In:
Translational Psychiatry, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-11-16)
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.
Type of Medium:
Online Resource
ISSN:
2158-3188
DOI:
10.1038/s41398-021-01680-5
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2021
detail.hit.zdb_id:
2609311-X
