1. Genetic associations with dementia-related proteinopathy: Application of item response theory.
- Author
-
Katsumata Y, Fardo DW, Shade LMP, Wu X, Karanth SD, Hohman TJ, Schneider JA, Bennett DA, Farfel JM, Gauthreaux K, Mock C, Kukull WA, Abner EL, and Nelson PT
- Subjects
- Humans, alpha-Synuclein genetics, DNA-Binding Proteins, Membrane Proteins genetics, Nerve Tissue Proteins genetics, TDP-43 Proteinopathies genetics, TDP-43 Proteinopathies pathology, Proteostasis Deficiencies, Dementia genetics, Biological Products, Alzheimer Disease pathology
- 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: 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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
- Published
- 2024
- Full Text
- View/download PDF