Dissection of the Polygenic Architecture of Neuronal Aβ Production Using a Large Sample of Individual IPSC Lines Derived from Alzheimer's Disease Patients

Overview

Journal Nat Aging

Specialty Geriatrics

Date 2023 Apr 28

PMID 37117761

Authors

Takayuki Kondo

Norikazu Hara

Satoshi Koyama

Yuichiro Yada

Kayoko Tsukita

Ayako Nagahashi

Takeshi Ikeuchi

Kenji Ishii

Takashi Asada

Tetsuaki Arai

Ryo Yamada

Haruhisa Inoue

Affiliations

Soon will be listed here.

Abstract

Genome-wide association studies have demonstrated that polygenic risks shape Alzheimer's disease (AD). To elucidate the polygenic architecture of AD phenotypes at a cellular level, we established induced pluripotent stem cells from 102 patients with AD, differentiated them into cortical neurons and conducted a genome-wide analysis of the neuronal production of amyloid β (Aβ). Using such a cellular dissection of polygenicity (CDiP) approach, we identified 24 significant genome-wide loci associated with alterations in Aβ production, including some loci not previously associated with AD, and confirmed the influence of some of the corresponding genes on Aβ levels by the use of small interfering RNA. CDiP genotype sets improved the predictions of amyloid positivity in the brains and cerebrospinal fluid of patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Secondary analyses of exome sequencing data from the Japanese ADNI and the ADNI cohorts focused on the 24 CDiP-derived loci associated with alterations in Aβ led to the identification of rare AD variants in KCNMA1.

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