Dataset Information

Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding.

ABSTRACT: OBJECTIVE:We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association. METHODS:Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [(11)C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes. RESULTS:Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A. CONCLUSIONS:Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.

SUBMITTER: Lazaris A

PROVIDER: S-EPMC4809461 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding.

Lazaris Andreas A Hwang Kristy S KS Goukasian Naira N Ramirez Leslie M LM Eastman Jennifer J Blanken Anna E AE Teng Edmond E Gylys Karen K Cole Greg G Saykin Andrew J AJ Shaw Leslie M LM Trojanowski John Q JQ Jagust William J WJ Weiner Michael W MW Apostolova Liana G LG

Neurology. Genetics 20151015 3

<h4>Objective</h4>We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association.<h4>Methods</h4>Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [(11)C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study association ...[more]

PMID: 27066559

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Project description:The APOE ε2, ε3, and ε4 alleles differentially impact various complex diseases and traits. We examined whether these alleles modulated associations of 94 single-nucleotide polymorphisms (SNPs) harbored by 26 genes in 19q13.3 region with 217 plasma metabolites using Framingham Heart Study data. The analyses were performed in the E2 (ε2ε2 or ε2ε3 genotype), E3 (ε3ε3 genotype), and E4 (ε3ε4 or ε4ε4 genotype) groups separately. We identified 31, 17, and 22 polymorphism-metabolite associations in the E2, E3, and E4 groups, respectively, at a false discovery rate PFDR < 0.05. These entailed 51 and 19 associations with 20 lipid and 12 polar analytes. Contrasting the effect sizes between the analyzed groups showed 20 associations with group-specific effects at Bonferroni-adjusted P < 7.14E−04. Three associations with glutamic acid or dimethylglycine had significantly larger effects in the E2 than E3 group and 12 associations with triacylglycerol 56:5, lysophosphatidylethanolamines 16:0, 18:0, 20:4, or phosphatidylcholine 38:6 had significantly larger effects in the E2 than E4 group. Two associations with isocitrate or propionate and three associations with phosphatidylcholines 32:0, 32:1, or 34:0 had significantly larger effects in the E4 than E3 group. Nine of 70 SNP-metabolite associations identified in either E2, E3, or E4 groups attained PFDR < 0.05 in the pooled sample of these groups. However, none of them were among the 20 group-specific associations. Consistent with the evolutionary history of the APOE alleles, plasma metabolites showed higher APOE-cluster-related variations in the E4 than E2 and E3 groups. Pathway enrichment mainly highlighted lipids and amino acids metabolism and citrate cycle, which can be differentially impacted by the APOE alleles. These novel findings expand insights into the genetic heterogeneity of plasma metabolites and highlight the importance of the APOE-allele-stratified genetic analyses of the APOE-related diseases and traits.

Project description:BackgroundAlzheimer disease (AD) is a progressive neurodegenerative disease closely related to genes and characterized by the atrophy of the cerebral cortex. Correlations between imaging phenotypes and the susceptibility genes for AD, as demonstrated in the findings of genome-wide association studies (GWASs), still need to be addressed due to the complicated structure of the human cortex.MethodsIn our study, an improved GWAS method, whole cortex characteristics GWAS (WCC-GWAS), was proposed. The WCC-GWAS uses multiple cortex characteristics of gray-matter volume (GMV), cortical thickness (CT), cortical surface area (CSA), and local gyrification index (LGI). A cohort of 496 participants was enrolled and divided into 4 groups: normal control (NC; n=122), early mild cognitive impairment (EMCI; n=196), late mild cognitive impairment (LMCI; n=62), and AD (n=116). Based on the Desikan-Killiany atlas, the brain was parcellated into 68 brain regions, and the WCC of each brain region was individually calculated. Four cortex characteristics of GMV, CT, CSA, and LGI across the 4 groups optimized with multiple comparisons and the ReliefF algorithm were taken as magnetic resonance imaging (MRI) brain phenotypes. Under the model of multiple linear additive genetic regression, the correlations between the MRI brain phenotypes and single-nucleotide polymorphisms (SNPs) were deduced.ResultsThe findings identified 2 prominent correlations. First, rs7309929 of neuron navigator 3 (NAV3) located on chromosome 12 correlated with the decreased GMV for the left middle temporal gyrus (P=0.0074). Second, rs11250992 of long intergenic non-protein-coding RNA 700 (LINC00700) located on chromosome 10 correlated with the decreased CT for the left supramarginal gyrus (P=0.0019).ConclusionsThe findings suggested that the correlations between phenotypes and genotypes could be effectively evaluated. The strategy of extracting MRI phenotypes as endophenotypes provided valuable indications in AD GWAS.

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Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding.

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Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding.

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