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Sarnowski, C.* ; Zhang, Y.* ; Ammous, F.* ; Shade, L.M.P.* ; DiCorpo, D.* ; Jian, X.* ; Arnett, D.K.* ; Austin, T.R.* ; Beiser, A.* ; Bis, J.C.* ; Blangero, J.* ; Boerwinkle, E.* ; Bressler, J.* ; Curran, J.E.* ; DeCarli, C.S.* ; Doddapaneni, H.* ; Dupuis, J.* ; Fardo, D.W.* ; Florez, J.C.* ; Gabriel, S.* ; Gibbs, R.A.* ; Glahn, D.C.* ; Gupta, N.* ; González, H.M.* ; González, K.A.* ; Hatzikotoulas, K. ; Hayden, K.M.* ; Heckbert, S.R.* ; Hidalgo, B.* ; Huerta-Chagoya, A.* ; Hughes, T.M.* ; Kardia, S.L.R.* ; Kooperberg, C.L.* ; Launer, L.J.* ; Longstreth, W.T. Jr.* ; Mandla, R.* ; Mathias, R.A.* ; Morris, A.P. ; Mosley, T.H.* ; Nasrallah, I.M.* ; Nyquist, P.A.* ; Psaty, B.M.* ; Qi, Q.* ; Raffield, L.M.* ; Rayner, N.W. ; Reiner, A.P.* ; Satizabal, C.L.* ; Selvin, E.* ; Sevilla-Gonzalez, M.D.R.* ; Smith, A.V.* ; Smith, J.A.* ; Smith, K.* ; Snively, B.M.* ; Southam, L. ; Sofer, T.* ; Suzuki, K.* ; Taylor, H.J.* ; Udler, M.S.* ; Viaud-Martinez, K.A.* ; Wassertheil-Smoller, S.* ; Wood, A.C.* ; Yanek, L.R.* ; Yin, X.* ; Manning, A.K.* ; Rotter, J.I.* ; Rich, S.S.* ; Meigs, J.B.* ; Fornage, M.* ; Seshadri, S.* ; Morrison, A.C.*

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

Comm. Biol. 8:1352 (2025)

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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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