The article "Rare Variants Create Synthetic Genome-Wide Associations" by Samuel P. Dickson et al. explores the possibility that common genetic variants identified through genome-wide association studies (GWAS) may be influenced by rare variants that create "synthetic associations." The authors propose that these rare variants, which are less common than the associated common variant, can occur more frequently with one allele at the common site compared to another, leading to significant association signals that are attributed to the common variant. Using computer simulations, they demonstrate that synthetic associations are not only possible but inevitable under certain genetic models and conditions. The study also illustrates this phenomenon in real datasets, showing that rare causal mutations responsible for hearing loss and sickle cell anemia create genome-wide significant synthetic associations. The authors conclude that the interpretation and follow-up of GWAS signals must carefully consider the potential role of rare variants in creating synthetic associations, which could explain many of the observed signals and have implications for understanding the genetic architecture of human diseases.The article "Rare Variants Create Synthetic Genome-Wide Associations" by Samuel P. Dickson et al. explores the possibility that common genetic variants identified through genome-wide association studies (GWAS) may be influenced by rare variants that create "synthetic associations." The authors propose that these rare variants, which are less common than the associated common variant, can occur more frequently with one allele at the common site compared to another, leading to significant association signals that are attributed to the common variant. Using computer simulations, they demonstrate that synthetic associations are not only possible but inevitable under certain genetic models and conditions. The study also illustrates this phenomenon in real datasets, showing that rare causal mutations responsible for hearing loss and sickle cell anemia create genome-wide significant synthetic associations. The authors conclude that the interpretation and follow-up of GWAS signals must carefully consider the potential role of rare variants in creating synthetic associations, which could explain many of the observed signals and have implications for understanding the genetic architecture of human diseases.