The Genetics of Blood Pressure and Body Mass Index: The Tale of Two Major Risk Factors.

Abstract

High blood pressure and obesity are two major public health problems and important contributors to multiple chronic disorders including cardiovascular disease, stroke, and type II diabetes. Heritability studies have shown that there is a substantial fraction of the interindividual variation in blood pressure and body mass index (BMI) that is due to additive genetic variation. Recent genome-wide association studies (GWAS) have identified many novel chromosomal regions associated with these traits that are highly significant (p<5x10-8) and replicate across multiple studies. Because most of the single nucleotide polymorphisms (SNPs) in these chromosomal regions fall in non-coding sequences, their functional mechanisms are not well understood. To develop a deeper knowledge of the biological mechanisms that may be underlying the genetic associations for blood pressure and BMI, we examined the relationship between genetic variants and gene expression levels among non-Hispanic white sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). In addition, we estimated the heritability of the gene expression levels from the 27 blood pressure-related genes and the 30 BMI-related genes. The heritability study found that approximately 67% of the 27 BP-related genes and 47% of the 30 BMI-related genes had gene expression levels that were significantly heritable (p<0.05). The genetic association study revealed that many genetic variants within a gene region contribute to variation in expression levels. However, only a few of these gene expression levels were also associated with the phenotypic traits of blood pressure and BMI. For example, ULK4 was the only gene that was found to have genetic variants explaining significant variation in ULK4 expression and its expression was also significantly associated with blood pressure levels. Lastly, we investigated whether the relationship between gene expression levels and the outcomes of blood pressure and BMI were influenced by genetic variants. Our results indicated that the relationship between CACNB2 expression and systolic blood pressure could be modified by genetic variants. This dissertation took an important step in following up the recently identified GWAS genetic loci associated with blood pressure and BMI to better understand the molecular epidemiology of these major risk factors.