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

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<sup>-5</sup>) and European (P<sub>EA</sub> = 3.0 × 10<sup>-8</sup>) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (B<sub>EA</sub> = -0.13, P<sub>EA</sub> = 0.0002) and lateral ventricular volume (B<sub>EA</sub> = 0.09, P<sub>EA</sub> = 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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Journal
Communications Biology
Published
2025-09-24
DOI
https://doi.org/10.1038/s42003-025-08674-9
Primary Topic
Genetic Associations and Epidemiology
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article
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article

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

Jan Bressler, Bruce M. Psaty, Nigel W. Rayner, Charles Kooperberg et al.
Communications Biology
Genetic Associations and Epidemiology
article

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

Jan Bressler, Bruce M. Psaty, Nigel W. Rayner, Charles Kooperberg, John Blangero, Susan R. Heckbert, Alexis C. Wood, Magdalena Sevilla-González, Ilya M. Nasrallah, Sudha S. Seshadri, Alicia Huerta‐Chagoya, Eric Boerwinkle, Xueqiu Jian, Lenore J. Launer, Kathleen M. Hayden, Elizabeth Selvin, Tamar Sofer, Paul Nyquist, Lincoln M. P. Shade, Alisa K. Manning, Beverly Snively, Jerome I. Rotter, Sonia Thomas, Laura M. Raffield, Konstantinos Hatzikotoulas, Farah Ammous, HarshaVardhan Doddapaneni, Henry J. Taylor, Thomas R. Austin, Lorraine Southam, Daniel DiCorpo, Richard A. Gibbs, Jennifer A. Smith, Miriam S. Udler, Ken Suzuki, Kirk Smith, Joshua C. Bis, Alexa S. Beiser, Timothy M. Hughes, Rasika A. Mathias, Lisa R. Yanek, Namrata Gupta, Qibin Qi, Karine A. Viaud‐Martinez, Stephen S. Rich, Charles S DeCarli, Héctor M. González, David C. Glahn, Alex P. Reiner, Alanna C. Morrison, Kevin A. González, Chloé Sarnowski, David W. Fardo, Bertha Hidalgo, Joanne E. Curran, Ravi Mandla, Yixin Zhang, Xianyong Yin, Myriam Fornage, Andrew P. Morris, Albert V. Smith, Sharon L. R. Kardia, Claudia Liliana Satizábal, Sylvia Wassertheil‐Smoller, Donna K. Arnett, Josée Dupuis, James B. Meigs, Stacey B. Gabriel, W.T. Longstreth, Eric Boerwinkle, Jose C. Florez
article en

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<sup>-5</sup>) and European (P<sub>EA</sub> = 3.0 × 10<sup>-8</sup>) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (B<sub>EA</sub> = -0.13, P<sub>EA</sub> = 0.0002) and lateral ventricular volume (B<sub>EA</sub> = 0.09, P<sub>EA</sub> = 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.

Communications BiologyVol. 8(1)
Broad Institute (US), Boston University (US), University of North Carolina at Chapel Hill (US), Brigham and Women's Hospital (US), Boston Children's Hospital (US), National Institutes of Health (US), Albert Einstein College of Medicine (US), Beth Israel Deaconess Medical Center (US), Harvard University (US), University of Kentucky (US), Johns Hopkins University (US), University of South Carolina (US), The University of Texas at San Antonio Health Science Center (US), Illumina (United States) (US), Baylor College of Medicine (US), University of Washington (US), University of Cambridge (GB), University of Michigan (US), Johns Hopkins Medicine (US), UCLA Medical Center (US), The University of Texas Rio Grande Valley (US), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Helmholtz Zentrum München (DE), British Heart Foundation (GB), University of Alabama at Birmingham (US), Massachusetts General Hospital (US), Fred Hutch Cancer Center (US), National Human Genome Research Institute (US), Alzheimer’s Disease Neuroimaging Initiative (US), Arthritis UK (GB), Brown Foundation (US), National Institute on Aging (US), Children's Nutrition Research Center at Baylor College of Medicine (US), Institute for Community Living (US), The University of Texas Health Science Center (US), Harbor–UCLA Medical Center (US), Hartford Financial Services (United States), Wake Forest University (US), McGill University (CA), University of Virginia (US), University of Tartu (EE), The University of Tokyo (JP), University of Pennsylvania (US), Nanjing Medical University (CN), University of California, Davis (US), The University of Texas Health Science Center at Houston (US), The University of Osaka (JP)
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Genetic Associations and Epidemiology
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