Recent development in pharmacogenomics: from candidate genes to genome-wide association studies.
Genetic diversity, most notably through single nucleotide polymorphisms and copy-number variation, together with specific environmental exposures, contributes to both disease susceptibility and drug response variability. It has proved difficult to isolate disease genes that confer susceptibility to complex disorders, and as a consequence, even fewer genetic variants that influence clinical drug responsiveness have been uncovered. As such, the candidate gene approach has largely failed to deliver and, although the family-based linkage approach has certain theoretical advantages in dealing with common/complex disorders, progress has been slower than was hoped. More recently, genome-wide association studies have gained increasing popularity, as they enable scientists to robustly associate specific variants with the predisposition for complex disease, such as age-related macular degeneration, Type 2 diabetes, inflammatory bowel disease, obesity, autism and leukemia. This relatively new methodology has stirred new hope for the mapping of genes that regulate drug response related to these conditions. Collectively, these studies support the notion that modern high-throughput single nucleotide polymorphism genotyping technologies, when applied to large and comprehensively phenotyped patient cohorts, will readily reveal the most clinically relevant disease-modifying and drug response genes. This review addresses both recent advances in the genotyping field and highlights from genome-wide association studies, which have conclusively uncovered variants that underlie disease susceptibility and/or variability in drug response in common disorders.
Grant
Struan F A
SF
Center for Applied Genomics, The Children's Hospital of Philadelphia, PA 19104-4318, USA. grants@chop.edu
Hakonarson
Hakon
H
D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D023281:Genomics / Q000379:methods* / Q000639:trends*; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics / Q000639:trends*