Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in context
Summary: Background: Apolipoprotein E (APOE) variation is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease. Prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. Me...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425002129 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849387147994333184 |
|---|---|
| author | Ehsan Khajouei Valentina Ghisays Ignazio S. Piras Kiana L. Martinez Anthony T. Vicenti Marcus Naymik Preston Ngo Tam C. Tran Joshua C. Denny Travis J. Wheeler Matthew J. Huentelman Eric M. Reiman Jason H. Karnes |
| author_facet | Ehsan Khajouei Valentina Ghisays Ignazio S. Piras Kiana L. Martinez Anthony T. Vicenti Marcus Naymik Preston Ngo Tam C. Tran Joshua C. Denny Travis J. Wheeler Matthew J. Huentelman Eric M. Reiman Jason H. Karnes |
| author_sort | Ehsan Khajouei |
| collection | DOAJ |
| description | Summary: Background: Apolipoprotein E (APOE) variation is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease. Prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. Methods: We utilised a phenome-wide association study (PheWAS) to explore APOE-associated phenotypes in the All of Us Research Program. We determined APOE alleles for 181,880 participants, representing seven ancestry groups. We tested association of APOE variants, ordered based on Alzheimer’s disease risk hierarchy (ε2/ε2 < ε2/ε3 < ε3/ε3 < ε2/ε4 < ε3/ε4 < ε4/ε4), with 2318 phenotypes. Bonferroni-adjusted analyses were performed overall, by ancestry, by sex, and with adjustment for social determinants of health (SDOH). Findings: In the overall cohort, PheWAS identified 17 significant associations, including increased odds of hyperlipidaemia (OR 1.15 [1.14–1.16] per APOE genotype group; P = 1.8 × 10−129), dementia, and Alzheimer’s disease (OR 1.55 [1.40–1.70]; P = 5 × 10−19), and reduced odds of fatty liver disease 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. Significant heterogeneity was observed for hyperlipidaemia 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. Interpretation: We replicate extensive phenotypic associations with APOE alleles in a large, diverse cohort. We provide a comprehensive catalogue of APOE-associated phenotypes and evidence of unique phenotypic associations by sex and ancestry, as well as heterogeneity in effect size across ancestry. Funding: Funding is listed in the Acknowledgements section. |
| format | Article |
| id | doaj-art-32eae6da113e4e1bab94c2dbc9da1cff |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-32eae6da113e4e1bab94c2dbc9da1cff2025-08-20T03:55:22ZengElsevierEBioMedicine2352-39642025-07-0111710576810.1016/j.ebiom.2025.105768Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in contextEhsan Khajouei0Valentina Ghisays1Ignazio S. Piras2Kiana L. Martinez3Anthony T. Vicenti4Marcus Naymik5Preston Ngo6Tam C. Tran7Joshua C. Denny8Travis J. Wheeler9Matthew J. Huentelman10Eric M. Reiman11Jason H. Karnes12Department of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USABanner Alzheimer’s Institute, Phoenix, AZ, USANeurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USADepartment of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USADepartment of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USANeurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USADepartment of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USANational Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USANational Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; All of Us Research Program, National Institutes of Health, Bethesda, MD, USADepartment of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USANeurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USABanner Alzheimer’s Institute, Phoenix, AZ, USADepartment of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA; Corresponding author. R. Ken Coit College of Pharmacy, University of Arizona, 1295 N Martin AVE, Tucson, AZ 85721, USA.Summary: Background: Apolipoprotein E (APOE) variation is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease. Prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. Methods: We utilised a phenome-wide association study (PheWAS) to explore APOE-associated phenotypes in the All of Us Research Program. We determined APOE alleles for 181,880 participants, representing seven ancestry groups. We tested association of APOE variants, ordered based on Alzheimer’s disease risk hierarchy (ε2/ε2 < ε2/ε3 < ε3/ε3 < ε2/ε4 < ε3/ε4 < ε4/ε4), with 2318 phenotypes. Bonferroni-adjusted analyses were performed overall, by ancestry, by sex, and with adjustment for social determinants of health (SDOH). Findings: In the overall cohort, PheWAS identified 17 significant associations, including increased odds of hyperlipidaemia (OR 1.15 [1.14–1.16] per APOE genotype group; P = 1.8 × 10−129), dementia, and Alzheimer’s disease (OR 1.55 [1.40–1.70]; P = 5 × 10−19), and reduced odds of fatty liver disease 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. Significant heterogeneity was observed for hyperlipidaemia 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. Interpretation: We replicate extensive phenotypic associations with APOE alleles in a large, diverse cohort. We provide a comprehensive catalogue of APOE-associated phenotypes and evidence of unique phenotypic associations by sex and ancestry, as well as heterogeneity in effect size across ancestry. Funding: Funding is listed in the Acknowledgements section.http://www.sciencedirect.com/science/article/pii/S2352396425002129Apolipoprotein EPhenome-wide association studyHealth disparitiesAlzheimer’s diseaseHypercholesterolaemia |
| spellingShingle | Ehsan Khajouei Valentina Ghisays Ignazio S. Piras Kiana L. Martinez Anthony T. Vicenti Marcus Naymik Preston Ngo Tam C. Tran Joshua C. Denny Travis J. Wheeler Matthew J. Huentelman Eric M. Reiman Jason H. Karnes Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in context EBioMedicine Apolipoprotein E Phenome-wide association study Health disparities Alzheimer’s disease Hypercholesterolaemia |
| title | Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in context |
| title_full | Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in context |
| title_fullStr | Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in context |
| title_full_unstemmed | Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in context |
| title_short | Phenome-wide association of APOE alleles in the All of Us Research ProgramResearch in context |
| title_sort | phenome wide association of apoe alleles in the all of us research programresearch in context |
| topic | Apolipoprotein E Phenome-wide association study Health disparities Alzheimer’s disease Hypercholesterolaemia |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425002129 |
| work_keys_str_mv | AT ehsankhajouei phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT valentinaghisays phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT ignaziospiras phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT kianalmartinez phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT anthonytvicenti phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT marcusnaymik phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT prestonngo phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT tamctran phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT joshuacdenny phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT travisjwheeler phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT matthewjhuentelman phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT ericmreiman phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext AT jasonhkarnes phenomewideassociationofapoeallelesintheallofusresearchprogramresearchincontext |