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[Preprint]. 2025 Apr 14:2025.04.11.25325582.

doi: 10.1101/2025.04.11.25325582.

Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness

Devendra Meena¹, Jian Huang¹, Marjan Zare², Natalie R Hasbani³, Boua Palwendé Romuald⁴, Rima Mustafa¹, Sander W van der Laan⁵, Huichun Xu⁶, James G Terry⁷, Joshua C Bis⁸, Deepti Jain⁹, Nicholette D Palmer¹⁰, Nancy Heard-Costa^{11

12}, Yuan-I Min¹³, Xiuqing Guo¹⁴, Jie Yao¹⁴, Kent D Taylor¹⁴, Jingyi Tan¹⁴, Juan Peralta^{15

16}, Alexandre C Pereira^{17

18}, Alyna Khan⁹, Ananyo Choudhury¹⁹, Anne B Newman²⁰, Anny H Xiang²¹, Aroon Hingorani²², Barry I Freedman²³, Christopher J O'Donnell²⁴, Claudia Giambartolomei²⁵, David M Herrington²⁶, David R Jacobs Jr²⁷, Derek Klarin^{28

29}, Fei Fei Wang⁹, Gerardo Heiss³⁰, HarshaVardhan Doddapaneni³¹, Howard N Hodis³², Jai Broome⁹, James G Wilson³³, Jean-Tristan Brandenburg¹⁹, John Blangero^{15

16}, Jose E Krieger¹⁸, Josh D Smith^{34

35}, Karine A Viaud-Martinez³⁶, Kathleen A Ryan⁶, Leslie A Lange³⁷, May E Montasser⁶, Michael C Mahaney^{15

16}, Michal Mokry³⁸, Myriam Fornage³⁹, Patricia Munroe^{40

41}, Richard A Gibbs^{31

42}, Russell P Tracy⁴³, Ryan W Kim⁴⁴, Scott M Damrauer⁴⁵, Stephen S Rich⁴⁶, Willa A Hsueh⁴⁷, Yii-Der Ida Chen¹⁴; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, The Million Veteran Program (MVP), TOPMed Atherosclerosis Working Group; Alanna C Morrison³, Braxton D Mitchell^{6

48}, John Jeffrey Carr⁷, Bruce M Psaty^{8

49

50}, Donald W Bowden¹⁰, Ramachandran S Vasan^{12

51

52}, Adolfo Correa^{13

53}, Wendy S Post⁵⁴, Mark O Goodarzi⁵⁵, Leslie J Raffel⁵⁶, Joanne E Curran^{15

16}, Michele Ramsay¹⁹, Jerome I Rotter¹⁴, Paul Elliott^{57

58

59}, Nora Franceschini³⁰, Paul S de Vries³, Ioanna Tzoulaki^{1

60

61}, Abbas Dehghan¹

Affiliations

¹ Department of Epidemiology and Biostatistics, Imperial College London School of Public Health, London, UK.
² Maternal-fetal medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
³ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴ Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, CNRST, Burkina Faso.
⁵ Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁶ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Department of Radiology, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹ Genetic Analysis Center, Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
¹⁰ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹¹ Boston University School of Medicine, Boston, MA, USA.
¹² National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
¹³ Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁴ 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.
¹⁵ Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁶ South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁷ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁸ Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of S√£o Paulo, S√£o Paulo, Brazil.
¹⁹ Division of Human Genetics at the National Health Laboratory Service, University of the Witwatersrand, Johannesburg, South Africa.
²⁰ Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
²¹ Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA USA.
²² Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom.
²³ Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁴ VA Boston Healthcare System, West Roxbury VA Medical Center, Cardiology Section, Boston, MA, USA.
²⁵ Department of Pathology and Laboratory Medicine, University of California (UCLA), Los Angeles, Los Angeles, CA, USA.
²⁶ Department of Internal Medicine, Section of Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁷ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
²⁸ VA Palo Alto Healthcare System, Palo Alto, CA.
²⁹ Department of Surgery, Stanford University Medical Center, Stanford, CA.
³⁰ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
³¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
³² Department of Preventive Medicine, Department of Medicine, Atherosclerosis Research Unit, Keck School of Medicine, University of Southern California, Los Angeles, CA USA.
³³ Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³⁴ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
³⁵ Northwest Genomics Center, University of Washington, Seattle, WA, USA.
³⁶ Illumina Laboratory Services, Illumina Inc., San Diego, CA, USA.
³⁷ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
³⁸ Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.
³⁹ Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁰ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK.
⁴¹ NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square, London, UK.
⁴² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴³ Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
⁴⁴ Psomagen Inc., Rockville, MD, USA.
⁴⁵ Division of Vascular Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.
⁴⁶ Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
⁴⁷ Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH USA.
⁴⁸ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
⁴⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁰ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁵¹ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁵² Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁵³ Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁵⁴ Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵⁵ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA USA.
⁵⁶ Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California, Irvine, CA USA.
⁵⁷ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
⁵⁸ UK Dementia Research Institute, Imperial College London, London UK.
⁵⁹ National Institute for Health Research Imperial College Biomedical Research Centre, Imperial College London, London, UK.
⁶⁰ British Heart Foundation Centre of Excellence, Imperial College London, London, UK.
⁶¹ Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece.

PMID: 40321265
PMCID: PMC12047956
DOI: 10.1101/2025.04.11.25325582

Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness

Devendra Meena et al. medRxiv. 2025.

[Preprint]. 2025 Apr 14:2025.04.11.25325582.

doi: 10.1101/2025.04.11.25325582.

Authors

Affiliations

¹ Department of Epidemiology and Biostatistics, Imperial College London School of Public Health, London, UK.
² Maternal-fetal medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
³ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴ Clinical Research Unit of Nanoro, Institut de Recherche en Sciences de la Santé, CNRST, Burkina Faso.
⁵ Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
⁶ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁷ Department of Radiology, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹ Genetic Analysis Center, Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
¹⁰ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹¹ Boston University School of Medicine, Boston, MA, USA.
¹² National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
¹³ Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁴ 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.
¹⁵ Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁶ South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁷ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁸ Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of S√£o Paulo, S√£o Paulo, Brazil.
¹⁹ Division of Human Genetics at the National Health Laboratory Service, University of the Witwatersrand, Johannesburg, South Africa.
²⁰ Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
²¹ Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA USA.
²² Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom.
²³ Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁴ VA Boston Healthcare System, West Roxbury VA Medical Center, Cardiology Section, Boston, MA, USA.
²⁵ Department of Pathology and Laboratory Medicine, University of California (UCLA), Los Angeles, Los Angeles, CA, USA.
²⁶ Department of Internal Medicine, Section of Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁷ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
²⁸ VA Palo Alto Healthcare System, Palo Alto, CA.
²⁹ Department of Surgery, Stanford University Medical Center, Stanford, CA.
³⁰ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
³¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
³² Department of Preventive Medicine, Department of Medicine, Atherosclerosis Research Unit, Keck School of Medicine, University of Southern California, Los Angeles, CA USA.
³³ Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³⁴ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
³⁵ Northwest Genomics Center, University of Washington, Seattle, WA, USA.
³⁶ Illumina Laboratory Services, Illumina Inc., San Diego, CA, USA.
³⁷ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
³⁸ Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.
³⁹ Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁰ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK.
⁴¹ NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square, London, UK.
⁴² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴³ Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT, USA.
⁴⁴ Psomagen Inc., Rockville, MD, USA.
⁴⁵ Division of Vascular Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.
⁴⁶ Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.
⁴⁷ Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH USA.
⁴⁸ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
⁴⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵⁰ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁵¹ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
⁵² Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁵³ Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁵⁴ Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵⁵ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA USA.
⁵⁶ Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California, Irvine, CA USA.
⁵⁷ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
⁵⁸ UK Dementia Research Institute, Imperial College London, London UK.
⁵⁹ National Institute for Health Research Imperial College Biomedical Research Centre, Imperial College London, London, UK.
⁶⁰ British Heart Foundation Centre of Excellence, Imperial College London, London, UK.
⁶¹ Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece.

PMID: 40321265
PMCID: PMC12047956
DOI: 10.1101/2025.04.11.25325582

Abstract

Carotid artery intima-media thickness (cIMT) is a measurement of subclinical atherosclerosis that predicts future cardiovascular events, including stroke and myocardial infarction. Genome-wide association studies (GWAS) have identified only a fraction of the genetic variants associated with cIMT. We performed the largest GWAS for cIMT involving up to 131,000 individuals. For the first time, we meta-analysed a diverse range of ancestries including populations with African, Asian (Chinese), Brazilian, European, and Hispanic ancestries. Our study identified 59 independent loci (53 loci from the multi-ancestry single variant analysis of which 19 are novel, P<5×10^-8; 6 novel in gene-based analysis from single variant analysis, P=2.6×10^-6, 2 novel in meta-regression) associated with cIMT. Gene-based, tissue-expression and gene-set enrichment analyses revealed novel genes of potential interest and highlighted significant relationships between vascular tissues (aorta, coronary and tibial arteries) and genetic associations. We found that circulatory levels of seven proteins, including ACAN, BCAM, DUT, ERI1, APOE, FN1, and GLRX were potentially causally associated with cIMT levels. We found a strong genome-wide correlation between cIMT and various cardiometabolic, smoking phenotypes, and lipid traits. Using Mendelian randomisation, our analyses provide robust evidence for causal associations between cIMT and several clinically relevant traits, including lipids, blood pressure, and waist circumference. Our study extends our genetic knowledge of atherosclerosis and highlights potential causal relations between risk factors, atherosclerosis and clinical diagnoses.

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Conflict of interest statement

C.J.O. is a full-time employee at Novartis Institute of Biomedical Research. S.W.L. has received Roche funding for unrelated work. R.W.K. is an employee at Psomagen Inc. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. M.E.M. receives funding from Regeneron Pharmaceuticals Inc. unrelated to this project. KAV-M is an employee at Illumina Inc. All remaining authors declare no competing interests.

Figures

**Figure 1.. Manhattan and Fuji plots of common variants associated with cIMT**
**(a)** Fuji plot showing independent loci associated with cIMT. The colour-coded circles (from inside to outside) represent GWAS of 1) IMTmean-max GWAS in women in UKBB; 2) IMTmean-max GWAS in men in UKBB; 3) IMTmean in UKBB; 4) IMT mean-max in UKBB and 5) IMTmean-max multi-ancestry GWAS meta-analysis. Every dot represents a locus associated with cIMT; large dots represent cross-trait loci, while small dots represent trait-specific loci. Genes with an asterisk denote novel cIMT loci; **(b)** Manhattan plot for the multi-ancestry GWAS on cIMT showing the negative log₁₀ transformed P value for each SNP on the y axis and the base-pair position of the SNPs on each chromosome on the x-axis. The genome-wide-significance threshold (P < 5 × 10^–8) is represented as the horizontal red line. The 51 cIMT loci are annotated; red and black dots refer to novel and known loci, respectively; and **(c)** Gene-based analysis: Manhattan plot showing the genes associated with cIMT in the gene-based analysis. The y-axis shows the negative log₁₀ transformed P value of the gene-based test computed in MAGMA, and the x-axis shows the genomic position on each chromosome. The red line indicates the Bonferroni-corrected threshold for genome-wide significance (P = 2.6×10⁻⁶ (0.05/19,220 genes). The novel signals from the gene-based test are highlighted in red.

**Figure 2.. Functional annotation of cIMT-associated variants**
a) MAGMA tissue expression analysis using gene expression per tissue based on GTEx version 8 data for 53 specific tissue types. The horizontal dotted line indicates the Bonferroni-corrected significance threshold (P = 0.05/53; -log₁₀ transformed). Significant tissues are shown in red. **(b)** Differential expression gene analysis of prioritized genes across GTEx version 8 30 general tissue types. Genes with P-value ≤ 0.05 after Bonferroni correction and absolute log fold change ≥ 0.58 were defined as differentially expressed genes in a given tissue compared to others. Significantly enriched DEG (Bonferroni corrected P-value ≤ 0.05) are highlighted in red. **(c)** Gene-set and pathway enrichment analysis; and **(d)** Venn diagram showing overlap of genes implicated by positional mapping, chromatin interactions, GWGAS, and eQTL mapping. GWGAS, genome-wide gene-based association study; eQTL, Expression quantitative trait loci.

**Figure 3.. Association of the identified cIMT SNPs with clinical traits and diseases**
**(a)** Look up in GWAS catalog **(b) Look up in published GWAS on cardiovascular** diseases, and **(c) Look up in published GWAS on cardiovascular** traits. PAD, peripheral arterial disease; AD, Alzheimer’s disease; CAD, coronary artery disease; Plaque, carotid plaque; ASI, arterial stiffness index; BP, blood pressure.

**Figure 4.. Forest plot of the IVW, WM and MR-Egger estimates.**
**(a)** Effect of cardiovascular risk factors on cIMT, **(b)** Effect of cIMT on cardiovascular traits and diseases and c) Forest plot for the effect estimates of selected plasma proteins on cIMT. *Represents proteins with Wald ratio (causal estimate obtained for a single genetic variant). MR, Mendelian randomization; IVW, inverse-variance weighted; WM, weighted median.

**Figure 5.. Cell-type specific expression in carotid plaques of candidate genes.**
The y-axis shows cell types as previously described . The size of the dot shows the percentage of cells expressing the respective genes, and the colour indicates the average total expression in that cell-types.

See this image and copyright information in PMC

References

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This is a preprint.

Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness

Affiliations

Genome-wide association study and multi-ancestry meta-analysis identify common variants associated with carotid artery intima-media thickness

Authors

Affiliations

Abstract

Conflict of interest statement

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