Rare variants create synthetic genome-wide associations.
Abstract
Genome-wide association studies (GWAS) have now identified at least 2,000 common variants
that appear associated with common diseases or related traits (http://www.genome.gov/gwastudies),
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.
Type
Journal articleSubject
Anemia, Sickle CellGenetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Hearing Loss
Humans
Polymorphism, Single Nucleotide
Probability
Risk Factors
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https://hdl.handle.net/10161/4443Published Version (Please cite this version)
10.1371/journal.pbio.1000294Publication Info
Dickson, Samuel P; Wang, Kai; Krantz, Ian; Hakonarson, Hakon; & Goldstein, David B (2010). Rare variants create synthetic genome-wide associations. PLoS Biol, 8(1). pp. e1000294. 10.1371/journal.pbio.1000294. Retrieved from https://hdl.handle.net/10161/4443.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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David Benjamin Goldstein
Adjunct Professor in the Department of Molecular Genetics and Microbiology

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