Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressiv
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RESEARCH
Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy Samantha L. Strickland1†, Hélène Morel1†, Christian Prusinski1,5, Mariet Allen1, Tulsi A. Patel1, Minerva M. Carrasquillo1, Olivia J. Conway1, Sarah J. Lincoln1, Joseph S. Reddy2, Thuy Nguyen1, Kimberly G. Malphrus1, Alexandra I. Soto1, Ronald L. Walton1, Julia E. Crook2, Melissa E. Murray1, Bradley F. Boeve3, Ronald C. Petersen3, John A. Lucas4, Tanis J. Ferman4, Ryan J. Uitti5, Zbigniew K. Wszolek5, Owen A. Ross1, Neill R. Graff‑Radford5, Dennis W. Dickson1 and Nilüfer Ertekin‑Taner1,5*
Abstract Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer’s disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these muta‑ tions on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropatho‑ logically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle ( nTotal = 2008, nPSP = 1037, nLBD-NP = 971) and Thal phase amyloid plaque scores (nTotal = 1786, nPSP = 1018, nLBD-NP = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46–4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = − 0.822, 95% CI − 1.439 to − 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = − 0.995, 95% CI − 1.773 to − 0.218, p = 0.012) than LBD-NP patients (ß = − 0.292, 95% CI − 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed associa‑ tion with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = − 0.638, 95% CI − 1.139 to − 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropa‑ thology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively.
*Correspondence: [email protected] † Samantha L. Strickland and Hélène Morel have contributed equally. 1 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA Full list o
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