Show simple item record Dickson, SP Wang, K Krantz, I Hakonarson, H Goldstein, DB
dc.coverage.spatial United States 2011-06-21T17:31:05Z 2010-01-26
dc.identifier.citation PLoS Biol, 2010, 8 (1), pp. e1000294 - ?
dc.description.abstract Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with common diseases or related traits (, hundreds of which have been convincingly replicated. It is generally thought that the associated markers reflect the effect of a nearby common (minor allele frequency >0.05) causal site, which is associated with the marker, leading to extensive resequencing efforts to find causal sites. We propose as an alternative explanation that variants much less common than the associated one may create "synthetic associations" by occurring, stochastically, more often in association with one of the alleles at the common site versus the other allele. Although synthetic associations are an obvious theoretical possibility, they have never been systematically explored as a possible explanation for GWAS findings. Here, we use simple computer simulations to show the conditions under which such synthetic associations will arise and how they may be recognized. We show that they are not only possible, but inevitable, and that under simple but reasonable genetic models, they are likely to account for or contribute to many of the recently identified signals reported in genome-wide association studies. We also illustrate the behavior of synthetic associations in real datasets by showing that rare causal mutations responsible for both hearing loss and sickle cell anemia create genome-wide significant synthetic associations, in the latter case extending over a 2.5-Mb interval encompassing scores of "blocks" of associated variants. In conclusion, uncommon or rare genetic variants can easily create synthetic associations that are credited to common variants, and this possibility requires careful consideration in the interpretation and follow up of GWAS signals.
dc.format.extent e1000294 - ?
dc.language ENG
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Biol
dc.relation.isversionof 10.1371/journal.pbio.1000294
dc.subject Anemia, Sickle Cell
dc.subject Genetic Predisposition to Disease
dc.subject Genome-Wide Association Study
dc.subject Genotype
dc.subject Hearing Loss
dc.subject Humans
dc.subject Polymorphism, Single Nucleotide
dc.subject Probability
dc.subject Risk Factors
dc.title Rare variants create synthetic genome-wide associations.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-1-0 en_US
duke.description.endpage e1000294 en_US
duke.description.issue 1 en_US
duke.description.startpage e1000294 en_US
duke.description.volume 8 en_US
dc.relation.journal Plos Biology en_US
pubs.issue 1
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Institutes and Provost's Academic Units
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers/Duke Institute for Brain Sciences
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Center for Human Genome Variation
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Clinical Research Institute
pubs.publication-status Published online
pubs.volume 8
dc.identifier.eissn 1545-7885

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