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.

Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

“…Accordingly, gene expression analysis of amygdala from 19 AD patients revealed significantly lower SORCS1 expression compared to healthy controls [108]. Furthermore, SORCS1 genetically interacts with SNPs in APOE [313,314], SORCS2 and SORCS3 [84], respectively, to increase AD risk suggesting that these proteins functionally associate in shared actions. Several SNPs in SORCS1 have also been linked to neurodegenerative transmissible spongiform encephalopathies caused by accumulation of PrP sc .…”

Finding Memo: Versatile interactions of the VPS10p receptors in Alzheimer’s disease

“…Accordingly, gene expression analysis of amygdala from 19 AD patients revealed significantly lower SORCS1 expression compared to healthy controls [225]. Further, SORCS1 genetically interacts with SNPs in APOE [229,230], SORCS2 and SORCS3 [83], respectively, to increase AD risk suggesting that these proteins functionally associate in shared actions. Several SNPs in SORCS1 have also been linked to neurodegenerative transmissible spongiform encephalopathies caused by accumulation of PrP sc .…”

A Fast and Robust Strategy to Remove Variant-Level Artifacts in Alzheimer Disease Sequencing Project Data

“…2 In response to this observation, there has been a shift to start using exome sequencing (ES) or genome sequencing (GS) to help capture rare and/or coding variants that contribute to AD risk, which has led to several recent initial successes. 7-15…”

“…2 In response to this observation, there has been a shift to start using exome sequencing (ES) or genome sequencing (GS) to help capture rare and/or coding variants that contribute to AD risk, which has led to several recent initial successes. [7][8][9][10][11][12][13][14][15] In the United States, the Alzheimer Disease Sequencing Project (ADSP) has taken a leading role in the sequencing of AD-related samples at scale, with resultant data being made publicly available to researchers to generate new insights into the genetic etiology of AD. The ADSP has pursued both "whole" ES (WES) and "whole" GS (WGS) approaches (although it should be noted that these for now do not actually provide whole coverage due to technical limitations), where most recently, the focus is increasingly on GS.…”