講演情報
[P21-1]全ゲノムシーケンスによるアルツハイマー病に関連したMLKL遺伝子の日本人に特異的な新規希少バリアントの発見
○木村 哲晃1, 浅海 裕也1, 秋山 真太郎1, 光森 理紗1, 森園 隆1,2, 新飯田 俊平3, 尾崎 浩一1,2, 重水 大智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)
Alzheimer’s disease (AD) is the most common multifactorial neurodegenerative disease among elderly people. Genome-wide association studies (GWAS) have been highly successful in identifying genetic risk factors. However, GWAS investigate common variants, which tend to have small effect sizes, and rare variants with potentially larger phenotypic effects have not been sufficiently investigated. Whole-genome sequencing (WGS) enables us to detect those rare variants. Here, we performed rare-variant association studies by using WGS data from 140 individuals with probable AD and 798 cognitively normal elder controls (CN), as well as single-nucleotide polymorphism genotyping data from an independent large Japanese AD cohort of 1604 AD and 1235 CN subjects. We identified a rare variant as candidates for AD association: a stop-gain variant in MLKL (rs763812068, c.142 C ＞ T, p.Q48X). Subsequent in vitro functional analysis revealed that the MLKL stop-gain variant can contribute to increases not only in abnormal cells that should die by programmed cell death but do not, but also in the ratio of Aβ42 to Aβ40. To identify additional functional variants of MLKL in Japanese population, we further performed Sanger sequencing of 480 ADs, where two candidate rare variants were identified. We apply functional analysis of them, and report on the pathogenic mechanism.