Population‐wide copy number variation calling using variant call format files from 6,898 individuals

Abstract

Copy number variants (CNVs) play an important role in a number of human diseases, but the accurate calling of CNVs remains challenging. Most current approaches to CNV detection use raw read alignments, which are computationally intensive to process. We use a regression tree‐based approach to call germline CNVs from whole‐genome sequencing (WGS, >18x) variant call sets in 6,898 samples across four European cohorts, and describe a rich large variation landscape comprising 1,320 CNVs. Eighty‐one percent of detected events have been previously reported in the Database of Genomic Variants. Twenty‐three percent of high‐quality deletions affect entire genes, and we recapitulate known events such as the GSTM1 and RHD gene deletions. We test for association between the detected deletions and 275 protein levels in 1,457 individuals to assess the potential clinical impact of the detected CNVs. We describe complex CNV patterns underlying an association with levels of the CCL3 protein (MAF = 0.15, p = 3.6x10−12) at the CCL3L3 locus, and a novel cis‐association between a low‐frequency NOMO1 deletion and NOMO1 protein levels (MAF = 0.02, p = 2.2x10−7). This study demonstrates that existing population‐wide WGS call sets can be mined for germline CNVs with minimal computational overhead, delivering insight into a less well‐studied, yet potentially impactful class of genetic variant.

Genetic determinants of plasma protein levels in the Estonian population

“…This emphasises the value of the CNV data, especially if the purpose is to prioritise causal genetic variation underlying the pQTL signal. None of the associations reported by Png et al 15 were replicated in this study, possibly because there was only a partial overlap between the assayed protein sets, differences between cohorts (European ancestry vs a Greek population isolate with populationspecific CNVs) 76 , and differences in the approach used for CNV detection. www.nature.com/scientificreports/…”

“…The availability of the high-quality WGS data also gave us a unique opportunity to investigate the effect of CNVs on protein expression. To the best of our knowledge, one study has previously studied CNVs in this context, focusing only on deletions 15 . We conducted the first comprehensive CNV-based pQTL mapping and identified 12 associations (7 cis and 5 trans ) between plasma proteins and CNVs, including those with a trans -association hub CNV in the 3q12.1 region.…”

“…For example, a recent landmark study conducted on the Icelandic population revealed 18,084 genetic associations with protein levels, 19% of which were with rare variants 8 . Investigation of the effects of other structural variants, such as copy number variants (CNVs), on protein levels has thus far been limited 15 .…”

Copy number variations and their effect on the plasma proteome

“…Few previous studies have focused on CNV calling using high-throughput sequencing combined with CNV-phenotype association analysis. A recent study developed a novel method for CNV discovery at population level with 1,457 individuals and tested for association with 275 protein biomarkers ( Png et al 2020 ). They report 4 significant associations ( , resolution: 15 kb).…”

“…A previous study using data from UK Biobank found CNVs in 28 genes to be associated with 13 blood biomarkers ( Sinnott-Armstrong et al 2021 ). A different study in a cohort of 1,457 individuals has found 4 genome-wide associations between CNVs and protein levels ( Png et al 2020 ).…”