title: Abundant pleiotropy in human complex diseases and traits.
abstract: We present a systematic review of pleiotropy among SNPs and genes reported to show genome-wide association with common complex diseases and traits. We find abundant evidence of pleiotropy; 233 (16.9%) genes and 77 (4.6%) SNPs show pleiotropic effects. SNP pleiotropic status was associated with gene location (p = 0.024; pleiotropic SNPs more often exonic [14.5% versus 4.9% for nonpleiotropic, trait-associated SNPs] and less often intergenic [15.8% versus 23.6%]), "predicted transcript consequence" (p = 0.001; pleiotropic SNPs more often predicted to be structurally deleterious [5% versus 0.4%] but not more often in regulatory sequences), and certain disease classes. We develop a method to calculate the likelihood that pleiotropic links between traits occurred more often than expected and demonstrate that this approach can identify etiological links that are already known (such as between fetal hemoglobin and malaria risk) and those that are not yet established (e.g., between plasma campesterol levels and gallstones risk; and between immunoglobulin A and juvenile idiopathic arthritis). Examples of pleiotropy will accumulate over time, but it is already clear that pleiotropy is a common property of genes and SNPs associated with disease traits, and this will have implications for identification of molecular targets for drug development, future genetic risk-profiling, and classification of diseases.
authors.affiliation: Centre for Population Health Sciences, The University of Edinburgh, Edinburgh EH8 9AG, UK.
authors.forename: Shanya
authors.initials: S
authors.lastname: Sivakumaran
authors.forename: Felix
authors.initials: F
authors.lastname: Agakov
authors.forename: Evropi
authors.initials: E
authors.lastname: Theodoratou
authors.forename: James G
authors.initials: JG
authors.lastname: Prendergast
authors.forename: Lina
authors.initials: L
authors.lastname: Zgaga
authors.forename: Teri
authors.initials: T
authors.lastname: Manolio
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Paul
authors.initials: P
authors.lastname: McKeigue
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
mesh_terms: D030541:Databases, Genetic; D004194:Disease / Q000235:genetics*; D058685:Genetic Pleiotropy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*
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