Genetic investigation of complex disease

This thesis describes genetic approaches toward the understanding of multifactorial human diseases. Candidate gene, animal model, and Mendelian linkage approaches were utilized to investigate genetic factors influencing blood pressure, autoimmune disease susceptibility, and bone density.; Blood pressure is a multifactorial trait, in which a large fraction of individual variation is genetically determined. However, for the majority of hypertensive patients, the genetic susceptibility factors remain unknown. Natriuretic peptide signalling is an important component of blood pressure regulation. Atrial natriuretic peptide (ANP) is released from the heart and interacts with guanylate cyclase (GC-A) receptors in the vasculature and kidney, leading to vasodilation, natriuresis, and diuresis, decreased blood volume, and a resulting reduction in blood pressure. Mouse models with ANP and GC-A gene deletions show significantly elevated blood pressure. Mutation screening of hypertensive patients revealed many variants in these genes. Two mutations in GC-A, a premature stop mutation and a missense mutation in the dimerization domain of the receptor, significantly impair natriuretic peptide signalling and may be causing high blood pressure in the hypertensive patients in whom they occur.; Systemic lupus erythematosus is an autoimmune inflammatory disease with high morbidity and mortality. Many genetic and environmental factors are believed to contribute to disease. Studies of lupus-prone mice can identify genetic loci underlying murine disease, which become strong candidates for human lupus genes. Genome-wide analysis of linkage in a backcross of the lupus-prone MRL strain demonstrated linkage of high antibody levels to chromosome 13 and kidney histopathology to chromosomes 14 and 19.; Bone density is a complex trait, with a substantial genetic component. Several Mendelian bone density disorders have been linked to chromosome 11q12-13. This region has also been linked to normal variation in bone density, suggesting that the gene or genes responsible for the Mendelian disorders may also influence bone density and osteoporosis risk in the general population. Here, a novel form of high bone density is described and shown to be linked to the same region of chromosome 11, with odds of over one million to one in favor of linkage.