Can rare variants fake common GWAS hits?
Collections of rare causal variants can create synthetic genome-wide association signals at common SNPs.
Source
Rare variants create synthetic genome-wide associations
Study at a glance
- Design
- Computational / modelling — Genealogical simulations of rare causal variants generating synthetic common-SNP GWAS signals
- N
- Simulation study (~30% of runs detect genome-wide associations) — no empirical sample N
- Population
- Simulated genealogies with rare disease alleles
- Outcome
- Synthetic genome-wide associations created by rare causal variants
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Can rare variants fake common GWAS hits?
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
What kind of GWAS signal can rare variants create?
rare variants that contribute to disease is likely to create “synthetic” signals of association .
Assumed frequency range for modeled causal variants?
allele frequency between 0.005 and 0.02, which is generally below the range of reliable detection (either by inclusion or indirect representation) using the genome-wide association platforms currently in use.
What they did
Modeled how rare disease-causing variants distributed in genealogies generate association signals detectable at common polymorphisms.
What they found
Even when individual rare alleles are uncommon (e.g., 0.005–0.02), as a disease class grows they can collectively create synthetic GWAS signals unless variants are extremely numerous and evenly spread.
The limits
What it doesn't show
Not every GWAS hit is synthetic; it shows a plausible generative mechanism for some signals.
Key terms
- Synthetic association
- Common-SNP signal generated by multiple rare causal variants.
- Rare variant
- Low-frequency allele that may strongly affect risk.
- GWAS
- Genome-wide association study of common variants.
- Disease class
- Set of causal alleles that together influence disease.
- Genealogy
- Ancestral tree relating sampled chromosomes.
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Synthetic association means:
Common questions
What is synthetic association?
Rare causal variants creating a common-SNP GWAS signal.
Assumed rare allele frequency range?
About 0.005 to 0.02.
When does the effect fail?
When causal variants are so numerous they are evenly distributed.
Teaching point?
Common GWAS hits need not imply a common causal allele.
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