1. A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages
- Author
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Jun Young Park, Dongsoo Lee, Jang Jae Lee, Jungsoo Gim, Tamil Iniyan Gunasekaran, Kyu Yeong Choi, Sarang Kang, Ah Ra Do, Jinyeon Jo, Juhong Park, Kyungtaek Park, Donghe Li, Sanghun Lee, Hoowon Kim, Immanuel Dhanasingh, Suparna Ghosh, Seula Keum, Jee Hye Choi, Gyun Jee Song, Lee Sael, Sangmyung Rhee, Simon Lovestone, Eunae Kim, Seung Hwan Moon, Byeong C. Kim, SangYun Kim, Andrew J. Saykin, Kwangsik Nho, Sung Haeng Lee, Lindsay A. Farrer, Gyungah R. Jun, Sungho Won, Kun Ho Lee, and for the Alzheimer’s Disease Neuroimaging Initiative
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
- Published
- 2021
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