Sex differences in gene expression patterns associated with the APOE4 allele

Abstract

Background: The APOE gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the APOE gene: APOE2, APOE3, and APOE4. The APOE4 allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. Methods: In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the APOE4 allele in order to identify possible sex-related differences that may be relevant to AD. Results: Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of APOE in APOE4-positive individuals. The number of these genes was much higher in APOE4-positive females than in APOE4-positive males, who in turn had more of such genes than APOE4-negative control groups. Our findings also indicate a significant sex* genotype interaction for the CNTNAP2 gene, a member of the neurexin family and a significant interaction for brain area*sex* genotype for PSEN2, a risk factor gene for AD. Conclusions: Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of APOE with respect to sex differences and AD.

Keywords: APOE4; Alzheimer's Disease; Systems Genetics.

Figure 1.. Keyword enrichment.

Representative keyword enrichment based on GO Term classification. ( A) Females and ( B) males, frontal white matter; ( C) females and ( D) males, hippocampus; ( E) females and ( F) males, parietal cortex; ( G) females and ( H) males, temporal cortex. X-axis, keyword categories; Y-axis, frequency of occurrence.

Figure 2.. Pathway enrichment.

KEGG pathway categories for female gene correlates. ( A) Positive correlates and ( B) negative correlates, frontal white matter; ( C) positive correlates and ( D) negative correlates, hippocampus; ( E) positive correlates and ( F) negative correlates; parietal cortex; ( G) positive correlates and ( G) negative correlates, temporal cortex. X-axis, frequency of occurrence; Y-axis, biological function.

Figure 3.. Sex differences in gene expression.

( A) Top differentially expressed genes in the frontal white matter of APOE4-positive females and ( B) representative top genes differentially expressed in APOE4-positive males. X-axis, gene symbol; Y-axis, fold difference values.