SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population

Abstract

Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing

“…A Bam HI restriction site was located 913 bp upstream from the CAG repeat, making the complete capture design 1125 bp, under the assumption that the CAG repeat count is 19, as in the GRCh38 human reference genome. There is an SNP (rs2857935) located in the Bam HI site, occurring at a frequency of 34% in a cross‐section of the Swedish population (Ameur et al., ), which is the origin of the patients participating in this study. In samples where this particular SNP is present, the Bam HI restriction site closest to the CAG expansion will be unrecognizable and another Bam HI RE site, located 1736 bp upstream from the rs2857935, is utilized instead.…”

Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias

“…PileupPipe pipeline performs SNV calling using three callers: the GATK haplotype caller (McKenna et al., ), Bcftools (Li et al., ), and Freebayes (https://github.com/ekg/freebayes). The SNVs detected by these three callers were merged using the GATK‐CombineVariants tool, and annotated using VEP and the SweFreq frequency database (Ameur et al., ).…”

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

“…In the gnomAD database, Gln530* is present in 7 of 55 818 non‐Finnish European individuals, but absent from all other populations. The variant is also absent from SweGen, 2000 Danes, 1000 genomes Norway, and the Telemark database, which together contain 8000 alleles 15, 16, 23. This supports that the variant is associated with a significant increase in QTc and with an increased risk of cardiac events, although this risk is reported to be lower than for KCNQ1 missense variants 24…”

“…Additional databases of allele frequencies, such as gnomAD,14 SweGen,15 2000 Danes,16 and the in‐house Telemark database with ≈1000 exomes, were consulted when manually reviewing the variants that remained after filtering. Sequence variants that were synonymous (predicting no change in amino acids), intronic (outside splice sites), or in untranslated regions were discarded, unless they had previously been reported as pathogenic or likely pathogenic.…”