New Perspectives for the Elucidation of Genetic Disorders

For almost 15 years, genome research has focused on the search for major risk factors in common diseases, with disappointing results. Only recently, whole-genome association studies have begun to deliver because of the introduction of high-density single-nucleotide–polymorphism arrays and massive enlargement of cohort sizes, but most of the risk factors detected account for only a small proportion of the total genetic risk, and their diagnostic value is negligible. There is reason to believe that the complexity of many “multifactorial” disorders is primarily due to genetic heterogeneity, with defects of different genes causing the same disease. Moreover, de novo copy-number variation has been identified as a major cause of mental retardation and other complex disorders, suggesting that new mutations are an important, previously overlooked factor in the etiology of complex diseases. These observations support the notion that research into the previously neglected monogenic disorders should become a priority of genome research. Because of the introduction of novel high-throughput, low-cost sequencing methods, sequencing and genotyping will soon converge, with far-reaching implications for the elucidation of genetic disease and health care.