Abstract
An array-based genotyping approach has been the standard practice for genome-wide association studies (GWASs); however, as sequencing costs plummet over the past years, ultra low-coverage whole-genome sequencing (ulcWGS <0.5× coverage) has emerged as a promising alternative that provides superior genomic coverage with substantial reduction of genotyping cost. To evaluate the potential utility of ulcWGS, we performed a whole-genome sequencing (WGS) of 72 European individuals to a target coverage of 0.4× and compared its performance with the widely used Infinium Global Screening Multi-Disease Array (GSA-MD). We showed that the number of variants captured by ulcWGS is comparable with imputed GSA-MD platform, particularly for low-frequency (95.5%) and common variants (99.9%), with high imputation R2 accuracy (mean 0.93 for SNPs and 0.86 for indels). Using deep-coverage 30× WGS as the “truth” genotypes, we found that ulcWGS has higher overall nonreference genotype concordance compared with imputed GSA-MD for both SNPs (0.90 vs. 0.88) and indels (0.86 vs. 0.83). In addition, ulcWGS proved to be as sensitive as the genotyping-based method in sex imputation and ancestry prediction producing similar principal component (PC) scores. Our findings provide important evidence that the cost efficient ulcWGS of <0.5× generates high genotype accuracy, outperforming the standard genotyping arrays, making it an attractive alternative to the array-based method in next-generation GWAS design.
Highlights
Over the past decade, genome-wide association studies (GWASs) have identified genetic variation contributing to a plethora of complex disease traits (Visscher et al, 2012; Visscher et al, 2017; Buniello et al, 2019)
On a sample of 72 melanoma patients with genotype data generated by GSA-MD (v2 or v3), we performed ultra low-coverage whole-genome sequencing (ulcWGS) to a target depth of 0.4× sequencing coverage (Figure 1)
We explored, for the first time, the feasibility and effectiveness of ulcWGS (0.4× coverage) as a sequencing-based GWAS alternative to standard SNP array genotyping
Summary
Genome-wide association studies (GWASs) have identified genetic variation contributing to a plethora of complex disease traits (Visscher et al, 2012; Visscher et al, 2017; Buniello et al, 2019). Despite the high genotype accuracy and affordable cost, genotype-based GWAS designs are often limited by ascertainment bias of the genotyped variants present at particular SNP arrays. This limits the genome-wide variant coverage for the discovery of the. Introduced whole-genome sequencing (WGS)-based GWAS emerges as a promising alternative to probe large fraction of genetic variation in a comprehensive and unbiased fashion, improving the power of the association tests and downstream fine mapping analyses. High-coverage WGS remains cost prohibitive in GWAS designs that often require assessment of a large cohort of sample population
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