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Genome-wide association analyses of migraine and its subtypes identify new susceptibility loci, including rare variants with large effects implicating PRRT2, SCN11A and KCNK5.

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.

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.

Genome-wide-association analyses of datasets from Iceland and the UK identify risk variants for nasal polyps and chronic rhinosinusitis. Notably, a loss-of-function missense variant in ALOX15 confers protection against both phenotypes, thus identifying a potential target for therapeutic intervention.

Whole-genome sequencing of monozygotic twins, along with their parents, spouses and children, identifies postzygotic mutations present in the somatic tissue of one twin, but not the other, and characterizes differences in the number and timing of these mutations.

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.

While the consequences of homozygous loss of function variants have been studied, the effect of missense variants is less understood. Here, the authors identify pathogenic genotypes through an observed deficit of homozygous carriers of missense variants in a population, elucidating previously unexplained recessive disease and miscarriage.

Creatine kinase (CK) and lactate dehydrogenase (LDH) are biomarkers of tissue damages including myopathy and myocardial infarction. Here, Patrick Sulem and colleagues perform a genome-wide association study to identify common and rare genetic variants that associates with serum CK or LDH levels.

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.

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.

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.

Whole-genome sequencing identifies a rare missense variant in IKBKB associated with high risk of cutaneous and systemic lupus erythematosus among people with African ancestry.

The concentration of SARS-CoV-2 changes during an individual’s infection, and mutations accumulate as viruses are transmitted between people. Here, the authors use data from Iceland to demonstrate how this information can be exploited at the population-level to determine the phase of the epidemic.

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.

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.

Analysis of whole-genome sequence data of Icelandic individuals has revealed a rare nonsense mutation within the LGR4 gene that is strongly associated with, among other things, low bone mineral density, late onset of menarche, and increased risk of biliary tract cancer.

Analysis of whole-genome sequencing data from Iceland and the UK Biobank identifies an excess burden of rare loss-of-function variants in HECTD2 and AKAP11 in individuals diagnosed with bipolar disorder.

Understanding the underlying pathophysiology of obesity can help prevent this condition. Here, the authors perform a GWAS of BMI in diverse ancestries, finding four missense variants in FRS3 that affect BMI.

Finding safe inhibitors of phosphodiesterase 4, the enzyme that breaks down cAMP, has been a longstanding goal in pharmaceutical development. Burgin et al. use crystal structure data to develop allosteric inhibitors that lack the emetic side effects of existing inhibitors in animals.

Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

A coding mutation in APP, the gene that encodes the amyloid-β precursor protein, is found to protect against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease.

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.

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.

Genome-wide analyses identify 27 loci associated with attention-deficit hyperactivity disorder and provide insights into its genetic architecture in relation to other psychiatric disorders and cognitive traits.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

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.

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.

The underlying genetics of carpal tunnel syndrome is not well understood. Here, the authors perform a GWAS meta-analysis for carpal tunnel syndrome finding variants at 50 loci with connections to the extracellular matrix discovered through various functional analyses.

Hilma Holm et al. report a rare missense variant MYH6 that is associated with a high risk of sick sinus syndrome in Icelanders. This heart condition is found most often in elderly people and is the most frequent reason a heart pacemaker is implanted.

The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.

Lumbar disc herniation (LDH) can cause persistent sciatica, and in some cases surgery is required to relieve symptoms. Here, the authors carry out a genome-wide association study using microdiscectomy as an indicator of severe LDH, and find a locus on chromosome 8 associated with this condition.

Diagnosis and classification of peripheral neuropathy (PN) is facilitated by nerve conduction (NC) studies. Here, Bjornsdottir et al. find a low-frequency PRPH splice-donor variant that associates with NC amplitude and neurological assessment of recalled PRPH variant carriers reveals increased risk of a mild sensory-negative PN.

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.

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.

Iceland has used four different SARS-CoV-2 vaccines in various combinations. Here, the authors describe differences in the immune responses elicited by different initial/booster vaccine combinations, and then use population-level data to assess the effects of booster doses against Delta and Omicron infection.

Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants.

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.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Ingression of magmatic gas into a geothermal aquifer generated cyclical deformation and primed the system for the 2021 Fagradalsfjall eruption, Iceland, according to a catalogue of 39,500 precursory earthquakes combined with a poroelastic model.

John Perry, Ken Ong and colleagues perform a genome-wide association study for reproductive ability, behavior and success to determine underlying genetic factors. They find 38 variants associated with age of first sexual intercourse and show that both physical and neurobehavioral traits influence the onset of reproductive activity.

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.

Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.

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%.

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.

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.

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, Kari Stefansson and colleagues report the identification of a rare nonsynonymous variant in the C3 gene, encoding complement factor 3, that is associated with age-related macular degeneration.