Journal article
Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids
Translational psychiatry, Vol.15(1), 207
06/20/2025
DOI: 10.1038/s41398-025-03418-z
PMCID: PMC12179276
PMID: 40537477
Abstract
Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P < 10−5) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P < 5 × 10−8) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.
Details
- Title: Subtitle
- Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids
- Creators
- Amy R Bentley - National Human Genome Research InstituteMichael R. Brown - The University of Texas Health Science Center at HoustonSolomon K. MusaniKaren L. Schwander - Division of Statistical Genomics, Washington UniversityThomas W. Winkler - University of RegensburgMario Sims - University of California, RiversideTuomas O. Kilpeläinen - Novo Nordisk (United States)Hugues Aschard - Harvard UniversityTraci M. Bartz - University of WashingtonLawrence F. Bielak - University of MichiganJin-Fang Chai - National University Health SystemKumaraswamy Naidu Chitrala - University of HoustonNora Franceschini - University of North Carolina at Chapel HillMariaelisa Graff - University of North Carolina at Chapel HillXiuqing Guo - Harbor–UCLA Medical CenterFernando P. Hartwig - Universidade Federal de PelotasAndrea R.V.R. Horimoto - Universidade de São PauloElise Lim - Boston UniversityYongmei Liu - Duke UniversityAlisa K. Manning - Massachusetts General HospitalIlja M. Nolte - University of GroningenRaymond Noordam - Leiden University Medical CenterMelissa A. Richard - The University of Texas Health Science Center at HoustonAlbert V. Smith - University of MichiganYun Ju Sung - Washington University in St. LouisDina Vojinovic - Erasmus MCRujia Wang - King's College LondonYujie Wang - University of North Carolina at Chapel HillMary F. Feitosa - Division of Statistical Genomics, Washington UniversitySarah E. Harris - University of EdinburghLeo-Pekka Lyytikäinen - Tampere UniversityGiorgio Pistis - University of LausanneRainer Rauramaa - Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise MedicinePeter J. van der Most - University Medical Center GroningenErin Ware - University of MichiganStefan Weiss - Universitätsmedizin GreifswaldWanqing Wen - Vanderbilt University Medical CenterLisa R. Yanek - Johns Hopkins MedicineDan E. Arking - Johns Hopkins MedicineDonna K. Arnett - University of South CarolinaChristie Ballantyne - Baylor College of MedicineEric Boerwinkle - Baylor College of MedicineYii-Der Ida Chen - The Lundquist InstituteMartha L. Daviglus - University of Illinois Urbana-ChampaignLisa de las Fuentes - Washington University in St. LouisPaul S. de Vries - The University of Texas Health Science Center at HoustonJoseph A. C. Delaney - University of ManitobaAmanda M. Fretts - University of WashingtonLynette Ekunwe - University of Mississippi Medical CenterJessica D. Faul - University of MichiganLinda C. Gallo - San Diego State UniversitySami Heikkinen - University of Eastern FinlandGeorg Homuth - Universitätsmedizin GreifswaldM. Arfan Ikram - Erasmus MCCarmen R. Isasi - Albert Einstein College of MedicineJost Bruno Jonas - Institute of Molecular and Clinical Ophthalmology BaselLiisa Keltikangas-Järvinen - University of HelsinkiPirjo Komulainen - Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise MedicineAldi T. Kraja - University of Mississippi Medical CenterJose E. Krieger - Universidade de São PauloLenore Launer - National Institutes of HealthJianjun Liu - Agency for Science, Technology and ResearchKurt Lohman - Duke UniversityAnnemarie I. Luik - Erasmus MCAni W. Manichaikul - University of VirginiaPedro Marques-Vidal - University of LausanneYuri Milaneschi - Amsterdam NeuroscienceStanford E. MwasongweJeffrey R. O’Connell - University of Maryland, BaltimoreKenneth Rice - University of WashingtonStephen S. Rich - University of VirginiaPamela J. Schreiner - University of MinnesotaLars Schwettmann - Helmholtz Zentrum MünchenJames M. Shikany - University of Alabama at BirminghamXiao-ou Shu - Vanderbilt University Medical CenterJennifer A. Smith - University of MichiganHarold Snieder - University of GroningenNona Sotoodehnia - University of WashingtonE. Shyong Tai - National University of SingaporeKent D. Taylor - UCLA Medical CenterLesley Tinker - Fred Hutch Cancer CenterMichael Y. Tsai - University of MinnesotaAndré G. Uitterlinden - Erasmus MCCornelia M. van Duijn - Erasmus MCDiana van Heemst - Leiden University Medical CenterMelanie Waldenberger - Helmholtz Zentrum MünchenRobert B. Wallace - University of IowaHwee-Lin Wee - National University of SingaporeDavid R. Weir - University of MichiganWen-Bin Wei - Capital Medical UniversityKo Willems van Dijk - Leiden University Medical CenterGregory Wilson - Jackson State UniversityJie Yao - Ronald Reagan UCLA Medical CenterKristin L. Young - University of North Carolina at Chapel HillXiaoyu Zhang - Boston UniversityWei Zhao - University of MichiganXiaofeng Zhu - Case Western Reserve UniversityAlan B. Zonderman - National Institute on AgingIan J. Deary - University of EdinburghChristian Gieger - Helmholtz Zentrum MünchenHans Jörgen Grabe - Universitätsmedizin GreifswaldTimo A. Lakka - University of Eastern FinlandTerho Lehtimäki - Tampere UniversityAlbertine J. Oldehinkel - University Medical Center GroningenMartin Preisig - University of LausanneYa-Xing Wang - Capital Medical UniversityWei Zheng - Vanderbilt University Medical CenterMichele K. Evans - National Institutes of HealthMichael Province - Division of Statistical Genomics, Washington UniversityJames Gauderman - University of Southern CaliforniaVilmundur Gudnason - University of IcelandCatharina A. Hartman - University Medical Center GroningenBernardo L. Horta - Universidade Federal de PelotasSharon L. R. Kardia - University of MichiganCharles Kooperberg - Fred Hutch Cancer CenterChing-Ti Liu - Boston UniversityDennis O. Mook-Kanamori - Leiden University Medical CenterBrenda WJH Penninx - Vrije Universiteit AmsterdamAlexandre C. Pereira - Universidade de São PauloPatricia A. Peyser - University of MichiganBruce M. Psaty - University of WashingtonJerome I. Rotter - UCLA Medical CenterXueling Sim - National University Health SystemKari E. North - University of North Carolina at Chapel HillDabeeru C. Rao - Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics (I2BD), Washington University School of MedicineLaura Bierut - Washington University in St. LouisClint L. Miller - University of VirginiaAlanna C. Morrison - The University of Texas Health Science Center at HoustonCharles N. Rotimi - National Human Genome Research InstituteMyriam Fornage - The University of Texas Health Science Center at HoustonLifelines Cohort StudyErvin R. Fox - University of Mississippi Medical Center
- Resource Type
- Journal article
- Publication Details
- Translational psychiatry, Vol.15(1), 207
- DOI
- 10.1038/s41398-025-03418-z
- PMID
- 40537477
- PMCID
- PMC12179276
- NLM abbreviation
- Transl Psychiatry
- ISSN
- 2158-3188
- eISSN
- 2158-3188
- Publisher
- Nature Publishing Group UK
- Grant note
- Z01HG200362 / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) (https://doi.org/10.13039/100000051) U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) (https://doi.org/10.13039/100000093) U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD) (https://doi.org/10.13039/100000052) U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) (https://doi.org/10.13039/100000062)
- Language
- English
- Date published
- 06/20/2025
- Academic Unit
- Epidemiology; Injury Prevention Research Center
- Record Identifier
- 9984832081302771
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