title: Progress and promise in understanding the genetic basis of common diseases.
abstract: Susceptibility to common human diseases is influenced by both genetic and environmental factors. The explosive growth of genetic data, and the knowledge that it is generating, are transforming our biological understanding of these diseases. In this review, we describe the technological and analytical advances that have enabled genome-wide association studies to be successful in identifying a large number of genetic variants robustly associated with common disease. We examine the biological insights that these genetic associations are beginning to produce, from functional mechanisms involving individual genes to biological pathways linking associated genes, and the identification of functional annotations, some of which are cell-type-specific, enriched in disease associations. Although most efforts have focused on identifying and interpreting genetic variants that are irrefutably associated with disease, it is increasingly clear that--even at large sample sizes--these represent only the tip of the iceberg of genetic signal, motivating polygenic analyses that consider the effects of genetic variants throughout the genome, including modest effects that are not individually statistically significant. As data from an increasingly large number of diseases and traits are analysed, pleiotropic effects (defined as genetic loci affecting multiple phenotypes) can help integrate our biological understanding. Looking forward, the next generation of population-scale data resources, linking genomic information with health outcomes, will lead to another step-change in our ability to understand, and treat, common diseases.
authors.affiliation: Department of Epidemiology, Harvard T. H. Chan School of Public Health, 655 Huntington Ave, Boston, MA 02115, USA Department of Biostatistics, Harvard T. H. Chan School of Public Health, 655 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Chris C A
authors.initials: CC
authors.lastname: Spencer
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK donnelly@well.ox.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
mesh_terms: D004194:Disease / Q000235:genetics*; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype
keywords: common diseases; genome-wide association studies; human genetics