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A hallmark of diverticular disease is pouches in the bowel wall which can become infected and inflamed, causing the more severe diverticulitis. Here, the authors report the first genome-wide association study on these interconnected conditions and identifyARHGAP15, COLQ and FAM155Aas novel risk loci.

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.

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.

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.

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.

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.

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.

A predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of FLT3 ligand, leading to increased risk of autoimmune thyroid disease.

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.

Endometriosis is a common gynaecological disease but the underlying pathogenesis is poorly understood, however there is a strong familial component. Here the authors conduct a genome wide association study and identify a novel susceptibility locus that correlates with disease severity.

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 migraine and its subtypes identify new susceptibility loci, including rare variants with large effects implicating PRRT2, SCN11A and KCNK5.

Asthma is a common allergic airway disease with significant inter-individual heterogeneity. Here, Olafsdottir et al. report a genome-wide meta-analysis of two large population-based cohorts to identify sequence variants that associate with asthma risk and perform follow-up functional analyses on a protective loss-of-function variant in TNFRSF8.

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.

Lynch syndrome is characterized by predisposition to colorectal cancer and mutations in genes involved in mismatch repair. Here, the authors use whole genome sequencing and immunohistochemistry of mismatch repair proteins to show a high prevalence of Lynch syndrome in the Icelandic population.

Genome-wide association meta-analysis of data sets from Iceland and the UK identifies 16 new risk loci for osteoarthritis, including missense variants in SMO, IL11, and COL11A1.

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.

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.

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.

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.

Unnur Thorsteinsdottir, Kari Stefansson and colleagues identify low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. The newly discovered variants include an intronic variant associated with altered expression of CCND2, two independent missense variants in PAM and a rare frameshift variant in PDX1.

Size and shape of bones are important for height and body shape. Here, Styrkarsdottir et al identify 12 loci in a GWAS for bone area derived from DXA scans and show that these loci associate with other bone-related phenotypes including osteoarthritis, height, bone mineral density and risk of hip fracture.

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.

Uterine leiomyomas are common benign tumors. Here, a meta-analysis of two European leiomyoma GWAS uncovers 21 leiomyoma risk variants at 16 loci, providing evidence of genetic overlap between leiomyoma and various benign and malignant tumors and highlighting the role of estrogen in tumor growth.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

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.

Burden testing in three large European ancestry cohorts identifies new risk genes for a number of common cancer types, including pan-cancer protective variants in AURKB and breast cancer protective variants in PPP1R15A.

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.

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.

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. Here the authors describe 14 genetic variants that affect IgG levels in blood. The data provide new insight into the regulation of humoral immunity that could be useful in the development of antibody-based therapeutics.

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.

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.

Genome-wide analyses identify loci associated with nonalcoholic fatty liver disease, including rare, protective loss-of-function variants in MTARC1 and GPAM. Plasma proteomic analyses provide insight into proteins involved in disease pathogenesis.

Kari Stefansson, Unnur Styrkarsdottir and colleagues identify rare genotypes in COMP and CHADL associated with high risk of total hip replacement due to osteoarthritis. The high odds ratios associated with these rare risk genotypes suggest that they may represent Mendelian forms of osteoarthritis.

Following a replicated genome-wide association study for basal cell carcinoma, Thorunn Rafnar and Patrick Sulem and colleagues have identified a locus associated with multiple cancers that contains the telomerase reverse transcriptase gene TERT and the CLPTM1L gene implicated in cisplatin-induced apoptosis.

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.

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.

Holm, Ivarsdottir, Olafsdottir et al. compare symptoms and physical measures between Icelanders post SARS-CoV-2 infection with uninfected controls. From reported symptoms, they estimate the prevalence of long COVID as 7% at a median of 8 months after infection, while objective differences between cases and controls in the physical measures were few.

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.

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.

Here, in the first of three papers on the genetics of schizophrenia, a genome-wide association study of single nucleotide polymorphisms using data from several large genome-wide scans reveals significant associations to individual loci that implicate perturbations in immunity, brain development, memory and cognition in the predisposition to schizophrenia.

Kari Stefansson and colleagues report discovery of 13 variants with large effects on non-HDL cholesterol, LDL cholesterol, HDL cholesterol or triglyceride lipid fractions. They further show that, among these lipid fractions, the non-HDL cholesterol genetic risk score associates most strongly with coronary disease and confers risk beyond that of LDL cholesterol and that, after accounting for non-HDL cholesterol, neither HDL cholesterol nor triglyceride genetic risk scores associate with coronary disease.

A study of 768 convalescent SARS CoV-2-infected and 500 uninfected Icelanders reveals broad and stable T-cell responses 3-8 months from infection. HLA alleles, disease severity, and age contribute to the heterogeneity of cellular immunity.

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.

Gudjon Oskarsson et al. report a genome-wide association study of hemoglobin concentration in more than 680,000 individuals from Iceland and the UK. They identify six novel rare coding variants at the ACO1 locus that associate with either increased or decreased hemoglobin concentration, two of which have large and opposite effects.

Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and colleagues identified a rare coding mutation in the gene of a BRCA1-interacting factor, BRIP1, that confers a high relative risk of ovarian cancer.