Meta-Analysis

. 2025 Jun 20;15(1):207.

doi: 10.1038/s41398-025-03418-z.

Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids

Amy R Bentley^#¹, Michael R Brown^#², Solomon K Musani³, Karen L Schwander⁴, Thomas W Winkler⁵, Mario Sims⁶, Tuomas O Kilpeläinen^{7

8}, Hugues Aschard^{9

10}, Traci M Bartz¹¹, Lawrence F Bielak¹², Jin-Fang Chai¹³, Kumaraswamy Naidu Chitrala¹⁴, Nora Franceschini¹⁵, Mariaelisa Graff¹⁵, Xiuqing Guo¹⁶, Fernando P Hartwig¹⁷, Andrea R V R Horimoto^{11

18}, Elise Lim¹⁹, Yongmei Liu²⁰, Alisa K Manning^{21

22}, Ilja M Nolte²³, Raymond Noordam²⁴, Melissa A Richard^{25

26}, Albert V Smith²⁷, Yun Ju Sung²⁸, Dina Vojinovic^{29

30

31}, Rujia Wang³², Yujie Wang¹⁵, Mary F Feitosa⁴, Sarah E Harris³³, Leo-Pekka Lyytikäinen^{34

35}, Giorgio Pistis³⁶, Rainer Rauramaa³⁷, Peter J van der Most²³, Erin Ware³⁸, Stefan Weiss^{39

40}, Wanqing Wen⁴¹, Lisa R Yanek⁴², Dan E Arking⁴³, Donna K Arnett⁴⁴, Christie Ballantyne^{45

46}, Eric Boerwinkle^{2

47}, Yii-Der Ida Chen¹⁶, Martha L Daviglus⁴⁸, Lisa de Las Fuentes^{49

50}, Paul S de Vries², Joseph A C Delaney^{51

52

53

54}, Amanda M Fretts^{51

53}, Lynette Ekunwe⁵⁵, Jessica D Faul³⁸, Linda C Gallo⁵⁶, Sami Heikkinen⁵⁷, Georg Homuth³⁹, M Arfan Ikram²⁹, Carmen R Isasi⁵⁸, Jost Bruno Jonas^{59

60}, Liisa Keltikangas-Järvinen⁶¹, Pirjo Komulainen³⁷, Aldi T Kraja⁶², Jose E Krieger¹⁸, Lenore Launer⁶³; Lifelines Cohort Study; Jianjun Liu⁶⁴, Kurt Lohman⁶⁵, Annemarie I Luik²⁹, Ani W Manichaikul^{66

67

68}, Pedro Marques-Vidal⁶⁹, Yuri Milaneschi⁷⁰, Stanford E Mwasongwe⁷¹, Jeffrey R O'Connell⁷², Kenneth Rice¹¹, Stephen S Rich^{66

67

68}, Pamela J Schreiner⁷³, Lars Schwettmann^{74

75}, James M Shikany⁷⁶, Xiao-Ou Shu⁴¹, Jennifer A Smith^{12

38}, Harold Snieder²³, Nona Sotoodehnia⁷⁷, E Shyong Tai⁷⁸, Kent D Taylor⁷⁹, Lesley Tinker⁸⁰, Michael Y Tsai⁸¹, André G Uitterlinden⁸², Cornelia M van Duijn^{29

83}, Diana van Heemst²⁴, Melanie Waldenberger⁸⁴, Robert B Wallace⁸⁵, Hwee-Lin Wee¹³, David R Weir³⁸, Wen-Bin Wei⁸⁶, Ko Willems van Dijk^{87

88}, Gregory Wilson⁸⁹, Jie Yao¹⁶, Kristin L Young¹⁵, Xiaoyu Zhang¹⁹, Wei Zhao^{12

38}, Xiaofeng Zhu⁹⁰, Alan B Zonderman⁶³, Ian J Deary³³, Christian Gieger^{84

91

92}, Hans Jörgen Grabe^{93

94}, Timo A Lakka^{37

57

95}, Terho Lehtimäki^{34

35}, Albertine J Oldehinkel⁹⁶, Martin Preisig³⁶, Ya-Xing Wang⁶⁰, Wei Zheng⁴¹, Michele K Evans⁶³, Michael Province⁴, James Gauderman⁹⁷, Vilmundur Gudnason^{98

99}, Catharina A Hartman⁹⁶, Bernardo L Horta¹⁰⁰, Sharon L R Kardia¹², Charles Kooperberg⁸⁰, Ching-Ti Liu¹⁹, Dennis O Mook-Kanamori^{101

102}, Brenda Wjh Penninx⁷⁰, Alexandre C Pereira¹⁸, Patricia A Peyser¹², Bruce M Psaty¹⁰³, Jerome I Rotter¹⁶, Xueling Sim¹³, Kari E North¹⁵, Dabeeru C Rao⁴⁹, Laura Bierut¹⁰⁴, Clint L Miller^{66

67

68}, Alanna C Morrison², Charles N Rotimi^#¹⁰⁵, Myriam Fornage^#²⁵, Ervin R Fox^#⁵⁵

Collaborators, Affiliations

Collaborators

Lifelines Cohort Study:
Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A Kuivenhoven, Esteban A Lopera Maya, Ilja M Nolte, Serena Sanna, Harold Snieder, Morris A Swertz, Peter M Visscher, Judith M Vonk, Cisca Wijmenga, Naomi Wray

Affiliations

¹ Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, 20892, USA. amy.bentley@nih.gov.
² Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
³ MerexAgRight Farm, Ltd., Kitale, Kenya.
⁴ Division of Statistical Genomics, Washington University, St. Louis, MO, USA.
⁵ Department of Epidemiology, University of Regensburg, Regensburg, 93051, Germany.
⁶ Department of Social Medicine, Population and Public Health, University of California, Riverside School of Medicine, Riverside, CA, 92521, USA.
⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK-2200, Denmark.
⁸ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁹ Institut Pasteur, Université Paris Cité, Department of Computational Biology, F-75015, Paris, France.
¹⁰ Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA.
¹¹ Department of Biostatistics, University of Washington, Seattle, WA, 98101, USA.
¹² Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
¹³ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore, 117549, Singapore.
¹⁴ Department of Engineering Technology, University of Houston, Sugar Land, TX, 77479, USA.
¹⁵ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27516, USA.
¹⁶ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
¹⁷ Department of Epidemiology, Federal University of Pelotas, Pelotas, RS, 96020-220, Brazil.
¹⁸ Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, 05403-900, Brazil.
¹⁹ Department of Biostatistics, Boston University, Boston, MA, 02118, USA.
²⁰ Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC, 27701-2047, USA.
²¹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
²² Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
²³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.
²⁴ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2333ZA, the Netherlands.
²⁵ McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
²⁶ Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
²⁷ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁸ Division of Biostatistics, Washington University, St. Louis, MO, 63110, USA.
²⁹ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
³⁰ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
³¹ IQVIA, 1101 CT, Amsterdam, the Netherlands.
³² Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³³ Lothian Birth Cohorts, Department of Psychology, The University of Edinburgh, Edinburgh, EH8 9JZ, UK.
³⁴ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
³⁵ Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
³⁶ Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Vaud, 1008, Switzerland.
³⁷ Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland.
³⁸ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA.
³⁹ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.
⁴⁰ German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, 17475, Germany.
⁴¹ Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.
⁴² Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁴³ McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁴⁴ Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29169, USA.
⁴⁵ Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, 77030, USA.
⁴⁶ Houston Methodist Debakey Heart and Vascular Center, Houston, TX, 77030, USA.
⁴⁷ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
⁴⁸ Institute for Minority Health Research, University of Illinois Chicago, Chicago, IL, 60612, USA.
⁴⁹ Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics (I2BD), Washington University School of Medicine, St. Louis, MO, 63110, USA.
⁵⁰ Division of Cardiology, Washington University, St. Louis, MO, 63110, USA.
⁵¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵² Department of Medicine, University of Washington, Seattle, WA, USA.
⁵³ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
⁵⁴ College of Pharmacy, University of Manitoba, Winnipeg, MB, R3E 0T5, Canada.
⁵⁵ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39213, USA.
⁵⁶ Department of Psychology, San Diego State University, San Diego, CA, USA.
⁵⁷ Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70100, Finland.
⁵⁸ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁵⁹ Institute of Molecular and Clinical Ophthalmology Basel IOB, Basel, Switzerland.
⁶⁰ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁶¹ Department of Psychology and Logopedics, University of Helsinki, Helsinki, 00014, Finland.
⁶² University of Mississippi Medical Center, Jackson, MS, 39213, USA.
⁶³ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
⁶⁴ Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore, 138672, Singapore.
⁶⁵ Department of Medicine, Duke Molecular Physiology Institute Duke University School of Medicine, Durham, NC, 27701-2047, USA.
⁶⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
⁶⁷ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁶⁸ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
⁶⁹ Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, CH- 1011, Lausanne, Switzerland.
⁷⁰ Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1081 HJ, the Netherlands.
⁷¹ Veritas Management Group, Inc., Alpharetta, GA, 30072, USA.
⁷² Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷³ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
⁷⁴ Department of Health Services Research, School of Medicine and Health Services, Carl von Ossietzky Universität Oldenburg, Oldenburg, 26111, Germany.
⁷⁵ Institute for Health Economics and Health Care Management, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁷⁶ Division of Preventive Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35205, USA.
⁷⁷ Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, Washington, 98195, USA.
⁷⁸ Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore, 119228, Singapore.
⁷⁹ Department of Pediatrics, LA Biomed at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
⁸⁰ Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
⁸¹ Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
⁸² Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
⁸³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁴ Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁸⁵ Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA.
⁸⁶ Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁸⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands.
⁸⁸ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands.
⁸⁹ School of Public Health, Jackson State University, Jackson, MS, 39213, USA.
⁹⁰ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
⁹¹ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁹² German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany.
⁹³ German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, 17475, Germany.
⁹⁴ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, 17489, Germany.
⁹⁵ Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
⁹⁶ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands.
⁹⁷ Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, 90032, USA.
⁹⁸ Icelandic Heart Association, Icelandic Heart Association, Kópavogur, 201, Iceland.
⁹⁹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁰⁰ Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, RS, 96020-220, Brazil.
¹⁰¹ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333ZA, the Netherlands.
¹⁰² Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2333ZA, the Netherlands.
¹⁰³ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, USA.
¹⁰⁴ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁰⁵ Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, 20892, USA.

^# Contributed equally.

PMID: 40537477
PMCID: PMC12179276
DOI: 10.1038/s41398-025-03418-z

Meta-Analysis

Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids

Amy R Bentley et al. Transl Psychiatry. 2025.

. 2025 Jun 20;15(1):207.

doi: 10.1038/s41398-025-03418-z.

Authors

Collaborators

Lifelines Cohort Study:
Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A Kuivenhoven, Esteban A Lopera Maya, Ilja M Nolte, Serena Sanna, Harold Snieder, Morris A Swertz, Peter M Visscher, Judith M Vonk, Cisca Wijmenga, Naomi Wray

Affiliations

¹ Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, 20892, USA. amy.bentley@nih.gov.
² Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
³ MerexAgRight Farm, Ltd., Kitale, Kenya.
⁴ Division of Statistical Genomics, Washington University, St. Louis, MO, USA.
⁵ Department of Epidemiology, University of Regensburg, Regensburg, 93051, Germany.
⁶ Department of Social Medicine, Population and Public Health, University of California, Riverside School of Medicine, Riverside, CA, 92521, USA.
⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK-2200, Denmark.
⁸ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁹ Institut Pasteur, Université Paris Cité, Department of Computational Biology, F-75015, Paris, France.
¹⁰ Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA.
¹¹ Department of Biostatistics, University of Washington, Seattle, WA, 98101, USA.
¹² Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
¹³ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore, 117549, Singapore.
¹⁴ Department of Engineering Technology, University of Houston, Sugar Land, TX, 77479, USA.
¹⁵ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27516, USA.
¹⁶ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
¹⁷ Department of Epidemiology, Federal University of Pelotas, Pelotas, RS, 96020-220, Brazil.
¹⁸ Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, 05403-900, Brazil.
¹⁹ Department of Biostatistics, Boston University, Boston, MA, 02118, USA.
²⁰ Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC, 27701-2047, USA.
²¹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
²² Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
²³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.
²⁴ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2333ZA, the Netherlands.
²⁵ McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
²⁶ Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
²⁷ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁸ Division of Biostatistics, Washington University, St. Louis, MO, 63110, USA.
²⁹ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
³⁰ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
³¹ IQVIA, 1101 CT, Amsterdam, the Netherlands.
³² Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³³ Lothian Birth Cohorts, Department of Psychology, The University of Edinburgh, Edinburgh, EH8 9JZ, UK.
³⁴ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
³⁵ Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33014, Finland.
³⁶ Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Vaud, 1008, Switzerland.
³⁷ Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland.
³⁸ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA.
³⁹ Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.
⁴⁰ German Center for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, 17475, Germany.
⁴¹ Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.
⁴² Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁴³ McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
⁴⁴ Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, 29169, USA.
⁴⁵ Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, 77030, USA.
⁴⁶ Houston Methodist Debakey Heart and Vascular Center, Houston, TX, 77030, USA.
⁴⁷ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
⁴⁸ Institute for Minority Health Research, University of Illinois Chicago, Chicago, IL, 60612, USA.
⁴⁹ Center for Biostatistics and Data Science, Institute for Informatics, Data Science, and Biostatistics (I2BD), Washington University School of Medicine, St. Louis, MO, 63110, USA.
⁵⁰ Division of Cardiology, Washington University, St. Louis, MO, 63110, USA.
⁵¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵² Department of Medicine, University of Washington, Seattle, WA, USA.
⁵³ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
⁵⁴ College of Pharmacy, University of Manitoba, Winnipeg, MB, R3E 0T5, Canada.
⁵⁵ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39213, USA.
⁵⁶ Department of Psychology, San Diego State University, San Diego, CA, USA.
⁵⁷ Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70100, Finland.
⁵⁸ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁵⁹ Institute of Molecular and Clinical Ophthalmology Basel IOB, Basel, Switzerland.
⁶⁰ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁶¹ Department of Psychology and Logopedics, University of Helsinki, Helsinki, 00014, Finland.
⁶² University of Mississippi Medical Center, Jackson, MS, 39213, USA.
⁶³ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
⁶⁴ Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore, 138672, Singapore.
⁶⁵ Department of Medicine, Duke Molecular Physiology Institute Duke University School of Medicine, Durham, NC, 27701-2047, USA.
⁶⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, USA.
⁶⁷ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁶⁸ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
⁶⁹ Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 46, CH- 1011, Lausanne, Switzerland.
⁷⁰ Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1081 HJ, the Netherlands.
⁷¹ Veritas Management Group, Inc., Alpharetta, GA, 30072, USA.
⁷² Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷³ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
⁷⁴ Department of Health Services Research, School of Medicine and Health Services, Carl von Ossietzky Universität Oldenburg, Oldenburg, 26111, Germany.
⁷⁵ Institute for Health Economics and Health Care Management, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁷⁶ Division of Preventive Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35205, USA.
⁷⁷ Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, Washington, 98195, USA.
⁷⁸ Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore, 119228, Singapore.
⁷⁹ Department of Pediatrics, LA Biomed at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
⁸⁰ Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
⁸¹ Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
⁸² Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
⁸³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁴ Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁸⁵ Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA.
⁸⁶ Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁸⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands.
⁸⁸ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands.
⁸⁹ School of Public Health, Jackson State University, Jackson, MS, 39213, USA.
⁹⁰ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
⁹¹ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁹² German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany.
⁹³ German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, 17475, Germany.
⁹⁴ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, 17489, Germany.
⁹⁵ Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
⁹⁶ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, the Netherlands.
⁹⁷ Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, 90032, USA.
⁹⁸ Icelandic Heart Association, Icelandic Heart Association, Kópavogur, 201, Iceland.
⁹⁹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁰⁰ Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, RS, 96020-220, Brazil.
¹⁰¹ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333ZA, the Netherlands.
¹⁰² Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2333ZA, the Netherlands.
¹⁰³ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, USA.
¹⁰⁴ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁰⁵ Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, MD, 20892, USA.

^# Contributed equally.

PMID: 40537477
PMCID: PMC12179276
DOI: 10.1038/s41398-025-03418-z

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.

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Conflict of interest statement

Competing interests: The authors declare the following competing interests: BMP serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; CMvD was sponsored by GlaxoSmithKline; HJG received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm and Janssen Cilag as well as research funding from Fresenius Medical Care; JBJ serves in the Advisory Board Novartis; Patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and / or anti-angiogenic factor; Patent number: 20120263794), and Europäische Patentanmeldung 16 720 043.5 and Patent application US 2019 0085065 A1 (Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia). Ethics Approval and Consent to Participate: For all participating cohorts, the appropriate institutional review boards approved research activities and informed consent was obtained from each participant. Further details on all participating cohorts is given in the Supplementary Note.

Figures

**Fig. 1. Study design.**
African ancestry (AFR), Asian ancestry (ASN), Brazilian (BRZ), European ancestry (EUR), Hispanic (HISP), cross-population meta-analysis (CPMA)1 Brazilian samples were only available in Stage 1, so a Stage 1 + *2 meta-analysis of BRZ was not possible. These samples are include in the cross-population Stage 1* + *2 meta-analysis; 2 As the 2df results joinly measure the variant's main and interaction effects, our main results only include those 2df findings that are also more than 500 kb from known lipids loci*.

**Fig. 2. Forest Plots of Key Findings.**
Forest plot showing all studies contributing data on an interaction of A. rs11949029 × social support (SOCS) on LDLC using a 1df test of the interaction term (this interaction was also statistically significant using the 2df joint test of the main effect and interaction, shown in Supplementary Figure 4D); and B. rs59808825 × anxiety symptoms (ANXT) on LDLC. Box size represents the precision of the estimate, with larger boxes shown for results with lower variance. *Abbreviations: African ancestry (AFR), Brazilian (BRZ), Effect Allele Frequency (EAF), European Ancestry (EUR), Hispanic (HISP), cross-population meta-analysis (CPMA)*.

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References

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Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids

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Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids

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