{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T21:45:29Z","timestamp":1775943929546,"version":"3.50.1"},"posted":{"date-parts":[[2024,9,4]]},"group-title":"Genetic and Genomic Medicine","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Genetic variation in\n                    <jats:italic>APOE<\/jats:italic>\n                    is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease risk. However, prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. We utilized a phenome-wide association study (PheWAS) approach to explore\n                    <jats:italic>APOE<\/jats:italic>\n                    - associated phenotypes in the\n                    <jats:italic>All of Us<\/jats:italic>\n                    Research Program.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We determined\n                    <jats:italic>APOE<\/jats:italic>\n                    alleles for 181,880\n                    <jats:italic>All of Us<\/jats:italic>\n                    participants with whole genome sequencing and electronic health record (EHR) data, representing seven gnomAD ancestry groups. We tested association of\n                    <jats:italic>APOE<\/jats:italic>\n                    variants, ordered based on Alzheimer\u2019s disease risk hierarchy (\u03b52\/\u03b52&lt;\u03b52\/\u03b53&lt;\u03b53\/\u03b53&lt;\u03b52\/\u03b54&lt;\u03b53\/\u03b54&lt;\u03b54\/\u03b54), with 2,318 EHR-derived phenotypes. Bonferroni-adjusted analyses were performed overall, by ancestry, by sex, and with adjustment for social determinants of health (SDOH).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>\n                    In the overall cohort, PheWAS identified 17 significant associations, including an increased odds of hyperlipidemia (OR 1.15 [1.14\u20131.16] per\n                    <jats:italic>APOE<\/jats:italic>\n                    genotype group;\n                    <jats:italic>P<\/jats:italic>\n                    =1.8\u00d710\n                    <jats:sup>-129<\/jats:sup>\n                    ), dementia, and Alzheimer\u2019s disease (OR 1.55 [1.40\u20131.70];\n                    <jats:italic>P<\/jats:italic>\n                    =5\u00d710\n                    <jats:sup>-19<\/jats:sup>\n                    ), and a reduced odds of fatty liver disease (OR 0.93 [0.90\u20130.95];\n                    <jats:italic>P<\/jats:italic>\n                    =1.6\u00d710\n                    <jats:sup>-9<\/jats:sup>\n                    ) and chronic liver disease. ORs were similar after SDOH adjustment and by sex, except for an increased number of cardiovascular associations in males, and decreased odds of noninflammatory disorders of vulva and perineum in females (OR 0.89 [0.84\u20130.94];\n                    <jats:italic>P<\/jats:italic>\n                    =1.1\u00d710\n                    <jats:sup>-5<\/jats:sup>\n                    ). Significant heterogeneity was observed for hyperlipidemia and mild cognitive impairment across ancestry. Unique associations by ancestry included transient retinal arterial occlusion in the European ancestry group, and first-degree atrioventricular block in the American Admixed\/Latino ancestry group.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>\n                    We replicate extensive phenotypic associations with\n                    <jats:italic>APOE<\/jats:italic>\n                    alleles in a large, diverse cohort, despite limitations in accuracy for EHR-derived phenotypes. We provide a comprehensive catalog of\n                    <jats:italic>APOE<\/jats:italic>\n                    -associated phenotypes and present evidence of unique phenotypic associations by sex and ancestry, as well as heterogeneity in effect size across ancestry.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>Funding is listed in the acknowledgements.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.09.04.24313010","type":"posted-content","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T21:50:11Z","timestamp":1725486611000},"source":"Crossref","is-referenced-by-count":4,"title":["Phenome-Wide Association of\n                  <i>APOE<\/i>\n                  Alleles in the\n                  <i>All of Us<\/i>\n                  Research Program"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4565-7770","authenticated-orcid":false,"given":"Ehsan","family":"Khajouei","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8434-9407","authenticated-orcid":false,"given":"Valentina","family":"Ghisays","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignazio S.","family":"Piras","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiana L.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Naymik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Preston","family":"Ngo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tam C.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua C.","family":"Denny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2004-1785","authenticated-orcid":false,"given":"Travis J.","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Huentelman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric M.","family":"Reiman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5001-3334","authenticated-orcid":false,"given":"Jason H.","family":"Karnes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"4852","key":"2024090608100569000_2024.09.04.24313010v1.1","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1126\/science.3283935","article-title":"Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. 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