Genetic associations with dementia‐related proteinopathy: Application of item response theory

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.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.

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis

“…Along the same lines, its cognate protein RGNEF has been found to localize to hallmark TDP-43-immunoreactive inclusion bodies in ALS patient spinal cord motor neurons ( 232 , 233 ). We recently found that the ARHGEF28 SNP rs80190672 was associated with LATE-NC ( 234 ). This genotype-phenotype correlation may provide another point of etiologic connection between LATE-NC and the ALS/FTLD disease continuum.…”