Novel Alzheimer\u2019s disease risk variants identified based on whole-genome sequencing of APOE \u03b54 carriers

Jong Ho Park ,Woon Yoon,Seong Hye Choi,Ki Woong Kim,Eunjung Alice Lee,Junehawk Lee,Seong Yoon Kim,Jun Ho Lee,Kye Won Park,Sejoon Lee,Jee Hyang Jeong,Duk L Na,Min Soo Byun,Sun Ju Chung,Hyojin Kang,Dahyun Yi,Emilia Moonkyung Youm,Dong Hoon Lee ,Young-Hoon Kim ,Eun Joo Kim ,June Hee Park ,Nag-Choul Choi ,Sang Won Seo,Inho Park,Jongan Lee,Hoyoung An,Jong Won Kim

doi:10.1038/s41398-021-01412-9

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E−07) and rs12594991 (P = 2.03E−07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60–70% of all cases[1]
We conducted whole-genome sequencing (WGS) of AD patients and matched controls in a Korean population who were apolipoprotein E ε4 (APOE ε4) carriers, to find genetic variants dependent on APOE ε4 allele status, which is highly associated with AD pathogenesis
Large-scale genome-wide association studies (GWAS) such as the International Genomics of Alzheimer’s Project (IGAP) have reported various variants associated with AD; these studies have mainly focused on non-Asian populations, and the genetic architecture of AD is less clear in Asian populations

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60–70% of all cases[1]. Mendelian form of AD, accounts for >99% of AD and is highly heritable (estimates of 58–79%), with complex genetic etiology[5,6]. The APOE ε4 allele is the strongest genetic risk factor for LOAD, with a population attributable fraction of approximately 30–35%7. The search for additional genetic risk factors through genome-wide association studies (GWAS) conducted mainly in European populations have yielded a few dozen genetic loci, Park et al Translational Psychiatry (2021)11:296 beyond APOE ε4, associated with LOAD8–12. The genetic liability of AD by APOE and GWAS findings is estimated to be only 24–33%, which is not enough to explain the 58–79% heritability for AD revealed by twin studies[5,6]

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