Genetic Approaches for the Study of Complex Human Diseases
Abstract
The field of human genetics has evolved from its initial narrow focus on single-gene Mendelian disorders, which largely affect children, to our current understanding that for most diseases there is continuum of rare to common variants which can exert a range of phenotypic effects. Despite advances in sequencing capabilities and our overall understanding of diseases, there remains a large proportion of heritability unexplained. Through the use of next-generation sequencing technologies and DNA microarray, I have explored a spectrum of genetic variations from rare, single and structural variants to common variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; and iii) familial partial lipodystrophy. From my research efforts, we implicated rare loss-of-function variants in cardiomyopathy genes to “lone” atrial fibrillation, providing evidence that atrial cardiomyopathy is a genetic sub-phenotype of atrial fibrillation. Additionally, we determined that “lone” atrial fibrillation has a significant accumulation of common variants that together elevate susceptibility to the disease. Also, considering the application of genetics in Medicine, I directly evaluated the increasing responsibility that clinicians have to adjudicate causality of various genetic factors. For instance, having successfully identified a novel apparently pathogenic genetic variant in a family with hypercholesterolemia, I sought to determine its pathogenicity by performing cascade screening and co-segregation analysis in the extended family. My analysis demonstrated that the novel variant was independent of the disease phenotype, preventing a potential misdiagnosis and emphasized the importance of gathering additional confirmatory data in the clinical setting. Further, by studying a well-genotyped and phenotype familial partial lipodystrophy cohort, I uncovered that the prevalence of severe hypertriglyceridemia and its most severe complication, namely acute pancreatitis was more common in affected individuals who had concurrently developed diabetes. In spite of these contributions, significant work remains to explain the full genetic contributions to complex diseases. The benefits of understanding the complete genetic architecture of a disease are potentially immense, allowing advances in pre-symptomatic detection to the development of novel targeted therapies. For the patients this could translate into such benefits as earlier detection, screening for the family, personalized therapies, and a confirmed diagnosis.