-8211","authenticated-orcid":false,"given":"Nathan O.","family":"Stitziel","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA"},{"name":"Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA"},{"name":"John Cochran Veterans Affairs Medical Center, Saint Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4442-6655","authenticated-orcid":false,"given":"Ira M.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, CT, USA"},{"name":"Center for Genomic Health, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070612051308000_2026.07.01.735728v1.1","unstructured":"Human Pangenome Reference Consortium. 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