title: A comprehensive review of genetic association studies.
abstract: Most common diseases are complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. It has been proposed that common genetic variants, including single nucleotide polymorphisms (SNPs), influence susceptibility to common disease. This proposal has begun to be tested in numerous studies of association between genetic variation at these common DNA polymorphisms and variation in disease susceptibility. We have performed an extensive review of such association studies. We find that over 600 positive associations between common gene variants and disease have been reported; these associations, if correct, would have tremendous importance for the prevention, prediction, and treatment of most common diseases. However, most reported associations are not robust: of the 166 putative associations which have been studied three or more times, only 6 have been consistently replicated. Interestingly, of the remaining 160 associations, well over half were observed again one or more times. We discuss the possible reasons for this irreproducibility and suggest guidelines for performing and interpreting genetic association studies. In particular, we emphasize the need for caution in drawing conclusions from a single report of an association between a genetic variant and disease susceptibility.
authors.affiliation: Whitehead Institute/MIT Center for Genome Research, Cambridge, MA 02139, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Kirk
authors.initials: K
authors.lastname: Lohmueller
authors.forename: Edward
authors.initials: E
authors.lastname: Byrne
authors.forename: Kurt
authors.initials: K
authors.lastname: Hirschhorn
mesh_terms: D000483:Alleles; D004198:Disease Susceptibility; D004777:Environment; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D017408:Guidelines as Topic; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide