Chapter 14 - The regulatory genome and complex common diseases

Abstract

Over the years, various forms of analysis have been used to identify possible associations of variants in the genome that can account for certain phenotypic features, particularly specific unusual phenotypic features that include disease features. Later, investigators sort out to determine if any changes in microscopic chromosome morphology cosegregated with the specific unusual features in an individual. Studies on proteins and enzymes were also undertaken to identify variants associated with specific unusual phenotypic features or disease manifestations in an individual. Later DNA sequence analyses were carried out to determine if unusual phenotypic features or laboratory finding segregated with specific nucleotide variants present in the genomes. In 2005, Mayeux reported that single nucleotide polymorphisms constituted the common form of genetic variation. Array-based studies were designed that enabled analysis of 100,000 or more single nucleotide polymorphisms on a single array. Databases of variant sites were designed, and these led to studies on common diseases and genome-wide association studies (GWASs). GWAS-associated variants occurred in the nonprotein-coding regions of the genome, and some variants were shown to impact the level of expression of a specific gene expression quantitative trait (eQTLs). Splicing QTLs were noted to also be important and the authors cited evidence that 25% of gene expression level differences between alleles were noted to be due to splicing differences. Genome sequencing studies also led to the identification of disease-significant changes in promoter regions of genes. Both monogenic and polygenic risk factors have been found to be relevant to coronary heart disease, to hyperlipidemias, to Parkinson’s disease, to Alzheimer disease, immune system disorders, and certain neurobehavioral disorders including autism, attention deficit hyperactivity disorders. Aspects of penetrance and expressivity are also discussed.