Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer’s disease

This study utilized whole-genome sequencing (WGS) data from 140 individuals with probable Alzheimer's disease (AD) and 798 cognitively normal elder controls, along with single-nucleotide polymorphism genotyping data from a large independent Japanese AD cohort, to identify rare variants associated with AD. Two rare variants were identified as candidates: a missense variant in OR5G1 and a stop-gain variant in MLKL. In vitro functional analysis showed that the MLKL stop-gain variant increased the ratio of Aβ40 to Aβ42 and contributed to the accumulation of abnormal cells. Gene-based association tests identified further AD candidate genes, and a network-based meta-analysis revealed four functionally important hub genes (NCOR2, PLEC, DMD, and NEDD4). These findings offer novel insights into AD pathogenesis.

Daichi Shigemizu, Yugo Asanomi, Shintaro Akiyama, Risa Mitsumori, Shumpei Niida, Kouichi Ozaki