Whole genome characterization of sequence diversity of 15,220 Icelanders

Abstract

Understanding of sequence diversity is the cornerstone of analysis of genetic disorders, population genetics, and evolutionary biology. Here, we present an update of our sequencing set to 15,220 Icelanders who we sequenced to an average genome-wide coverage of 34X. We identified 39,020,168 autosomal variants passing GATK filters: 31,079,378 SNPs and 7,940,790 indels. Calling de novo mutations (DNMs) is a formidable challenge given the high false positive rate in sequencing datasets relative to the mutation rate. Here we addressed this issue by using segregation of alleles in three-generation families. Using this transmission assay, we controlled the false positive rate and identified 108,778 high quality DNMs. Furthermore, we used our extended family structure and read pair tracing of DNMs to a panel of phased SNPs, to determine the parent of origin of 42,961 DNMs.

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

“…With this sample size, assuming accurate imputation (imputation quality score >0.8), we had >80% power to detect T2D association (at α=5x10 -8 ) with variants of minor allele frequency (MAF) ≥5% and odds ratio (OR) ≥1.10, or MAF≥0.1% and OR≥1.60. After stringent harmonised quality control, 31 of the 32 GWAS were imputed using the 64,976 whole-genome sequenced haplotypes of the Haplotype Reference Consortium (HRC)4: the exception was the deCODE GWAS, which was imputed using a population-specific reference panel based on 30,440 Icelandic whole-genome sequenced haplotypes5 (Methods, Supplementary Table 1). We conducted T2D association analyses with and without adjustment for body-mass index (BMI).…”

“…Each scaffold, with exception of the deCODE GWAS, was then imputed up to the HRC reference panel4. The GWAS from deCODE was imputed up to a reference panel based on 30,440 Icelandic whole-genome sequences5, and only variants that were present on the HRC panel were considered for downstream analyses. Within each study, all variants were tested for association with T2D in a regression framework, with and without adjustment for BMI, in sex-combined and sex-specific analyses, under an additive model in the effect of the minor allele, with additional adjustment for study-specific covariates (Supplementary Table 1).…”

Identification of Lynch syndrome risk variants in the Romanian population

“…14 To filter out variants over a certain frequency threshold, we used a reference set of 38 000 Icelandic individuals whole-genome sequenced at deCODE genetics, an extension of a previously described set of 15 220 WGS Icelanders. 15 None of the variants described here had any carriers in the Icelandic dataset. Additional frequency filtering was performed using alleles from publicly available datasets of the Exome Aggregation Consortium.…”

“…Variants were annotated using release 8.0 of the Variant Effect Predictor (VEP‐Ensembl) . To filter out variants over a certain frequency threshold, we used a reference set of 38 000 Icelandic individuals whole‐genome sequenced at deCODE genetics, an extension of a previously described set of 15 220 WGS Icelanders . None of the variants described here had any carriers in the Icelandic dataset.…”

read_haps: using read haplotypes to detect same species contamination in DNA sequences

“…To limit the impact of genotyping error we examined the sequencing data of a 15.220 individuals (Jónsson et al, 2017), including 1,548 trios and determined (Halldorsson et al, 2016) a set of markers that showed low levels of inheritance errors and could generally be reliably genotyped across samples.…”