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Next-generation targeted resequencing of genome-wide association study (GWAS)-associated genomic regions is a common approach for follow-up of indirect association of common alleles. However, it is prohibitively expensive to sequence all the samples from a well-powered GWAS study with sufficient depth of coverage to accurately call rare genotypes. As a result, many studies may use next-generation sequencing for single nucleotide polymorphism (SNP) discovery in a smaller number of samples, with the intent to genotype candidate SNPs with rare alleles captured by resequencing. This approach is reasonable, but may be inefficient for rare alleles if samples are not carefully selected for the resequencing experiment.

Enriching targeted sequencing experiments for rare disease alleles