TY - JOUR
T1 - Association of ABI3 and PLCG2 missense variants with disease risk and neuropathology in Lewy body disease and progressive supranuclear palsy
AU - Strickland, Samantha L.
AU - Morel, Hélène
AU - Prusinski, Christian
AU - Allen, Mariet
AU - Patel, Tulsi A.
AU - Carrasquillo, Minerva M.
AU - Conway, Olivia J.
AU - Lincoln, Sarah J.
AU - Reddy, Joseph S.
AU - Nguyen, Thuy
AU - Malphrus, Kimberly G.
AU - Soto, Alexandra I.
AU - Walton, Ronald L.
AU - Crook, Julia E.
AU - Murray, Melissa E.
AU - Boeve, Bradley F.
AU - Petersen, Ronald C.
AU - Lucas, John A.
AU - Ferman, Tanis J.
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Ross, Owen A.
AU - Graff-Radford, Neill R.
AU - Dickson, Dennis W.
AU - Ertekin-Taner, Nilüfer
N1 - Funding Information:
RCP consults for Roche, Inc., Merck, Inc., Genentech, Inc., and Biogen, Inc., GE Healthcare, and receives royalties from Oxford University Press for the publication of Mild Cognitive Impairment. NRG-R has served on the editorial board of Alzheimer Disease and Therapy; has received publishing royalties from UpToDate; and has received research support from TauRx, Lilly, Biogen, and NIA. ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, and the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson’s Research Foundation. He serves as PI or Co-PI on Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301) grants. The remaining authors declare that they have no competing interests.
Funding Information:
This work was supported by National Institute on Aging [RF AG051504; U01 AG046139; R01 AG061796 to N.E.T]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to N.E.T]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information & Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to O.A.R). Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP|Society for Progressive Supranuclear Palsy and the Tau Consortium. Acknowledgements
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
KW - Amyloid ß
KW - Dementia with Lewy bodies
KW - Genetic associations
KW - Lewy body disease
KW - Neuropathology
KW - Progressive supranuclear palsy
KW - Tau
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U2 - 10.1186/s40478-020-01050-0
DO - 10.1186/s40478-020-01050-0
M3 - Article
C2 - 33092647
AN - SCOPUS:85093501482
SN - 2051-5960
VL - 8
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
M1 - 172
ER -