Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits

Lauren E Petty¹, Hung-Hsin Chen^{1

2}, Elizabeth G Frankel¹, Wanying Zhu¹, Carolina G Downie³, Mariaelisa Graff³, Phillip Lin¹, Priya Sharma³, Xinruo Zhang³, Alyssa C Scartozzi¹, Rashedeh Roshani¹, Joshua M Landman¹, Michael Boehnke⁴, Donald W Bowden^{5

6

7}, John C Chambers^{8

9

10

11

12}, Anubha Mahajan^{13

14}, Mark I McCarthy^{13

14

15}, Maggie C Y Ng^{1

5

6

16}, Xueling Sim¹⁷, Cassandra N Spracklen^{18

19}, Weihua Zhang^{8

9}, Michael Preuss²⁰, Erwin P Bottinger²⁰, Girish N Nadkarni^{20

21}, Ruth J F Loos^{20

22}, Yii-Der Ida Chen²³, Jingyi Tan²³, Eli Ipp²⁴, Pauline Genter²⁴, Leslie S Emery²⁵, Tin Louie²⁵, Tamar Sofer^{26

27

28}, Adrienne M Stilp²⁵, Kent D Taylor²³, Anny H Xiang²⁹, Thomas A Buchanan³⁰, Kathryn Roll²³, Chuan Gao³¹, Nicholette D Palmer⁶, Jill M Norris³², Lynne E Wagenknecht³³, Darryl Nousome³⁴, Rohit Varma³⁵, Roberta McKean-Cowdin³⁴, Xiuqing Guo²³, Yang Hai²³, Willa Hsueh³⁶, Kevin Sandow²³, Esteban J Parra³⁷, Miguel Cruz³⁸, Adan Valladares-Salgado³⁸, Niels Wacher-Rodarte³⁹, Jerome I Rotter²³, Mark O Goodarzi⁴⁰, Stephen S Rich⁴¹, Alain Bertoni⁴², Leslie J Raffel⁴³, Jerry L Nadler⁴⁴, Fouad R Kandeel⁴⁵, Ravindranath Duggirala⁴⁶, John Blangero⁴⁶, Donna M Lehman⁴⁷, Ralph A DeFronzo⁴⁷, Farook Thameem⁴⁸, Yujie Wang³, Sheila Gahagan⁴⁹, Estela Blanco⁵⁰, Raquel Burrows⁵¹, Alicia Huerta-Chagoya^{52

53

54}, Jose C Florez^{27

53

54}, Teresa Tusie-Luna⁵⁵, Clicerio González-Villalpando⁵⁶, Lorena Orozco⁵⁷, Christopher A Haiman⁵⁸, Craig L Hanis⁵⁹, Rebecca Rohde³, Eric A Whitsel^{3

60}, Alexander P Reiner^{61

62}, Charles Kooperberg⁶², Yun Li¹⁸, Qing Duan¹⁸, Miryoung Lee⁶³, Paulina Correa-Burrows⁵¹, Susan K Fried⁶⁴, Kari E North³, Joseph B McCormick⁶³, Susan P Fisher-Hoch⁶³, Eric R Gamazon^{1

65}, Andrew P Morris⁶⁶, Josep M Mercader^{27

53

54}, Heather M Highland³, Jennifer E Below⁶⁷; DIAMANTE Hispanic/Latino Consortium; Global Hispanic Lipids Consortium

Affiliations

¹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
² Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC.
³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁶ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷ Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁸ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁹ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, London, UK.
¹⁰ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
¹¹ MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
¹² Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
¹³ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁴ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁵ Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁶ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
¹⁸ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁹ Department of Epidemiology and Biostatistics, University of Massachusetts-Amherst, Amherst, MA, USA.
²⁰ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²¹ Digital Health Center, Hasso-Plattner-Institut, Potsdam, Germany.
²² The Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁴ Division of Endocrinology & Metabolism, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁵ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁶ Departments of Medicine and Biostatistics, Harvard University, Boston, MA, USA.
²⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁸ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
²⁹ Department of Research & Evaluation, Division of Biostatistics Research, Kaiser Permanente of Southern California, Pasadena, CA, USA.
³⁰ Department of Medicine, Division of Endocrine, Keck School of Medicine of USC, Los Angeles, CA, USA.
³¹ Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-, Salem, NC, USA.
³² Department of Epidemiology, University of Colorado Denver, Aurora, CO, USA.
³³ Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁴ Department of Preventative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
³⁵ Southern California Eye Institute, CHA Hollywood Presbyterian Medical Center, Los Angeles, CA, USA.
³⁶ Department of Internal Medicine, Diabetes and Metabolism Research Center, Ohio State University Wexner Medical Center, Columbus, OH, USA.
³⁷ Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON, Canada.
³⁸ Unidad de Investigación Médica en Bioquimica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico.
³⁹ Unidad de Investigación Médica en Epidemiologia Clinica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico.
⁴⁰ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴¹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁴² Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁴³ Department of Pediatrics, Division of Medical Genetics, UCI Irvine School of Medicine, Irvine, CA, USA.
⁴⁴ Department of Medicine and Pharmacology, New York Medical College, Valhalla, NY, USA.
⁴⁵ Departments of Clinical Diabetes, Endocrinology & Metabolism and Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA, USA.
⁴⁶ Human Genetics and STDOI, University of Texas Rio Grande Valley, Edinburg, TX, USA.
⁴⁷ Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁴⁸ Department of Biochemistry, Faculty of Medicine, Health Science Center, Kuwait University, Safat, Kuwait.
⁴⁹ Division of Academic General Pediatrics, Child Development and Community Health, University of California at San Diego, San Diego, CA, USA.
⁵⁰ College y Escuela de Salud Pública, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁵¹ Department of Public Health Nutrition, Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile.
⁵² Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁵³ Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵⁴ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵⁵ Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México/Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁵⁶ Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico.
⁵⁷ Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
⁵⁸ Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA.
⁵⁹ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶⁰ Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁶² Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶³ Department of Epidemiology, Human Genetics & Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, TX, USA.
⁶⁴ Diabetes, Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁵ Clare Hall & MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁶⁶ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.
⁶⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. jennifer.e.below@vanderbilt.edu.

PMID: 40210677
PMCID: PMC11985957
DOI: 10.1038/s41467-025-58574-z

Meta-Analysis

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits

Lauren E Petty et al. Nat Commun. 2025.

. 2025 Apr 11;16(1):3438.

doi: 10.1038/s41467-025-58574-z.

Authors

Affiliations

¹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
² Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC.
³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁵ Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁶ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷ Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁸ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁹ Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, London, UK.
¹⁰ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
¹¹ MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
¹² Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
¹³ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁴ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹⁵ Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁶ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁷ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
¹⁸ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁹ Department of Epidemiology and Biostatistics, University of Massachusetts-Amherst, Amherst, MA, USA.
²⁰ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²¹ Digital Health Center, Hasso-Plattner-Institut, Potsdam, Germany.
²² The Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁴ Division of Endocrinology & Metabolism, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁵ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁶ Departments of Medicine and Biostatistics, Harvard University, Boston, MA, USA.
²⁷ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁸ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
²⁹ Department of Research & Evaluation, Division of Biostatistics Research, Kaiser Permanente of Southern California, Pasadena, CA, USA.
³⁰ Department of Medicine, Division of Endocrine, Keck School of Medicine of USC, Los Angeles, CA, USA.
³¹ Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-, Salem, NC, USA.
³² Department of Epidemiology, University of Colorado Denver, Aurora, CO, USA.
³³ Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁴ Department of Preventative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
³⁵ Southern California Eye Institute, CHA Hollywood Presbyterian Medical Center, Los Angeles, CA, USA.
³⁶ Department of Internal Medicine, Diabetes and Metabolism Research Center, Ohio State University Wexner Medical Center, Columbus, OH, USA.
³⁷ Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON, Canada.
³⁸ Unidad de Investigación Médica en Bioquimica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico.
³⁹ Unidad de Investigación Médica en Epidemiologia Clinica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico.
⁴⁰ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁴¹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁴² Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁴³ Department of Pediatrics, Division of Medical Genetics, UCI Irvine School of Medicine, Irvine, CA, USA.
⁴⁴ Department of Medicine and Pharmacology, New York Medical College, Valhalla, NY, USA.
⁴⁵ Departments of Clinical Diabetes, Endocrinology & Metabolism and Translational Research and Cellular Therapeutics, City of Hope, Duarte, CA, USA.
⁴⁶ Human Genetics and STDOI, University of Texas Rio Grande Valley, Edinburg, TX, USA.
⁴⁷ Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁴⁸ Department of Biochemistry, Faculty of Medicine, Health Science Center, Kuwait University, Safat, Kuwait.
⁴⁹ Division of Academic General Pediatrics, Child Development and Community Health, University of California at San Diego, San Diego, CA, USA.
⁵⁰ College y Escuela de Salud Pública, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁵¹ Department of Public Health Nutrition, Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile.
⁵² Consejo Nacional de Ciencia y Tecnología (CONACYT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁵³ Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵⁴ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵⁵ Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México/Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
⁵⁶ Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico.
⁵⁷ Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
⁵⁸ Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA, USA.
⁵⁹ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶⁰ Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁶² Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶³ Department of Epidemiology, Human Genetics & Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, TX, USA.
⁶⁴ Diabetes, Obesity Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁵ Clare Hall & MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁶⁶ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.
⁶⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. jennifer.e.below@vanderbilt.edu.

PMID: 40210677
PMCID: PMC11985957
DOI: 10.1038/s41467-025-58574-z

Abstract

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (n_max = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

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Conflict of interest statement

Competing interests: A.M. and M.I.M. are employees of Genentech and a holders of Roche stock. L.S.E. is now an employee of Bristol Myers Squibb (BMS) and a holder of BMS stock. The remaining authors declare no competing interests.

Figures

**Fig. 1. UpSet plots of gene/protein-based findings across omics.**
UpSet plot (an extension of Venn diagrams to visualize overlap of more than three datasets) for type 2 diabetes (A) HDL cholesterol (B), LDL cholesterol (C) total cholesterol (D) triglycerides (E) and showing all nominally significant (p < 0.05) annotation results across gene/protein-based analyses for novel genes identified in S-PrediXcan discovery genetically regulated expression association analyses: Mendelian randomization of S-PrediXcan findings, transcriptomic association analyses, and proteomic association analyses. Intersections empty for all traits are excluded (GReX, MR, RNASeq, and Proteomics; and GReX, RNASeq, and Proteomics). GReX represents genetically regulated expression analysis (S-PrediXcan) results, MR represents Mendelian randomization results, RNASeq represents transcriptomic differential expression results, and Proteomics represents proteomic differential abundance results. Blue represents novel loci, purple represents novel genes/proteins in known loci, and pink represents known genes/proteins in known loci.

**Fig. 2. Single variant result counts for each trait, categorized by their status relative to previously reported variants and loci.**
A novel variant in a known locus was defined as a locus that had known variants within one Mb, but no known variants contained in its 95% credible set(s). A known locus was defined as a locus with known variants contained in its 95% credible set(s). A novel locus was defined as a variant with no known variants within one Mb or contained in its 95% credible set(s). Pink represents known variants in known loci, purple represents novel variants in known loci, and blue represents novel loci. Traits included are type 2 diabetes (T2D), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG).

See this image and copyright information in PMC

References

1. U.S. Centers for Disease Control and Prevention (ed U.S Department of Health and Human Services). https://www.cdc.gov/diabetes/php/data-research/index.html (2024).
1. Carroll, M. D. & Fryar, C. D. (ed National Center for Health Statistics). https://www.cdc.gov/nchs/products/databriefs/db363.htm (Hyattsville, MD, 2020).
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1. Popejoy, A. B. & Fullerton, S. M. Genomics is failing on diversity. Nature538, 161–164 (2016). - PMC - PubMed
1. Hu, Y. et al. Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study. PLoS Genet.16, e1008684 (2020). - PMC - PubMed

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Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits

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Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits

Authors

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Abstract

Conflict of interest statement

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