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Whole-genome sequencing of 78 Icelandic parent–offspring trios is used to study the de novo mutation rate at the genome-wide level; the rate is shown to increase by about two mutations a year as a function of the increasing age of the father at conception, highlighting the importance of father’s age on the risk of diseases such as autism and schizophrenia.

Around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

Complete human recombination maps are presented that enable exploration of both cross-over and non-cross-over events during meiosis, with the potential to provide insight into the causes of aneuploidies and pregnancy loss.

Daniel Gudbjartsson, Kari Stefansson and colleagues propose a new weighted Bonferroni approach for determining significance thresholds for human genome-wide association studies (GWAS). They demonstrate that the weighted approach, which is based on sequence annotation enrichments, improves power over standard GWAS methods.

Here, human genome-wide single-nucleotide polymorphism (SNP) data from more than 15,000 parent–offspring pairs have been used to construct the first recombination maps that are based on directly observed recombination events. The data reveal interesting differences between the sexes: for instance, in males recombination tends to shuffle exons, whereas in females it generates new combinations of nearby genes. Comparison of these maps with others also reveals population differences.

Stacy Steinberg, Hreinn Stefansson, Thorlakur Jonsson and colleagues found that rare variants predicted to alter the function of ABCA7 are associated with risk of Alzheimer's disease. The association was found in Iceland and replicated in northern Europe and the United States.

Sulem et al. report two previously unknown loci associated with variation in pigmentation in Northern Europeans. In two separate studies, Brown et al. and Gudbjartsson et al. report that some variants affecting human pigmentation, including variants on 20q11.22 near ASIP, also confer risk of cutaneous melanoma and basal cell carcinoma.

Here, the authors conduct a GWAS for autoimmune thyroid disease, finding 225 loci including a start codon variant in LAG3 that confers a 3.4-fold risk of autoimmune thyroid disease and reduces expression and plasma levels of LAG−3.

Allele-specific DNA methylation data in whole blood from 7,179 individuals sequenced by Nanopore, and gene expression profiles from 896 samples, show that DNA sequence variability accounts for most of the correlation between CpG methylation and gene expression.

Comparisons of phenotypic and genetic association with protein levels from Icelandic and UK Biobank cohorts show that using multiple analysis platforms and stratifying populations by ancestry improves the detection of associations and allows the refinement of their location within the genome.

A barcode-based approach applied to UK Biobank and an Icelandic cohort identifies drivers of clonal hematopoiesis (CH) and finds associations between CH and multiple diseases. Genome-wide association analyses identify 25 loci associated with CH susceptibility.

A genome-wide association study of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders highlights links with over 370 disease endpoints and other traits.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.

Renal cell carcinoma (RCC) accounts for 80–90% of all kidney cancers, but to date, only five genome-wide significant RCC risk loci have been identified. Here, Gudmundsson et al.identify a new RCC susceptibility locus and provide insight into the genetic basis of the disease.

Basal cell carcinoma is a common cancer among people of European ancestry, with associated high economic costs to monitor and treat. Here Stacey et al.conduct a genome-wide association study on Icelandic and other European populations, identifying four novel loci associated with cancer susceptibility.

To measure selection on variants, whole-genome sequencing of approximately 150,000 individuals from the UK Biobank is used to rank sequence variants by their level of depletion.

The effect of sequence variants on phenotypes may depend on parental origin. Here, a method is developed that takes parental origin — the impact of which, to date, has largely been ignored — into account in genome-wide association studies. For 38,167 Icelanders genotyped, the parental origin of most alleles is determined; furthermore, a number of variants are found that show associations specific to parental origin, including three with type 2 diabetes.

Bone mineral density (BMD) is the best predictor of osteoporotic fracture risk. Here, the authors perform a genome wide association study in Icelanders and people of European and East-Asian descent, and identify a new allele in intron 15 of the PTCH1gene that associates with reduced BMD.

Little is known about the biology of back pain, a leading cause of disability. Here the authors report 30 new back pain loci, implicating genes involved in cartilage/bone biology, as well as neurological and inflammatory processes.

Elderly males are often affected by benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS), but their link to prostate cancer risk is not well defined. Here, a genome-wide association study of BPH/LUTS patients from Iceland and the UK found 23 significant variants at 14 loci, and 15 of these variants associate with prostate specific antigen, which is linked to prostate cancer risk.

Two hundred and eighty-five methylomes and 11,617 transcriptomes from peripheral blood samples with parent-of-origin-phased haplotypes produce a new map of imprinted methylation and gene expression patterns across the human genome.

Non-medullary thyroid cancers include papillary and follicular subtypes, and are the most common type of thyroid cancer. Here, the authors extend previous work by performing a large genome-wide association study and find five novel loci associated with this disease.

Adult height has a strong genetic component and is highly heritable. Here the authors whole-genome sequence 8,453 Icelanders and find novel parent-of-origin derived associations in IGF2-H19 and DLK1-MEG3.

Hilma Holm and colleagues report genome-wide association studies to electrocardiographic measures of heart rate, PR interval, QRS duration and QT interval.

Mutations in genes encoding NAPDH oxidase subunits are known to be causative for the primary immunodeficiency chronic granulomatous disease (CGD). Here, the authors identify CYBC1 mutations in patients with CGD and show that CYBC1 is important for formation of the NADPH complex and respiratory burst.

Kari Stefansson and colleagues report the whole-genome sequencing of 2,636 individuals from Iceland to a median of 20× coverage, providing a valuable genomic resource for this population isolate. They characterize patterns of genetic variation and population structure and demonstrate the usefulness of this resource for genetic discovery for several disease phenotypes.

Ingileif Jonsdottir, Björn Nilsson, Kari Stefansson and colleagues perform a genome-wide association study for immunoglobulin levels in Icelandic and Swedish cohorts. They find 38 new variants associated with IgA, IgG, IgM or composite immunoglobulin traits and identify candidate genes underlying the regulation of immunoglobulin levels.

Analysis of long-read sequencing data from 3,622 Icelanders identifies a set of high-confidence structural variants and provides insights into their effect on human traits and diseases.

Analysis of 1,007 sibling pairs from 251 families identifies 878 de novo mutations shared by siblings at 448 sites. Recurrence probability based on parental somatic mosaicism, sibling sharing, parent of origin, mutation type and genomic position can range from 0.011% to 28.5%.

Julius Gudmundsson, Kari Stefansson and colleagues identify a low-frequency variant at 8q24 strongly associated with prostate cancer risk. They also confirm association of a recently reported risk variant in HOXB13 in samples from multiple European populations.

Thorunn Rafnar and colleagues identify a variant on 4p16.3 near FGFR3 associated with increased risk of urinary bladder cancer. They find that the risk allele is more frequent among individuals with tumors that carry an activating somatic mutation in FGFR3, suggesting a link between germline variation, somatic mutation status and cancer risk.

Simon Stacey, Kari Stefansson and colleagues show that a germline variant in the TP53 polyadenylation signal is associated with increased risk of basal cell carcinoma and other solid tumors.

Patrick Sulem, Hannes Helgason and colleagues identify homozygous and compound heterozygous loss-of-function variants of minor allele frequency <2% in 7.7% of the genotyped Icelandic population. Under transmission of some of these variants from heterozygous parents provides evidence that they are actually deleterious.

Whole-genome sequencing data of 14,688 Icelanders, including 1,548 parent–offspring trios, show how the age and sex of parents affect the rate and spectrum of de novo mutations.

Gudmar Thorleifsson and colleagues report a genome-wide association study for primary open angle glaucoma, identifying a susceptibility locus near CAV1 and CAV2.

Kari Stefansson and colleagues report results of a genome-wide association study for urinary bladder cancer. The strongest association was with a variant on 8q24, located 30 kb upstream of MYC in a haplotype block distinct from previously reported 8q24 cancer risk variants.

Simon Stacey and colleagues report several new susceptibility variants for basal cell carcinoma, including coding variants in KRT5, a variant at 9p21 near CDKN2A and CDKN2B and a variant at 7q32 near KLF14. The latter is an imprinted gene, and the effect at this locus is dependent on the parental origin of the risk allele.

Ingileif Jonsdottir, Kari Stefansson and colleagues show that variants in the HLA class II region contribute to tuberculosis risk in populations of European ancestry. They propose that the associated variants influence disease risk by altering expression of HLA class II molecules presenting protective M. tuberculosis antigens to T cells.

Patrick Sulem, Daniel Gudbjartsson, Bragi Walters and colleagues identify two low-frequency variants associated with serum uric acid levels and gout in the Icelandic population. The variants were discovered by whole-genome sequencing and are associated with two- to threefold differences in disease risk.

Kari Stefansson and colleagues performed a genome-wide association study for severe hand osteoarthritis and found associated variants within the ALDH1A2 gene and at 1p31.