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

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

doi:10.1038/s41380-022-01483-0

Abstract

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 two rare variants as candidates for AD association: a missense variant in OR51G1 (rs146006146, c.815 G > A, p.R272H) and 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. We further detected AD candidate genes through gene-based association tests of rare variants; a network-based meta-analysis using these candidates identified four functionally important hub genes (NCOR2, PLEC, DMD, and NEDD4). Our findings will contribute to the understanding of AD and provide novel insights into its pathogenic mechanisms that can be used in future studies.

Highlights

Alzheimer’s disease (AD) is the most common multifactorial neurodegenerative disease among elderly people [1, 2]
98.3% were mapped to the human reference genome (GRCh37) and 7.6% were removed as duplicate PCR read pairs (Supplementary Table S1)
Four of them have not been verified as expressed in brain tissues through the Human Protein Atlas database [31], which provides quantitative transcriptomics at the tissue and organ level and is publicly accessible at http://www. proteinatlas.org (Fig. S3), but we considered the remaining four (i.e., NCOR2, DMD, NEDD4, and PLEC) to be strong candidate hub genes associated with AD pathogenesis

Summary

Introduction

Alzheimer’s disease (AD) is the most common multifactorial neurodegenerative disease among elderly people [1, 2]. EOAD accounts for up to 5% of all AD cases, most of which are caused by rare autosomal dominant mutations in one of three genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) [5]. The majority of AD cases are sporadic LOAD, a heterogeneous disorder with complex interactions between genetic and environmental risk factors, which are influenced by multiple common variants with low effect sizes [6, 7]. The ε4 polymorphism in the protein encoded by the apolipoprotein E (APOE) gene, located on chromosome 19, is considered to be the strongest genetic risk factor for LOAD [9]. The APOE ε4 effect accounts for only 27.3% of the overall heritability [10], and a large proportion of the heritability remains unexplained

Methods

Results

Conclusion