Genetic bases for common polygenic diseases.

The present group of articles on the genetic basis of common diseases inaugurates a new policy on the part of the editors of the Proceedings. The editors plan to present a series of written minisymposia on dynamic and emerging areas of research of interest to broad groups of readers. We will solicit and present groups of interrelated articles by leading authorities and contributors describing their perspectives on recent developments in their field. We anticipate that such collections of reviews and discussions will provide a broader perspective' and more insights into the state of a field and the reasons for the current interest in that field that can often be derived from a single review. To broaden the interest in these symposia, the individual articles will be limited in size with an emphasis on changing concepts more than technical details of a subfield. We hope that these collections of reviews will be a resource for a broad group of scientists as well as objects of special interest for the relevant experts. Understanding the molecular causes for many "simple Mendelian disorders" is one of the great achievements of current biomedical science. The fundamental scheme underlying this advance is simple enough. First, the number of potential "candidate" genes for a disorder must be limited to a small enough number to make analysis feasible. After this, each candidate gene must be examined for evidence of dysfunction manifest by either defective expression or production of an altered protein. The process of limiting the number of genes to be analyzed can be accomplished by selection of genes whose encoded proteins have catalytic or structural properties relevant to the phenotype of the disease in question or whose alteration is known from spontaneous or experimentally created mutations in animals to create a syndrome resembling that of the disease under study. Alternatively, chromosome abnormalities or genetic analyses can limit the chromosomal region bearing the mutation to a segment whose gene content is sufficiently small for analysis. Technical improvements are continuing to accumulate relevant to every step of the process of identifying mutant genes. In addition, the accrual of well defined contigs of yeast artificial chromosome, cosmid, or other genomic clones spanning large portions of the genome; the continued accumulation of highly polymorphic genetic markers; and the prospects for rapid accumulation of mapped expressed sequence tags all contribute to the growing number of successes in gene hunting endeavors. Nevertheless, some genetic disorders are laborious or impractical to map by current techniques. For example, hemochromatosis, although one of the most common disorders, maps into a gene-rich region with an unusual degree of extended linkage disequilibrium. This difficult gene can be expected to yield within the next few years. Other disorders are more recalcitrant because the phenotype of the mutant does not suggest obvious candidate genes and the clinical material is not qualitatively or quantitatively appropriate to narrow down the genomic region sufficiently. An extreme example of the last type would be a disease such as progeria (1) that has no obvious candidate genes and that may be a sporadic dominant with all affected individuals infertile. In the future, it is not inconceivable that molecular biologic methods to enrich for DNA fragments bearing sequence variations unique to affected individuals could be developed to the point where even these difficult problems could be approached in an efficient way. With the reservations described above, the process of identifying genes responsible for penetrant single gene disorders is proceeding at an accelerating rate and predictably will continue to do so until most of the more common disorders have their defects identified, probably within the next few years. In contrast, the major challenge for medical genetics for the next decade is to systematically identify genes responsible for the hereditary contributions to a range of disorders that are not inherited in a simple Mendelian fashion but that have a definite or probable genetic component. The list of these disorders embraces a large fraction of the common causes of disability and death in western society and includes atherosclerosis, hypertension, psychiatric disorders, Alzheimer disease, type I and type II diabetes, asthma, rheumatoid arthritis,