Finally, we evaluated the genomic pattern of synthetic associations using two real-world examples: hearing loss and sickle cell anemia. These two examples represent two possible extremes for synthetic associations. Sickle cell anemia is a serious Mendelian disease in which the body makes sickle-shaped red blood cells. The disease mostly affects subjects with African ancestry, and prevalence among African Americans in the United States is approximately 1 in 600 [10]. It is known to be caused by autosomal recessive mutations in HBB, and the frequency of the most common causal variant (Hb S allele) is ∼3.6% in Americans of African ancestry [11]. In comparison, hearing loss is a complex human disease, occurring in one per 1,000 newborns on average [12]. More than two dozen causal genes have been identified for autosomal recessive nonsyndromic hearing loss [13],[14], but mutations in the GJB2/GJB6 locus account for about half of the cases of European ancestry [12],[15]. Among hundreds of known causal mutations in the GJB2/GJB6 locus [14], the 35delG mutation in GJB2 is the most common, with an allele frequency of 1.25% in European
