Apolipoprotein B gene regulation under healthy and neuropathological conditions.

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We have recently identified apolipoprotein B (APOB) as a putative CSF indicator of early synaptic and Tau pathology in cognitively unimpaired individuals with a parental history of Alzheimer's disease (AD). The goal of this study is to understand how APOB is regulated under healthy and AD-related neuropathological conditions. Genomic and transcriptomic data from the following public databases were screened for APOB expression quantitative trait loci (eQTL): the Brain eQTL Almanac (BRAINEAC), the Religious Orders Study and Memory and Aging Project (ROSMAP), the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Genotype-Tissue Expression (GTEx) project. Statistical analyses were performed using SPSS, PLINK and the MatrixEQTL package from R. Trans-eQTL analysis using BRAINEAC data comprising of 134 human brains free of neurodegenerative disorders revealed a near genome-wide significant locus in PCSK5 gene region (p=9.8E-08). Using the same dataset, cis-eQTL analysis showed locus-wide significance for five single nucleotide polymorphisms (SNPs) located in or upstream APOB (p≤5.0E-05). Two of these SNPs showed locus-wide significance in the ROSMAP dataset including 491 brain samples with or without cognitive impairment (p≤5.0E-05) and, the same SNPs were also associated with the Mini-Mental State Examination (MMSE) score (p≤0.05). In ADNI, blood APOB mRNA levels measured in 735 individuals with or without cognitive impairment revealed significant associations with these two SNPs (p≤0.05), showing this interaction is not brain-specific. Indeed, the two SNPs were strongly associated with APOB mRNA levels measured in at least eight different tissues according to the GTEx database. APOB gene regulation is under tight genetic control and even when influenced by neurodegenerative conditions such as AD, significant cis-eQTLs are found across different tissues such as blood and brain.