Novel Alzheimer's disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers

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.

Fig. 1. Schematic workflows.

The schematic workflow shows the procedures for detecting novel genetic variants associated with Alzheimer’s Disease (AD) in a Korean population of APOE ε4 carriers (A) and for assessing the reproducibility of previously reported AD loci and suggestive novel loci shown to be population-specific (B). cAD customized genotyping AD chip, IGAP International Genomics of Alzheimer’s Project.

Fig. 2. Regional plot of known loci (11q14.2; PICALM and 19q13.32; APOE) that are significantly associated with Alzheimer’s disease (AD) in the cAD chip application set.

The figures show the regional association plot of known representative loci, (A) 11q14.2; PICALM and (B) 19q13.32; APOE, in the cAD chip application set (n = 1,437). The purple shaded diamond shape represents rs3851179 and rs429358, which are the most significant SNPs in 11q14.2 (A) and 19q13.32 (B), respectively. The blue line indicates the recombination rate, while filled color represents the linkage disequilibrium score based on r² values estimated from the 1000 genome Nov 2014 ASN data.

Fig. 3. Regional plot of novel candidate variants significantly associated within APOE ε4 carriers.

The figures show the regional association plot of known representative loci, (A) 10q25.1; SORCS1 and (B) 15q26.1; CHD2, in the cAD chip application set with a combined P value < 0.000001. The purple shaded diamond shape represents rs1890078 and rs12594991, which are the most significant SNPs in 10q25.1 (A) and 15q26.1 (B), respectively. The blue line indicates the recombination rate, while filled color represents the linkage disequilibrium score based on r² values estimated from the 1000 genome Nov 2014 ASN data.