A Non-Synonymous SHARPIN Variant is Associated with Limbic Degeneration and Family History of Alzheimer’s Disease

Abstract

Mapping the spatiotemporal dynamics of brain atrophy in the Alzheimer's disease (AD) aids in discovering vulnerable brain networks. Various MRI-derived measures including hippocampal volume loss are commonly used as imaging biomarkers of AD progression. Multivariate methods such as independent component analysis (ICA) have recently shown promise in revealing more complex patterns of brain atrophy.Here, we aimed to extract a data-driven signature of brain atrophy in AD and its heralding risk factor, the mild cognitive impairment (MCI) state. Structural brain changes were quantified in 1,892 MRI scans from 1,100 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) by Tensor-Based Morphometry (TBM).Brain morphometry maps of this population were fed into an ICA-based feature extraction algorithm which revealed that AD is associated with a characteristic signature of brain degeneration spanning several areas of the limbic system. The highest probability of brain atrophy in AD was localized to amygdalae (pICA z-score>22), followed by hippocampus (pICA z-score>14), and the mammillary bodies (pICA z-score>9) together with their white-matter connections including fimbrial and fornical tracts as a unified MRI endophenotype. This endophenotype performed better than the hippocampal volume measure in discriminating both AD and MCI subjects from the cognitively normal group, and we evaluated the potential for this feature set to serve as a disease-related endophenotype in a whole-genome association study. A protein-altering polymorphism in the synaptic scaffold gene, SHARPIN, affected loss of volume in this endophenotype among 8,852,807 whole-genome sequencing-based variants (rs34173062; p =2.1×10 -10 ). Other suggestive but subgenome-wide signals mapped to EPHA7 and FRMD4A, two known AD risk loci.In conclusion, by unsupervised decomposition of brain morphometry maps, we have provided a unified imaging endophenotype of AD that closely maps to the brain's memory center. Observation of bilateral amygdalae as the most vulnerable limbic structures spotlights impairment of emotional and memory processing integration in early AD.

Revealing the correlations between brain cortical characteristics and susceptibility genes for Alzheimer disease: a cross-sectional study

“…CT, one of the most sensitive imaging biomarkers of structural brain atrophy in AD, was selected as an endophenotype and was found to be strongly correlated with 4 genes (B4GALNT1, RAB44, LOC101927583, and SLC26A10) related to protein degradation, neuronal deletion, and apoptosis (25,26). Another GWAS study showed that the medial temporal circuit (MTC) could be used as another imaging phenotype and that the SNP rs34173062 in the SHARPIN gene had a genetic modifying effect on MTC atrophy (27). Recently, it was demonstrated that the SNP rs661526 modulated the expression of NFIA in the substantia nigra and the frontal cortex (FCTX), and the SNP rs10109716 modulated the expression of ST18 in the thalamus, which were significantly associated with increased CT in the left parahippocampal gyrus and left inferior frontal gyrus, respectively (28).…”