Genetic association analysis of overlapping biological pathways in cardiovascular and Alzheimer disease

Abstract

To gain insight into the importance of the genome for diseases, sequencing and genotyping efforts aim to identify the consequences of genetic variation on both a functional and population level. The task involves the fine-resolution mapping of biologically significant genes and regions discerned by linkage analysis.

This thesis focuses on genetic variation in two candidate genes, Angiotensin-Converting Enzyme (ACE) and ATP-Binding Cassette A1 (ABCA1) that are shown to potentially modify Alzheimer disease (AD) risk and related quantitative traits. AD is a disabling neurodegenerative disorder characterized by progressive memory loss that affects an increasing part of the aging population. Mutations in the Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2) have been described to cause the early-onset familial form of AD. However, the discovery of genes involved in sporadic late-onset AD has proven to be more difficult. Apolipoprotein-E (APOE) which mediates lipid and cholesterol metabolism is the only presently recognized susceptibility gene for sporadic AD.

The Angiotensin-Converting Enzyme modulates not only blood pressure homeostasis but also the clearance of amyloid-beta (Abeta), the pathogenic hallmark of AD, making ACE an intriguing biological candidate for both AD and cardiovascular disease. Significant effects for markers in the promoter and 3'-regions were found upon AD risk and disease age-of-onset, consistent with the presence of allelic heterogeneity in this genomic region. A unique differential relationship between genotypes for AD and obesity/ myocardial infarction was explored. The emerging pattern is consistent with the biological role of the ACE protein, but highlights the difficulties of analyzing pleiotropic genes. Computational analysis suggested functionally important promoter and splice variants that may be contributing to trait variability.

ATP-Binding Cassette AI facilitates cholesterol transport and regulates APOE levels in cells. The gene lies in proximity to an AD linkage peak on chromosome 9q, making ABCA1 both a biological and positional candidate. In four independent European populations, significant differences in genotype frequencies were found between cases and controls indicated by effects on disease risk. Correlations between quantitative traits related to disease progression complemented the data. To substantiate findings, cholesterol and metabolic traits were examined in a large cardiovascular disease population whereby significant association was determined only among smokers. The data highlight the importance of considering environmental factors that can modify genotype-phenotype relationships.

Applying association analysis across many traits using large replicating samples brings us closer to elucidating patterns of individual variations in genes that contribute to human diseases.