Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44907187 G>A
Position: (GRCh37/hg19):Chr19:45410444 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs769450
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 2

Findings

This common intronic variant has been associated with Alzheimer’s disease risk. However, its contribution to disease is uncertain. As illustrated in the table below, several large genome-wide association studies (GWAS) have found highly significant associations, but when the presence of the APOE2/3/4 alleles has been taken into account, the p-values of the associations drop dramatically. Moreover, one GWAS meta-analysis reported the allele as being not “credibly causal” based on a Bayesian model that uses fine-mapping to calculate the probability that a given polymorphism is driving an association signal (Jansen et al., 2019).

Data on the linkage between this variant and other nearby variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section). Note that even weak linkages can be important as they can lead to confounding effects without proper adjustment (e.g., Andrews et al., 2019).

Although the variant is frequent among people of European and African ancestries (0.41 and 0.38, respectively), it is less prevalent in Latino/Admixed Americans and East Asians (0.29 and 0.20, respectively), and absent from South Asians in the gnomAD variant database (v2.1.1, Jun 2022).

Non-Neurological Conditions

Several studies have reported associations of this variant with blood lipid and protein profiles. For example, a meta-analysis of 32 studies including data from more than 66,000 individuals (Asselbergs et al., 2012) and a GWAS including more than 350,000 individuals of mixed ancestry from the UK Biobank (Sinnott-Armstrong et al., 2021, GWAS Catalog), found c.43+520G>A associated with increased levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C). Two other studies reported similar associations and found evidence for c.43+520G>A having an effect on these traits independent of other variants (Musunuru et al., 2012; Pirim et al., 2019)—in one study, specifically independent of APOE4 and APOE2 (Pirim et al., 2019).

Of potential neurological interest, c.43+520G>A was found associated with levels of C-reactive protein in both African Americans and individuals of European descent (Ellis et al., 2014, Sinnott-Armstrong et al., 2021, GWAS Catalog). This protein is an inflammation marker in blood whose elevation in mid-life, appears to correlate with later cognitive decline (Feb 2019 news; Walker et al., 2019). However, whether the association is causal or not remains unknown.

Interestingly, genetic ancestry may play a role in determining the associations of this variant with physiological traits. For example, although the study was relatively small, Pirim and colleagues identified associations with total cholesterol, LDL-cholesterol, and triglycerides in non-Hispanic whites (623 individuals), but not in African Blacks (788 individuals) (Pirim et al., 2019). Moreover, Musunuru and co-workers reported increased LDL levels in both European- and African Americans, but only the European association qualified as likely independent (Musunuru et al., 2012).

This variant has also been examined in small cohorts in the context of other conditions, such as menopause (He et al., 2009, Spencer et al., 2013), bone density (Singh et al., 2010), leprosy (Wang et al., 2018), dietary effects on blood lipids (Shatwan et al., 2018), and risk of metabolic syndrome (Son et al., 2015).

Biological Effect

The biological effect of this variant is unknown, but its PHRED-scaled CADD score (4.31), which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, May 2022).

Table

^a24,087 LOAD cases; 47,793 offspring of parents with AD
^bData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) rs769450, Sep 2022
^cData from GWAS Catalog rs769450, Aug 2022
^dAssociation not found after APOE4 adjustment (p cut-off=5x10^-8)

OR=odds ratio, GWAS=genome-wide association study. Statistically significant associations (as assessed by the authors) are in bold. For data retrieved from NIAGADS, p-values <5x10^-8 are in bold. All data retrieved from the GWAS catalog (p-values <1x10^-5) are in bold. For Caucasian and mixed ancestry cohorts, only studies with at least 2,000 cases were included in the table. 

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References

News Citations

1. Midlife Peripheral Inflammation May Drive Later Cognitive Decline 20 Feb 2019

Paper Citations

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External Citations

1. GWAS catalog
2. GWAS Catalog

Further Reading

No Available Further Reading