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

• Chloé Sarnowski, University of Texas School of Public HealthFollow
• Yixin Zhang, Boston University School of Public Health
• Farah Ammous, University of Michigan School of Public Health
• Lincoln M.P. Shade, University of KentuckyFollow
• Daniel DiCorpo, Boston University School of Public Health
• Xueqiu Jian, The University of Texas Health Science Center at San Antonio
• Donna K. Arnett, University of South Carolina
• Thomas R. Austin, University of Washington
• Alexa Beiser, Boston University School of Public Health
• Joshua C. Bis, University of Washington
• John Blangero, The University of Texas Rio Grande Valley
• Eric Boerwinkle, University of Texas School of Public Health
• Jan Bressler, University of Texas School of Public Health
• Joanne E. Curran, The University of Texas Rio Grande Valley
• Charles S. DeCarli, University of California
• Harsha Doddapaneni, Baylor College of Medicine
• Josée Dupuis, Boston University School of Public Health
• David W. Fardo, University of KentuckyFollow
• Jose C. Florez, Harvard University
• Stacey Gabriel, Broad Institute
• Richard A. Gibbs, Baylor College of Medicine
• David C. Glahn, Children's Hospital Boston
• Namrata Gupta, Broad Institute
• Hector M. González, University of California San Diego Health

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.

Document Type

Article

Publication Date

12-1-2025

Notes/Citation Information

Publisher Copyright: © The Author(s) 2025.

Digital Object Identifier (DOI)

10.1038/s42003-025-08674-9

Archival?

Archival

Repository Citation

Sarnowski, Chloé; Zhang, Yixin; Ammous, Farah; Shade, Lincoln M.P.; DiCorpo, Daniel; Jian, Xueqiu; Arnett, Donna K.; Austin, Thomas R.; Beiser, Alexa; Bis, Joshua C.; Blangero, John; Boerwinkle, Eric; Bressler, Jan; Curran, Joanne E.; DeCarli, Charles S.; Doddapaneni, Harsha; Dupuis, Josée; Fardo, David W.; Florez, Jose C.; Gabriel, Stacey; Gibbs, Richard A.; Glahn, David C.; Gupta, Namrata; and González, Hector M., "Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program" (2025). Biostatistics Faculty Publications. 96.
https://uknowledge.uky.edu/biostatistics_facpub/96