Whole genome sequencing data from pedigrees suggests linkage disequilibrium among rare variants created by population...

Next-generation sequencing technologies have been designed to discover rare and de novo variants and are an important tool for identifying rare disease variants. Many statistical methods have been developed to test, using next-generation sequencing data, for rare variants that are associated with a trait. However, many of these methods make assumptions that rare variants are in linkage equilibrium in a gene. In this report, we studied whether transmitted or untransmitted haplotypes carry an excess of rare variants using the whole genome sequencing data of 15 large Mexican American pedigrees provided by the Genetic Analysis Workshop 18. We observed that an excess of rare variants are carried on either transmitted or nontransmitted haplotypes from parents to offspring. Further analyses suggest that such nonrandom associations among rare variants can be attributed to population admixture and single-nucleotide variant calling errors. Our results have significant implications for rare variant association studies, especially those conducted in admixed populations.