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<p>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 &gt;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 &lt; 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 &lt; 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.</p>

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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

  • 期刊论文

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  • 发表日期：

    2025年9月24日

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

摘要

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 (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 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.