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| Author | 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; Hsiao, John K; 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; Jagust, William; Knaack, Alexander; DeCarli, Charles; Harvey, Danielle; Fletcher, Evan; Beckett, Laurel; González, Hector; Jin, Chengshi; Tosun‐Turgut, Duygu; Neuhaus, John; Fockler, Juliet; Nosheny, Rachel; Koeppe, Robert A; Trojanowki, John Q; Shaw, Leslie M; 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 |
| Title | Genetic associations with dementia‐related proteinopathy: Application of item response theory |
| URL | https://escholarship.org/uc/item/89p9t949  |
| Publication Date | 2024 |
| University/Publisher | University of California |
| Abstract | IntroductionAlthough dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.MethodsWe 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.ResultsFinal 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.DiscussionA novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.HighlightsLatent 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. |
| Subjects/Keywords | Biomedical and Clinical Sciences; Biological Psychology; Clinical Sciences; Neurosciences; Psychology; Acquired Cognitive Impairment; Neurodegenerative; Brain Disorders; Dementia; Genetics; Prevention; Aging; 2.1 Biological and endogenous factors; Aetiology; Neurological; Humans; alpha-Synuclein; TDP-43 Proteinopathies; Proteostasis Deficiencies; DNA-Binding Proteins; Biological Products; Alzheimer Disease; Membrane Proteins; Nerve Tissue Proteins; Alzheimer's Disease Neuroimaging Initiative; National Alzheimer's Coordinating Center; ARHGEF28; Alzheimer's Coordinating Center; Alzheimer's Disease Sequencing Project; Alzheimer's disease neuropathologic changes; Item response theory; Lewy; RGNEF; Religious Orders Study; Rush Memory and Aging Project; SDHAF1; TMEM68; neuropathology; Geriatrics; Clinical sciences; Biological psychology |
| Rights | public |
| Country of Publication | us |
| Format | application/pdf |
| Record ID | oai:escholarship.org:ark:/13030/qt89p9t949 |
| Other Identifiers | qt89p9t949 |
| Repository | california |
| Date Retrieved | 2024-05-07 |
| Date Indexed | 2024-05-07 |