Genetic associations with dementia-related proteinopathy: Application of item response theory.
Alzheimers Dement
; 20(4): 2906-2921, 2024 04.
Article
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| MEDLINE
| ID: mdl-38460116
ABSTRACT
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 Aß, 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-, Aß/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.Palabras clave
ARHGEF28; Alzheimer's Coordinating Center; Alzheimer's Disease Neuroimaging Initiative; Alzheimer's Disease Sequencing Project; Alzheimer's disease neuropathologic changes (ADNC); Item response theory; Lewy; RGNEF; Religious Orders Study; Rush Memory and Aging Project (MAP); SDHAF1; TMEM68; neuropathology
Texto completo:
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Banco de datos:
MEDLINE
Asunto principal:
Productos Biológicos
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Demencia
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Proteinopatías TDP-43
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Deficiencias en la Proteostasis
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Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article