Rare Variants Create Synthetic Genome-Wide Associations

By Samuel P. Dickson, Kai Wang, Ian D. Krantz, Hakon Hakonarson, David B. Goldstein. PLoS Biology, 2010

920 citations recorded by the source corpus.

A large number of different common variants has been associated with very modest increases of risk for various common diseases. A simulation study shows that rare variants with much greater impacts on disease risk may be responsible for some of these associations.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6c6e047cc3dd335aa781b9f22ffb4a8dbb5b2701

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Citations in the corpus

Conditions Under Which Genome-Wide Association Studies Will be Positively Misleading (2010, methodology): “Dickson et al. (2010) used simulations to show that the presence of two or more rare causal variants in disequilibrium that can themselves not be detected due to lack of statistical power can produce spurious associations that are only distantly linked to the causal polymorphisms, and Atwell et al.…”
An efficient multi-locus mixed model approach for genome-wide association studies in structured populations (2012, positive): “Indeed, as it includes multiple loci in the model, MLMM helps identify evidence for allelic heterogeneity as well as interactions, although it is difficult to exclude that multiple associated SNPs within a region are due to partial linkage disequilibrium with an untyped causal variant 12,18,20 .”
Computer simulations: tools for population and evolutionary genetics (2012, methodology): “A recent study 33 used Genome to simulate the genealogy of a population in which some individuals had rare variants associated with a disease.”
Consistent Association of Type 2 Diabetes Risk Variants Found in Europeans in Diverse Racial and Ethnic Groups (2010, background): “We note that this pattern is unexpected under the recently described ‘‘common SNP, rare mutation’’ model of Goldstein that suggests that GWAS signals with common alleles for T2D and other diseases may be ‘‘synthetic associations’’ created by one or more rare alleles [19–21].”
Five years of GWAS discovery. (2012, background): “Synthetic Associations Dickson and colleagues suggested that the observed association between a common SNP and a complex trait might result when one or more rare variants at the locus is in LD with that SNP.76,93 Because common SNP alleles and rare causal variants cannot be highly correlated because”
Estimation of effect size distribution from genome-wide association studies and implications for future discoveries (2010, positive): “It is possible that next-generation genotyping and sequencing platforms, which will efficiently interrogate uncommon and rare variants, could magnify the effect sizes for some of the estimated loci that are currently being represented by common variants owing to synthetic associatio”
Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease (2011, neutral): “16 46,458,634–46,480,319 (7; 22) Exons 2–13 of LTF (NM_002343.”
The genomics of local adaptation in trees: are we out of the woods yet? (2017, background): “…1975) as well as their inflationary effect on heritability estimates (Zuk et al. 2012), (unmeasured) low-frequency variants of large effect (Dickson et al. 2010), genetic or variance heterogeneity of individual alleles (Leiserson et al. 2013; cf. Box 1 in Nelson et al. 2013), or common…”
Uncovering the roles of rare variants in common disease through whole-genome sequencing (2010, background): “Additionally, it seems possible that some, perhaps even many, of the current GWA signals could reflect the effect of multiple rare variants that have been credited to common variant”
Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study (2013, background): “Given that differential effect sizes were observed for many tagSNPs, we sought to leverage the data in order to assess the relative contributions of several factors that might contribute to the significant trend toward diluted effects, including gene–environment interaction with an exposure that var”
A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease (2015, positive): “We performed a joint association analysis to search for evidence of synthetic associations 16 , where multiple low-frequency susceptibility variants at a locus might be in LD with a common variant discovered as the lead variant in a GWAS, and to compile an FDR-defined list of informative variants…”
Genome-wide association study of leaf architecture in the maize nested association mapping population (2011, background): “Additionally, multiple rare causal variants that may be separated by relatively large genomic distances can create synthetic association”
The genetics of Alzheimer disease: back to the future. (2010, background): “…var et al., 2010; Gilissen et al., 2010; Ng et al., 2010), but also to ''resolve'' the complex patterns that typically emerge from GWAS approaches (Dickson et al., 2010; Johansen et al., 2010; Nejentsev et al., 2009), although most of these findings still await functional genetic confirmation and…”
Genetic heterogeneity in human disease. (2010, background): “GJB2, which encodes a gap junction protein, is the most frequently altered of these genes, although all mutations are individually rare.”