Human Genetics and Disease

The past 30 years have seen a revolution in knowledge of the basis of genetic disease. While early efforts focused on single gene, Mendelian disorders, efforts over the past decade have focused on common, complex diseases, empowered by new technological and statistical approaches in genomics and genetics. From linkage studies to candidate gene association studies to genomewide association studies (GWAS) to genome sequencing, each new approach to complex disease has yielded only partial success, the result of both technical limitations and the biological and genetic nature of the problem. GWAS have, for the first time, yielded remarkable successes for many diseases, identifying over 2000 confirmed disease susceptibility loci and/or causal variants. Nevertheless, for essentially all diseases studied the total loci/variants identified appear to account for only a small fraction of the total genetic risk of the disease. Progress towards identifying the genetic causation of complex disease will be considered in the context of the strengths, weaknesses, and flaws of these experimental approaches, with a view towards the near future based on high-throughput DNA sequencing of candidate genes and full genomes.