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

Abstract

Pharmacological progress, basic science and medical practice can benefit from objective biomarkers that assist in early diagnosis and prognostic stratification of diseases. In the field of Alzheimers disease (AD), the clinical presentation of early stage dementia may not fulfill any diagnostic criteria for years, and quantifying structural brain changes by magnetic resonance imaging (MRI) has shown promise in the discovery of sensitive biomarkers. Although hippocampal atrophy is often used as an in vivo measure of AD, data-driven neuroimaging has revealed complex patterns of regional brain vulnerability that may not perfectly map to anatomical boundaries. In addition to aiding diagnosis, decoding genetic influences on neuroimaging measures of the disease can enlighten molecular mechanisms of the underlying pathology in living patients and guide the therapeutic design.\n\nHere, we aimed to extract a data-driven MRI feature of brain atrophy in AD by decomposing structural neuroimages using independent component analysis (ICA), a method for performing unbiased computational search in high dimensional data spaces. Our study of the AD Neuroimaging Initiative dataset (n=1,100 subjects) revealed a disease-vulnerable feature with a network-like topology, comprising amygdala, hippocampus, fornix and the inter-connecting white-matter tracts of the limbic system. Whole-genome sequencing identified a nonsynonymous variant (rs34173062) in SHARPIN, a gene coding for a synaptic protein, as a significant modifier of this new MRI feature (p=2.1x10-10). The risk variant was brought to replication in the UK Biobank dataset (n=8,428 subjects), where it was associated with reduced cortical thickness in areas co-localizing with those of the discovery sample (left entorhinal cortex p=0.002, right entorhinal cortex p=8.6x10-4; same direction), as well as with the history of AD in both parents (p=2.3x10-6; same direction).\n\nIn conclusion, our study shows that ICA can transform voxel-wise volumetric measures of the brain into a data-driven feature of neurodegeneration in AD. Structure of the limbic system, as the most vulnerable focus of brain atrophy in AD, is affected by genetic variability of SHARPIN. The elevated risk of dementia in carriers of the minor allele supports engagement of SHARPIN in the disease pathways, and its role in neurotransmitter receptor scaffolding and integrin signaling may inform on new molecular mechanisms of AD pathophysiology.\n\nAbbreviationsAlzheimers disease (AD), genome-wide association study (GWAS), independent component analysis (ICA), mild cognitive impairment (MCI), medial temporal circuit (MTC), single-nucleotide polymorphism (SNP), tensor-based morphometry (TBM)