ArticlePLoS biology2010
Rare variants create synthetic genome-wide associations.
Article in PLoS biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 525 papers, 10 of them syntheses that pooled it.
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Who cites it
525 citing papers in PubMed, 10 syntheses or guidelines pooled it.
- Multi-ancestry genetic architecture of heart failure subtypes.Nature communications · 2026Pooled it
- Confirmation of GLRA3 as a susceptibility locus for albuminuria in Finnish patients with type 1 diabetes.Scientific reports · 2018Pooled it
- Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.Human molecular genetics · 2016Pooled it
- Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.American journal of human genetics · 2016Pooled it
- A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.Human molecular genetics · 2016Pooled it
- Deciphering associations for lung cancer risk through imputation and analysis of 12,316 cases and 16,831 controls.European journal of human genetics : EJHG · 2015Pooled it
- A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.Nature genetics · 2015Pooled it
- Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nature genetics · 2015Pooled it
- Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease.Arteriosclerosis, thrombosis, and vascular biology · 2015Pooled it
- Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.Nature genetics · 2014Pooled it
- Single nucleotide polymorphisms of the GJB2 and GJB6 genes are associated with autosomal recessive nonsyndromic hearing loss.BioMed research international · 2015Trial
- Novel Potential Risk Loci for Migraine in the Portuguese Population.International journal of molecular sciences · 2026Article
- Common and rare genetic variants show network convergence for a majority of human traits.EMBO reports · 2026Article
- Convergent evolution increases boron transport through SNPs and tandem duplications atProceedings of the National Academy of Sciences of the United States of America · 2026Article
- A Genome-Wide Association Study RevealsJournal of arrhythmia · 2026Article
- Investigating the genetic basis of susceptibility to amoebic gill disease and idiopathic gill lesions in Atlantic salmon populations using field data.Genetics, selection, evolution : GSE · 2026Article
- Decades' progress and prospects on maize functional genomics and molecular breeding.Science China. Life sciences · 2025Review
- A human YEATS4 variant confers resistance to TST and IGRA conversion despite Mycobacterium tuberculosis exposure.Genome medicine · 2025Article
- Potential synthetic associations created by epistasis.Genome biology · 2025Article
- Noncoding rare variant associations with blood traits in 166,740 UK Biobank genomes.Nature genetics · 2025Article
465 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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