Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy

Acta Neuropathologica Communications

Joseph S. Reddy¹  Julia E. Crook¹  Zbigniew K. Wszolek²  Ryan J. Uitti²  Neill R. Graff-Radford²  Bradley F. Boeve³  Ronald C. Petersen³  Samantha L. Strickland⁴  Kimberly G. Malphrus⁴  Ronald L. Walton⁴  Minerva M. Carrasquillo⁴  Sarah J. Lincoln⁴  Mariet Allen⁴  Hélène Morel⁴  Olivia J. Conway⁴  Alexandra I. Soto⁴  Melissa E. Murray⁴  Dennis W. Dickson⁴  Owen A. Ross⁴  Thuy Nguyen⁴  Tulsi A. Patel⁴  Christian Prusinski⁵  Nilüfer Ertekin-Taner⁵  Tanis J. Ferman⁶  John A. Lucas⁶ 

[1] Department of Health Sciences Research, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;Department of Neurology, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;Department of Neurology, Mayo Clinic Minnesota, 55905, Rochester, MN, USA;Department of Neuroscience, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;Department of Neuroscience, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;Department of Neurology, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;Department of Psychiatry and Psychology, Mayo Clinic Florida, 32224, Jacksonville, FL, USA;

关键词: Lewy body disease;    Dementia with Lewy bodies;    Progressive supranuclear palsy;    Neuropathology;    Tau;    Amyloid ß;    Genetic associations;   

DOI  :  10.1186/s40478-020-01050-0

来源: Springer

【 摘 要 】

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 mutations 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 neuropathologically 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 association 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 neuropathology. 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. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.

【 授权许可】

CC BY