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Carrier rate analysis of single-gene disorders based on 1000 genome project and exome aggregation consortium data

Objective: Screening variants underlying the single-gene disorder in the general population can help reduce the incidences of birth defects. To determine the most prevalent pathogenic variants causing autosomal recessive diseases, we investigated the frequencies of these variants in six major geographic ancestry groups from Exome Aggregation Consortium (ExAC) database and 26 populations from the 1,000 Genome Project, including three Chinese ethnic groups. Methods: We selected 64 autosomal recessive diseases and collected corresponding causal genes and variants from ClinVar for the analysis. The RS (reference single-nucleotide polymorphism) IDs of these variants were used to search the corresponding VCF file from the 1,000 Genomes Project and ExAC databases. We calculated the frequencies of heterozygotes of each disease variants in the 1,000 Genomes Project and ExAC samples and compared the distribution of disease alleles among different populations. Results: Our analysis revealed that 1,151/212 variants were carried by 60,706/2,504 individuals sequenced in the ExAC/1,000 Genomes Project. The average number of autosomal recessive disease alleles carried by samples from ExAC and 1,000 Genomes Project were 0.53 and 0.68, respectively. These disease alleles showed differential distribution among populations, and some disease alleles were significantly enriched in certain ethnic groups. In addition, 1–2 main pathogenic variants were identified in each disease. Meanwhile, several ClinVar variants with relatively high frequency (>1%) in the samples were found to be benign instead of “conflicting evaluations of pathogenicity.” Conclusions: Our observations revealed that main pathogenic variants existed in certain autosomal recessive disease, suggesting that screening of disease hypermutations in different populations is valuable in reducing the occurrence of birth defects.