RT Journal Article SR Electronic T1 Very rare pathogenic genetic variants detected by SNP-chips are usually false positives: implications for direct-to-consumer genetic testing JF bioRxiv FD Cold Spring Harbor Laboratory SP 696799 DO 10.1101/696799 A1 MN Weedon A1 L Jackson A1 JW Harrison A1 KS Ruth A1 J Tyrrell A1 AT Hattersley A1 CF Wright YR 2019 UL http://biorxiv.org/content/early/2019/07/09/696799.abstract AB Objective To determine the diagnostic accuracy of SNP-chips frequently used by direct-to-consumer genetic testing companies for genotyping rare genetic variants.Methods We assessed the diagnostic accuracy of genotypes from SNP-chips (index test) with next generation sequencing data (reference test) in 49,908 individuals recruited to UK Biobank. We compared the genotyping accuracy of SNP-chip variants covered by the next generation sequencing data by allele frequency. We further used the ClinVar database to select rare pathogenic variants in the BRCA1 and BRCA2 genes as an exemplar for detailed analysis. Cancer registry data was gathered for BRCA-related cancers (breast, ovarian, prostate and pancreatic) across all participants.Results SNP-chip genotype accuracy is high overall, but the likelihood of a true positive result reduces substantially with decreasing allele frequency. The sensitivity, specificity, positive predictive (PPV) and negative predictive value (NPV) for heterozygous genotypes are all >99% for 108,574 single nucleotide variants directly genotyped by the UK Biobank SNP-chips. However, for variants with a frequency <0.001% in UK Biobank the PPV is very low, and only 16% of 4,711 heterozygote genotypes from the SNP-chip confirm with sequencing data. For pathogenic variants in the BRCA1 and BRCA2 genes, the overall performance metrics of the SNP-chips in UK Biobank are: sensitivity 34.6%, specificity 98.3%, PPV 4.2% and NPV 99.9%. Rates of BRCA-related cancers in individuals with a positive SNP-chip result are similar to age-matched controls (OR 1.28, P=0.07, 95% CI: 0.98-1.67), while sequence-positive individuals have a significantly increased risk (OR 3.73, P=3.5×10−12, 95% CI: 2.57-5.40).Discussion SNP-chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.Section 1: What is already known on this topic SNP-chips are an accurate and affordable method for genotyping common genetic variants across the genome. They are often used by direct-to-consumer genetic testing companies and research studies, but there several reports suggesting they perform poorly for genotyping rare genetic variants.Section 2: What this study adds Our study confirms that SNP-chips are highly inaccurate for genotyping rare and clinically-actionable variants. Using large-scale SNP-chip and sequencing data from UK Biobank, we show that the SNP-chip false discovery rate is >84% for very rare variants (<0.001% frequency in UKB). Rare variants assayed using SNP-chips should not be reported back to patients without validation.