Genome‐wide association studies of TDP‐43 proteinopathy and hippocampal sclerosis reveal shared genetic associations with APOE and TMEM106B

作者：Dana Godrich, Jeremy Pasteris, Eden R. Martin, Brian W. Kunkle, Adam C. Naj, Kara Hamilton, Hui Wang, Wan‐Ping Lee, Logan Dumitrescu, Timothy J. Hohman, Richard Mayeux, Eric B. Larson, Paul K. Crane, C. Dirk Keene, Caitlin S. Latimer, Shubhabrata Mukherjee, Julia Kofler, M. Ilyas Kamboh, David Bennett, Laura Molina‐Porcel, Gerard D. Schellenberg, Margaret A. Pericak‐Vance, Michael L. Cuccaro, William K. Scott, Tatjana Rundek, Walter A. Kukull, Thomas J. Montine, Gary W. Beecham · 发表于：Alzheimer s & Dementia · 年份：2025 · DOI：10.1002/alz.70760 · 被引用次数：6 · 研究领域：Amyotrophic Lateral Sclerosis Research、Glycogen Storage Diseases and Myoclonus、Phosphodiesterase function and regulation

INTRODUCTION: Transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy has been linked to cognitive decline and often co-occurs with hippocampal sclerosis (HS). To identify genetic markers of TDP-43 proteinopathy and HS, we performed genome-wide association studies (GWASs) of HS and TDP-43 inclusions. METHODS: Genetic data were obtained through the Alzheimer Disease Genetics Consortium and collaborating sites (HS: N = 9509; TDP-43: N = 4669). Statistical analyses included association analysis with HS and TDP-43 inclusions and meta-analysis, a mediation analysis, and fine mapping of the transmembrane protein 106B (TMEM106B) region. RESULTS: Two regions achieved genome-wide significance with TDP-43: apolipoprotein E (APOE) and TMEM106B. Three loci reached genome-wide significance with HS: APOE, TMEM106B, and granulin precursor (GRN). Fine mapping of TMEM106B identified 93 variants in the credible set. Mediation analyses showed that genetic effects on HS were partially mediated through TDP-43 proteinopathy. DISCUSSION: We identified associations with TDP-43 inclusion and HS, showing shared genetic risk across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, and limbic-predominant age-related TDP-43 encephalopathy. HIGHLIGHTS: HS and TDP-43 contribute to dementia and often co-occur. The etiology and relationship of HS and TDP-43 remains unclear. HS and TDP-43 share genetic risk factors in the genes APOE and TMEM106B. Genes have ...