Initially, SHARPIN was found as a post-synaptic density protein. The multifunctional SHARPIN (SHANK-associated RH domain interactor) protein is associated with numerous physiologic functions and many diseases. Although these studies based on Caucasian cohorts have revealed functional variants in several genes, including TREM2, the identified variants have rarely occurred in Japanese populations.
To breach this missing heritability, next-generation sequencing technologies such as whole-genome sequencing (WGS) and whole-exome sequencing (WES) have been applied to discover LOAD-risk variants.
However, combining all known risk loci fails to account for the total estimated heritability of LOAD. The APOE ε4 allele is the strongest known genetic risk factor for LOAD. Since the 2010s, meta-analysis of genome-wide association studies (GWAS) has identified more than 40 loci associated with the risk of LOAD. A large twin study in 2006 revealed an estimated heritability ( h 2) of 58–79% for LOAD. LOAD arises from complex interactions among multiple genetic and environmental factors. Currently, the only available treatment for late-onset AD (LOAD) is to decelerate the progression of the disease. Alzheimer’s disease (AD), comprising familial (early-onset), and sporadic (late-onset) disease forms, is the most common form of dementia. The number of elderly adults with dementia is rapidly increasing and expected to reach 74.7 million in 2030 and 131.5 million in 2050. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.ĭementia is associated with a deterioration in cognitive function and is one of the leading causes of death worldwide. Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls ( P = 0.0016, odds ratio = 1.43). Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment.
In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial.
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