. 2025 Sep 24;8(1):1352.

doi: 10.1038/s42003-025-08674-9.

Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program

Chloé Sarnowski¹, Yixin Zhang², Farah Ammous^{3

4}, Lincoln M P Shade⁵, Daniel DiCorpo², Xueqiu Jian⁶, Donna K Arnett⁷, Thomas R Austin^{8

9}, Alexa Beiser^{2

10

11}, Joshua C Bis^{8

12}, John Blangero¹³, Eric Boerwinkle^{14

15}, Jan Bressler¹⁴, Joanne E Curran¹³, Charles S DeCarli¹⁶, Harsha Doddapaneni¹⁵, Josée Dupuis^{2

17}, David W Fardo^{5

18}, Jose C Florez^{19

20

21

22}, Stacey Gabriel²³, Richard A Gibbs¹⁵, David C Glahn^{24

25

26}, Namrata Gupta²³, Hector M González²⁷, Kevin A González²⁷, Konstantinos Hatzikotoulas²⁸, Kathleen M Hayden²⁹, Susan R Heckbert^{8

9}, Bertha Hidalgo³⁰, Alicia Huerta-Chagoya²¹, Timothy M Hughes³¹, Sharon L R Kardia³, Charles L Kooperberg³², Lenore J Launer³³, W T Longstreth Jr^{9

34}; T2DGGI consortium; MAGIC consortium; Ravi Mandla^{21

35}, Rasika A Mathias³⁶, Andrew P Morris^{28

37

38}, Thomas H Mosley³⁹, Ilya M Nasrallah⁴⁰, Paul Nyquist⁴¹, Bruce M Psaty^{8

9

12

42}, Qibin Qi^{43

44}, Laura M Raffield⁴⁵, Nigel W Rayner²⁸, Alexander P Reiner^{9

32}, Claudia L Satizabal^{6

10

11}, Elizabeth Selvin⁴⁶, Magdalena D R Sevilla-Gonzalez^{21

22

47}, Albert V Smith⁴⁸, Jennifer A Smith^{3

4}, Kirk Smith^{19

20

21}, Beverly M Snively⁴⁹, Lorraine Southam²⁸, Tamar Sofer^{50

51

52}, Ken Suzuki^{37

53

54}, Henry J Taylor^{55

56

57}, Miriam S Udler^{19

20

21

22}, Karine A Viaud-Martinez⁵⁸, Sylvia Wassertheil-Smoller⁴⁴, Alexis C Wood⁵⁹, Lisa R Yanek³⁶, Xianyong Yin^{48

60}, Alisa K Manning^{21

22

47}, Jerome I Rotter⁶¹, Stephen S Rich⁶², James B Meigs^{21

22

63}, Myriam Fornage^{14

64}, Sudha Seshadri^{6

10

11}, Alanna C Morrison¹⁴; TOPMed Diabetes working group; and the TOPMed Neurocognitive working group

Collaborators, Affiliations

Collaborators

MAGIC consortium:
Eric Boerwinkle
and the TOPMed Neurocognitive working group:
David C Glahn

Affiliations

¹ Department of Epidemiology, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. Chloe.Sarnowski@uth.tmc.edu.
² Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁴ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
⁶ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁷ Office of the Provost, University of South Carolina, Columbia, SC, USA.
⁸ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁰ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹¹ The Framingham Heart Study, Framingham, MA, USA.
¹² Department of Medicine, University of Washington, Seattle, WA, USA.
¹³ Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁴ Department of Epidemiology, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹⁶ Department of Neurology, University of California, Davis, CA, USA.
¹⁷ Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health, McGill University, Montreal, QC, Canada.
¹⁸ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
¹⁹ Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²¹ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²² Department of Medicine, Harvard Medical School, Boston, MA, USA.
²³ Genomics Platform, Broad Institute, Cambridge, MA, USA.
²⁴ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston, MA, USA.
²⁵ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
²⁶ Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA.
²⁷ Department of Neurosciences and the Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego, San Diego, CA, USA.
²⁸ Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
³⁰ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
³¹ Departments of Internal Medicine and Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
³² Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
³³ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIA/NIH/IRP, Baltimore, MD, USA.
³⁴ Department of Neurology, University of Washington, Seattle, WA, USA.
³⁵ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁶ GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁷ Division of Musculoskeletal and Dermatological Sciences, Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.
³⁸ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
³⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁰ Department of Radiology, Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.
⁴¹ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴² Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁴ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
⁴⁵ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴⁷ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴⁸ Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁹ Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁵⁰ Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁵¹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵³ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁵⁴ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
⁵⁵ Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁵⁶ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁷ Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
⁵⁸ Illumina Laboratory Services, Illumina, Inc., San Diego, CA, USA.
⁵⁹ USDA/ARS Children Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
⁶⁰ Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
⁶¹ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁶³ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶⁴ The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, Houston, TX, USA.

PMID: 40993182
PMCID: PMC12460837
DOI: 10.1038/s42003-025-08674-9

Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program

Chloé Sarnowski et al. Commun Biol. 2025.

. 2025 Sep 24;8(1):1352.

doi: 10.1038/s42003-025-08674-9.

Authors

Collaborators

MAGIC consortium:
Eric Boerwinkle
and the TOPMed Neurocognitive working group:
David C Glahn

Affiliations

¹ Department of Epidemiology, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. Chloe.Sarnowski@uth.tmc.edu.
² Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
⁴ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Biostatistics, University of Kentucky, Lexington, KY, USA.
⁶ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁷ Office of the Provost, University of South Carolina, Columbia, SC, USA.
⁸ Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
⁹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁰ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹¹ The Framingham Heart Study, Framingham, MA, USA.
¹² Department of Medicine, University of Washington, Seattle, WA, USA.
¹³ Division of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
¹⁴ Department of Epidemiology, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹⁶ Department of Neurology, University of California, Davis, CA, USA.
¹⁷ Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health, McGill University, Montreal, QC, Canada.
¹⁸ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
¹⁹ Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²¹ Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²² Department of Medicine, Harvard Medical School, Boston, MA, USA.
²³ Genomics Platform, Broad Institute, Cambridge, MA, USA.
²⁴ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston, MA, USA.
²⁵ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
²⁶ Olin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA.
²⁷ Department of Neurosciences and the Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego, San Diego, CA, USA.
²⁸ Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁹ Department of Social Sciences and Health Policy, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
³⁰ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
³¹ Departments of Internal Medicine and Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
³² Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
³³ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIA/NIH/IRP, Baltimore, MD, USA.
³⁴ Department of Neurology, University of Washington, Seattle, WA, USA.
³⁵ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁶ GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁷ Division of Musculoskeletal and Dermatological Sciences, Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.
³⁸ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
³⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁰ Department of Radiology, Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.
⁴¹ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴² Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁴ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
⁴⁵ Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴⁷ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴⁸ Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁹ Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
⁵⁰ Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁵¹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵³ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁵⁴ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
⁵⁵ Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁵⁶ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁷ Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
⁵⁸ Illumina Laboratory Services, Illumina, Inc., San Diego, CA, USA.
⁵⁹ USDA/ARS Children Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.
⁶⁰ Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
⁶¹ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁶³ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁶⁴ The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School, Houston, TX, USA.

PMID: 40993182
PMCID: PMC12460837
DOI: 10.1038/s42003-025-08674-9

Abstract

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P < 0.002) of the cross-population (P = 1.3 × 10^-5) and European (P_EA = 3.0 × 10^-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (B_EA = -0.13, P_EA = 0.0002) and lateral ventricular volume (B_EA = 0.09, P_EA = 0.002). We identify suggestive negative associations (P < 0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.

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Conflict of interest statement

Competing interests: L.M.R. and S.S.R. are consultants for the TOPMed Administrative Coordinating Center (through Westat). B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. All the other authors declare that they have no competing interests. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institute on Aging; or the National Institutes of Health. Ethics approval and consent to participate: All study participants provided informed consent, and each study was approved by their respective institutional review boards.

Figures

**Fig. 1. Analytic strategy to derive polygenic scores related to insulin resistance in TOPMed.**
LD Linkage Disequilibrium, T2D Type 2 Diabetes, FI Fasting Insulin, MtS Metabolic Syndrome, ALP alkaline phosphatase. EUR/AFR/AMR denotes LD reference panels provided by PRS-CSx and constructed using the UK Biobank data (Pan UKBB European ancestry, African ancestry, and Admixed American ancestry); Left-side panel has been adapted from Ruan et al..

See this image and copyright information in PMC

References

1. Karlsson, I. K. et al. Measuring heritable contributions to Alzheimer’s disease: polygenic risk score analysis with twins. Brain Commun.4, fcab308 (2022). - DOI - PMC - PubMed
1. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry63, 168–174 (2006). - DOI - PubMed
1. Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA303, 1832–1840 (2010). - DOI - PMC - PubMed
1. Pasquier, F., Boulogne, A., Leys, D. & Fontaine, P. Diabetes mellitus and dementia. Diabetes Metab.32, 403–414 (2006). - DOI - PubMed
1. Whitmer, R. A. Type 2 diabetes and risk of cognitive impairment and dementia. Curr. Neurol. Neurosci. Rep.7, 373–380 (2007). - DOI - PubMed

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Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program

Collaborators

Affiliations

Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources