Sequence variants from whole genome sequencing a large group of Icelanders.

We have accumulated considerable data on the genetic makeup of the Icelandic population by sequencing the whole genomes of 2,636 Icelanders to depth of at least 10X and by chip genotyping 101,584 more. The sequencing was done with Illumina technology. The median sequencing depth was 20X and 909 individuals were sequenced to a depth of at least 30X. We found 20 million single nucleotide polymorphisms (SNPs) and 1.5 million insertions/deletions (indels) that passed stringent quality control. Almost all the common SNPs (derived allele frequency (DAF) over 2%) that we identified in Iceland have been observed by either dbSNP (build 137) or the Exome Sequencing Project (ESP) while only 60 and 20% of rare (DAF<0.5%) SNPs and indels in coding regions, the most heavily studied parts of the genome, have been observed in the public databases. Features of our variant data, such as the transition/transversion ratio and the length distribution of indels, are similar to published reports.

Identification of a large set of rare complete human knockouts.

Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).

Large-scale whole-genome sequencing of the Icelandic population.

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

Localization of a susceptibility gene for common forms of stroke to 5q12.

Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9 x 10(-6)). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as "STRK1," does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.