TY - JOUR
T1 - Genetic associations with dementia-related proteinopathy
T2 - Application of item response theory
AU - The Alzheimer's Disease Neuroimaging Initiative
AU - The National Alzheimer's Coordinating Center
AU - Katsumata, Yuriko
AU - Fardo, David W.
AU - Shade, Lincoln M.P.
AU - Wu, Xian
AU - Karanth, Shama D.
AU - Hohman, Timothy J.
AU - Schneider, Julie A.
AU - Bennett, David A.
AU - Farfel, Jose M.
AU - Gauthreaux, Kathryn
AU - Mock, Charles
AU - Kukull, Walter A.
AU - Abner, Erin L.
AU - Nelson, Peter T.
AU - Carrillo, Maria
AU - Reiman, Eric M.
AU - Chen, Kewei
AU - Masterman, Donna
AU - Green, Robert C.
AU - Ho, Carole
AU - Fleisher, Adam
AU - Saykin, Andrew J.
AU - Nho, Kwangsik
AU - Apostolova, Liana G.
AU - Risacher, Shannon L.
AU - Jackson, Jonathan
AU - Forghanian-Arani, Arvin
AU - Borowski, Bret
AU - Ward, Chad
AU - Schwarz, Christopher
AU - Jack, Clifford R.
AU - Jones, David
AU - Gunter, Jeff
AU - Kantarci, Kejal
AU - Senjem, Matthew
AU - Vemuri, Prashanthi
AU - Reid, Robert
AU - Petersen, Ronald
AU - Hsiao, John K.
AU - Potter, William
AU - Masliah, Eliezer
AU - Hsiao, John K.
AU - Ryan, Laurie
AU - Bernard, Marie
AU - Silverberg, Nina
AU - Kormos, Adrienne
AU - Conti, Cat
AU - Veitch, Dallas
AU - Flenniken, Derek
AU - Sacrey, Diana Truran
N1 - Publisher Copyright:
© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2024
Y1 - 2024
N2 - INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.
AB - INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.
KW - ARHGEF28
KW - Alzheimer's Coordinating Center
KW - Alzheimer's Disease Neuroimaging Initiative
KW - Alzheimer's Disease Sequencing Project
KW - Alzheimer's disease neuropathologic changes (ADNC)
KW - Item response theory
KW - Lewy
KW - RGNEF
KW - Religious Orders Study
KW - Rush Memory and Aging Project (MAP)
KW - SDHAF1
KW - TMEM68
KW - neuropathology
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U2 - 10.1002/alz.13741
DO - 10.1002/alz.13741
M3 - Article
C2 - 38460116
AN - SCOPUS:85187865746
SN - 1552-5260
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
ER -