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Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data.

ABSTRACT: BACKGROUND:The conventional variant calling of pathogenic alleles in exome and genome sequencing requires the presence of the non-pathogenic alleles as genome references. This hinders the correct identification of variants with minor and/or pathogenic reference alleles warranting additional approaches for variant calling. RESULTS:More than 26,000 Exome Aggregation Consortium (ExAC) variants have a minor reference allele including variants with known ClinVar disease alleles. For instance, in a number of variants related to clotting disorders, the phenotype-associated allele is a human genome reference allele (rs6025, rs6003, rs1799983, and rs2227564 using the assembly hg19). We highlighted how the current variant calling standards miss homozygous reference disease variants in these sites and provided a bioinformatic panel that can be used to screen these variants using commonly available variant callers. We present exome sequencing results from an individual with venous thrombosis to emphasize how pathogenic alleles in clinically relevant variants escape variant calling while non-pathogenic alleles are detected. CONCLUSIONS:This article highlights the importance of specialized variant calling strategies in clinical variants with minor reference alleles especially in the context of personal genomes and exomes. We provide here a simple strategy to screen potential disease-causing variants when present in homozygous reference state.

SUBMITTER: Koko M

PROVIDER: S-EPMC5769444 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data.

Koko Mahmoud M Abdallah Mohammed O E MOE Amin Mutaz M Ibrahim Muntaser M

BMC genomics 20180115 1

<h4>Background</h4>The conventional variant calling of pathogenic alleles in exome and genome sequencing requires the presence of the non-pathogenic alleles as genome references. This hinders the correct identification of variants with minor and/or pathogenic reference alleles warranting additional approaches for variant calling.<h4>Results</h4>More than 26,000 Exome Aggregation Consortium (ExAC) variants have a minor reference allele including variants with known ClinVar disease alleles. For in ...[more]

PMID: 29334895

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Project description:BACKGROUND:Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. METHODS:Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. RESULTS:Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs <?0.1). Our computer simulations revealed that >?50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (<?0.1) were much larger than the expected ratios of GWAS's power imbalance, especially for diseases whose average risk allele frequencies were low, such as myopia, sudden cardiac arrest, and systemic lupus erythematosus. CONCLUSIONS:Minor alleles are more likely to be risk alleles in the published GWASs on complex diseases. One reason is that minor alleles are more easily detected as risk alleles in GWASs. Even when correcting for the GWAS's power imbalance, minor alleles are more likely to be risk alleles, especially in some diseases whose average risk allele frequencies are low. These analyses serve as a starting point for future studies on quantifying the degree of negative natural selection in various complex diseases.

Dataset Information

Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data.

Publications

Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data.

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