| Title: |
Genetic associations with dementia‐related proteinopathy: Application of item response theory |
| Authors: |
Katsumata, Yuriko; Fardo, David W; Shade, Lincoln MP; Wu, Xian; Karanth, Shama D; Hohman, Timothy J; Schneider, Julie A; Bennett, David A; Farfel, Jose M; Gauthreaux, Kathryn; Mock, Charles; Kukull, Walter A; Abner, Erin L; Nelson, Peter T; Carrillo, Maria; Reiman, Eric M; Chen, Kewei; Masterman, Donna; Green, Robert C; Ho, Carole; Fleisher, Adam; Saykin, Andrew J; Nho, Kwangsik; Apostolova, Liana G; Risacher, Shannon L; Jackson, Jonathan; Forghanian-Arani, Arvin; Borowski, Bret; Ward, Chad; Schwarz, Christopher; Jack, Clifford R; Jones, David; Gunter, Jeff; Kantarci, Kejal; Senjem, Matthew; Vemuri, Prashanthi; Reid, Robert; Petersen, Ronald; Hsiao, John K; Potter, William; Masliah, Eliezer; Ryan, Laurie; Bernard, Marie; Silverberg, Nina; Kormos, Adrienne; Conti, Cat; Veitch, Dallas; Flenniken, Derek; Sacrey, Diana Truran; Choe, Mark; Ashford, Miriam; Chen, Stephanie Rossi; Faber, Kelley; Nudelman, Kelly; Wilme, Kristi; Foroud, Tatiana M; Trojanowki, John Q; Shaw, Leslie M; Korecka, Magdalena; Figurski, Michal; Khachaturian, Zaven; Barnes, Lisa; Malone, Ian; Fox, Nick C; Beckett, Laurel; Weiner, Michael W; Jagust, William; Landau, Susan; Knaack, Alexander; DeCarli, Charles; Harvey, Danielle; Fletcher, Evan; González, Hector; Jin, Chengshi; Tosun‐Turgut, Duygu; Neuhaus, John; Fockler, Juliet; Nosheny, Rachel; Koeppe, Robert A; Yushkevich, Paul A; Das, Sandhitsu; Mathis, Chet; Toga, Arthur W; Zimmerman, Caileigh; Gessert, Devon; Shcrer, Elizabeth; Miller, Garrett; Coker, Godfrey; Jimenez, Gustavo; Salazar, Jennifer; Pizzola, Jeremy; Crawford, Karen; Hergesheimer, Lindsey; Donohue, Michael; Rafii, Michael |
| Source: |
Alzheimer's & Dementia, vol 20, iss 4 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
32 Biomedical and Clinical Sciences (for-2020); 5202 Biological Psychology (for-2020); 3202 Clinical Sciences (for-2020); 3209 Neurosciences (for-2020); 52 Psychology (for-2020); Acquired Cognitive Impairment (rcdc); Neurodegenerative (rcdc); Brain Disorders (rcdc); Prevention (rcdc); Aging (rcdc); Neurosciences (rcdc); Alzheimer's Disease Related Dementias (ADRD) (rcdc); Dementia (rcdc); Genetics (rcdc); Lewy Body Dementia (rcdc); Alzheimer's Disease (rcdc); Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc); 2.1 Biological and endogenous factors (hrcs-rac); Neurological (hrcs-hc); Humans (mesh); alpha-Synuclein (mesh); TDP-43 Proteinopathies (mesh); Proteostasis Deficiencies (mesh); Dementia (mesh); DNA-Binding Proteins (mesh); Biological Products (mesh); Alzheimer Disease (mesh); Membrane Proteins (mesh); Nerve Tissue Proteins (mesh); Alzheimer's Disease Neuroimaging Initiative |
| Time: |
2906 - 2921 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt89p9t949; https://escholarship.org/uc/item/89p9t949; https://escholarship.org/content/qt89p9t949/qt89p9t949.pdf |
| DOI: |
10.1002/alz.13741 |
| Availability: |
https://escholarship.org/uc/item/89p9t949; https://escholarship.org/content/qt89p9t949/qt89p9t949.pdf; https://doi.org/10.1002/alz.13741 |
| Rights: |
CC-BY-NC |
| Accession Number: |
edsbas.C5FE8BB7 |
| Database: |
BASE |