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Post‐Genome‐Wide Association Study Challenges for Lipid Traits: Describing Age as a Modifier of Gene‐Lipid Associations in the Population Architecture Using Genomics and Epidemiology (PAGE) Study |
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| Authors: | Logan Dumitrescu Cara L. Carty Nora Franceschini Lucia A. Hindorff Shelley A. Cole Petra Bůžková Fredrick R. Schumacher Charles B. Eaton Robert J. Goodloe David J. Duggan Jeff Haessler Barbara Cochran Brian E. Henderson Iona Cheng Karen C. Johnson Chris S. Carlson Shelly‐Ann Love Kristin Brown‐Gentry Alejandro Q. Nato Jr. Miguel Quibrera Garnet Anderson Ralph V. Shohet José Luis Ambite Lynne R. Wilkens Loïc Le Marchand Christopher A. Haiman Steven Buyske Charles Kooperberg Kari E. North Myriam Fornage Dana C. Crawford |
| Affiliation: | 1. Center for Human Genetics Research, Vanderbilt University, , Nashville, TN;2. Public Health Sciences, Fred Hutchinson Cancer Research Center, , Seattle, WA;3. Department of Epidemiology, University of North Carolina, , Chapel Hill, NC;4. Office of Population Genomics, National Human Genome Research Institute, , Bethesda, MD;5. Department of Genetics, Texas Biomedical Research Institute, , San Antonio, TX;6. Department of Biostatistics, University of Washington, , Seattle, WA;7. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, , Los Angeles, CA;8. Department of Family Medicine, Warren Alpert Medical School, Brown University, , Providence, RI;9. Translational Genomics Research Institute, , Phoenix, AZ;10. Baylor College of Medicine, , Houston, TX;11. Cancer Prevention Institute of California, , Fremont, CA;12. Department of Preventive Medicine, University of Tennessee Health Science Center, , Memphis, TN;13. Department of Genetics, Rutgers University, , Piscataway, NJ;14. Gillings School of Public Health, University of North Carolina, , Chapel Hill, NC;15. John A. Burns School of Medicine, University of Hawaii, , Honolulu, HI;16. Information Sciences Institute, University of Southern California, , Marina del Rey, CA;17. Epidemiology Program, University of Hawaii Cancer Center, , Honolulu, HI;18. Department of Genetics and Department of Statistics, Rutgers University, , Piscataway, NJ;19. Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, , Chapel Hill, NC;20. Division of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Sciences Center at Houston, , TX;21. Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, , TX;22. Department of Molecular Physiology and Biophysics, Vanderbilt University, , Nashville, TN |
| Abstract: | Numerous common genetic variants that influence plasma high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol (LDL‐C), and triglyceride distributions have been identified via genome‐wide association studies (GWAS). However, whether or not these associations are age‐dependent has largely been overlooked. We conducted an association study and meta‐analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre‐ or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age‐specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL‐C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E‐03, I2 = 89.8), with a significant association in older males (P = 1.39E‐06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP‐trait associations despite large sample sizes. |
| Keywords: | PAGE modifier age lipids genetic association |