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. 2023 Oct;28(10):4451-4462.
doi: 10.1038/s41380-023-02170-4. Epub 2023 Sep 5.

Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk

M Muaaz Aslam  1 , Kang-Hsien Fan  1 , Elizabeth Lawrence  1 , Margaret Anne Bedison  1 , Beth E Snitz  2 , Steven T DeKosky  3 , Oscar L Lopez  2 , Eleanor Feingold  1 , M Ilyas Kamboh  4
Affiliations

Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk

M Muaaz Aslam et al. Mol Psychiatry. 2023 Oct.

Abstract

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia. To our knowledge, no large genome-wide association study (GWAS) has been reported on plasma ApoE level. This study aimed to identify new genetic variants affecting plasma ApoE level as well as to test if baseline ApoE level is associated with cognitive function and incident dementia in a longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study. Baseline plasma ApoE concentration was measured in 3031 participants (95.4% European Americans (EAs)). GWAS analysis was performed on 2580 self-identified EAs where both genotype and plasma ApoE data were available. Lower ApoE concentration was associated with worse cognitive function, but not with incident dementia. As expected, the risk for AD increased from E2/2 through to E4/4 genotypes (P for trend = 4.8E-75). In addition to confirming the expected and opposite associations of APOE*2 (P = 4.73E-79) and APOE*4 (P = 8.73E-12) with ApoE level, GWAS analysis revealed nine additional independent signals in the APOE region, and together they explained about 22% of the variance in plasma ApoE level. We also identified seven new loci on chromosomes 1, 4, 5, 7, 11, 12 and 20 (P range = 5.49E-08 to 5.36E-10) that explained about 9% of the variance in ApoE level. Plasma ApoE level-associated independent variants, especially in the APOE region, were also associated with AD risk and amyloid deposition in the brain, indicating that genetically determined ApoE level variation may be a risk factor for developing AD. These results improve our understanding of the genetic determinants of plasma ApoE level and their potential value in affecting AD risk.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Flow chart of the GEM study subjects included in the plasma ApoE analysis in the total sample and plasma ApoE-genotype analysis in European Americans (EAs).
MCI = Mild cognitive impairment. Boxes with broken lines indicate that they were not included in the analysis.
Fig. 2
Fig. 2. Manhattan plot of genome-wide association with plasma ApoE levels.
The Red line depicts the genome-wide significance level (P < 5E-08) and the blue line represents suggestive associations (P < 1E-05).
Fig. 3
Fig. 3. Plasma ApoE levels among six APOE genotypes.
Values on the x-axis are the geometric mean of ApoE levels. R2 was adjusted for age and sex.
Fig. 4
Fig. 4. Regional plots of the association of plasma ApoE levels on chromosomes 1, 4, 5, 7, 11,12 and 20.
a Regional plot in the OPRD1 locus on chromosome 1; (b) Regional plot in the GBA3,PPARGC1A locus on chromosome 4; (c) Regional plot in the PLK2 locus on chromosome 5; (d) Regional plot in the PHF14 locus on chromosome 7; (e) Regional plot in the ZPR1 (ZNF259)/APOA5 locus on chromosome 11; (f) Regional plot in the LINC02403 locus on chromosome 12 after adjusting for APOC1P1,APOC4/rs35136575; (g) Regional plot in the BMP2 locus on chromosome 20.
Fig. 5
Fig. 5. Manhattan Plot of gene-based test computed by MAGMA.
The top genes are annotated. The Red line indicates the gene-wide significant threshold of P = 2.68E-06. ZNF259 (ZPR1); PVRL2 (NECTIN2). APOE (P = 3.16E-15), PVRL2 (P = 4.44E-15), TOMM40 (P = 5.98E-12) APOC1 (P = 4.94E-10), ZPR1/ZNF259, (P = 1.21E-08), APOA5 (P = 6.13E-08), BUD13 (P = 2.12E-06), CEACAM19 (P = 3.05E-06) and BCAM (P = 6.59E-06).
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