Rare variants can create synthetic genome-wide associations, challenging the common belief that GWAS signals are due to common variants. This study shows that rare variants, which are less common than the associated ones, can create synthetic associations by occurring more frequently with one allele of a common variant than the other. These synthetic associations are not only possible but inevitable under certain genetic models. The study used simulations to demonstrate that rare variants can generate genome-wide significant associations, even when they are not the direct cause. Real-world examples, such as hearing loss and sickle cell anemia, show that rare variants can create synthetic associations that are credited to common variants. For instance, in sickle cell anemia, rare mutations create genome-wide significant synthetic associations spanning a 2.5-Mb interval. The study also highlights that synthetic associations can persist even with recombination, and that they can be detected with smaller sample sizes than typically used in GWAS. The findings suggest that many GWAS signals may be due to rare variants rather than common ones, and that future studies should consider this possibility when interpreting GWAS results. The study emphasizes the importance of considering synthetic associations in the interpretation of GWAS signals and suggests that genome-wide sequencing in carefully phenotyped cohorts may be more effective than targeted sequencing within LD blocks. The results have implications for understanding the genetic architecture of human disease and for the design of future studies to detect causal genetic variants.Rare variants can create synthetic genome-wide associations, challenging the common belief that GWAS signals are due to common variants. This study shows that rare variants, which are less common than the associated ones, can create synthetic associations by occurring more frequently with one allele of a common variant than the other. These synthetic associations are not only possible but inevitable under certain genetic models. The study used simulations to demonstrate that rare variants can generate genome-wide significant associations, even when they are not the direct cause. Real-world examples, such as hearing loss and sickle cell anemia, show that rare variants can create synthetic associations that are credited to common variants. For instance, in sickle cell anemia, rare mutations create genome-wide significant synthetic associations spanning a 2.5-Mb interval. The study also highlights that synthetic associations can persist even with recombination, and that they can be detected with smaller sample sizes than typically used in GWAS. The findings suggest that many GWAS signals may be due to rare variants rather than common ones, and that future studies should consider this possibility when interpreting GWAS results. The study emphasizes the importance of considering synthetic associations in the interpretation of GWAS signals and suggests that genome-wide sequencing in carefully phenotyped cohorts may be more effective than targeted sequencing within LD blocks. The results have implications for understanding the genetic architecture of human disease and for the design of future studies to detect causal genetic variants.