Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk

Christopher R Simmons,Steven G Younkin,Steven Estus,Fanggeng Zou

doi:10.1186/1750-1326-6-62

Christopher R Simmons, Steven G Younkin + Show 2 more

Open Access

https://doi.org/10.1186/1750-1326-6-62

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Abstract

BackgroundRecent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD.ResultsSeventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with HMGCR exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with HMGCR exon 13 splicing in liver- and brain-derived cell lines.ConclusionsCholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD.

Highlights

Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol
Cholesterol-associated SNPs are associated with Alzheimer’s disease (AD) A review of GWAS via the Human Genome (HuGE) Navigator database identified eighteen non-redundant SNPs whose associations with total cholesterol, low-density lipoprotein (LDL) and/or high-density lipoprotein (HDL) are highly significant (p < 1 × 10-10) and have been replicated in at least two populations
The primary findings of our study are that: (1) SNPs unequivocally associated with plasma cholesterol demonstrate a significant global association with AD risk, (2) rs3846662 and rs1532085 are associated with AD age-of-onset, (3) rs3846662 is associated with HMGCR exon 13 splicing in human liver in vivo and in brain and liver-derived cell lines in vitro

Summary

Introduction

Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer’s disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are associated with AD. Genome-wide association studies (GWAS)s have recently uncovered single nucleotide polymorphisms (SNP)s that are robustly and reproducibly associated with total cholesterol, low-density lipoprotein (LDL) and/or high-density lipoprotein (HDL) [15,16,17,18,19,20,21,22,23] As such, these SNPs are essentially unequivocally associated with cholesterol and serve as outstanding tools to evaluate the genetic relatedness between cholesterol and AD. Based on (i) the significant heritability of AD, (ii) the robust involvement of APOE in AD risk, (iii) a growing body of evidence that cholesterol itself modulates AD risk and (iv) the ontological overrepresentation of cholesterol gene variants in AD GWAS results we hypothesize that SNPs associated with peripheral cholesterol via GWAS contribute to AD risk

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