講演情報
[P12-10]日本人における遅発性アルツハイマー病関連遺伝子SHARPINの同定と解析
○浅海 裕也1, 重水 大智1,2, 秋山 真太郎1, 光森 理紗1, 新飯田 俊平3, 尾崎 浩一1,2 (1.国立長寿医療研究センター 研究所 メディカルゲノムセンター, 2.理化学研究所 生命医科学研究センター, 3.国立長寿医療研究センター 研究所 研究推進基盤センター)
Despite the recent advances in genetic studies for late-onset Alzheimer's disease (LOAD), more than half of the heritability of the disease remains unclear. We have been conducting exploration studies for LOAD risk factors with dementia patients and cognitively healthy elderlies from Japanese cohorts registered in National Center for Geriatrics and Gerontology Biobank. To date, we performed whole-exome sequencing analyses for 202 Japanese LOAD patients without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility, and identified a rare functional variant of SHARPIN, rs572750141 (p.Gly186Arg), associated with an increased risk of the disease. Subsequently, two other risk variants of SHARPIN, never observed in Japanese, were reported from large-scale genome wide association studies in Caucasians, indicating the important role of SHARPIN in LOAD pathogenesis. Recently, we conducted further exploration of novel functional SHARPIN variants in Japanese patients. By means of the in silico target resequencing with whole-genome sequencing data of 364 patients, we found a functional risk variant of LOAD, rs77359862 (p.Arg274Trp) in SHARPIN. Further investigation focusing on the genetic relevance of SHARPIN with LOAD and the physiological role of SHARPIN could likely provide elucidation for the mechanism of LOAD onset. We have been performing functional analyses of the variant-type SHARPIN protein in in vitro studies. We are currently preparing knock-in cells with genome editing technology for further analysis of endogenous variant-type SHARPIN.