Actionable Genotypes and Their Association with Life Span in Iceland.

BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

Large-scale plasma proteomics comparisons through genetics and disease associations.

High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge the gap between the genome and diseases. Here we performed association studies of Olink Explore 3072 data generated by the UK Biobank Pharma Proteomics Project1 on plasma samples from more than 50,000 UK Biobank participants with phenotypic and genotypic data, stratifying on British or Irish, African and South Asian ancestries. We compared the results with those of a SomaScan v4 study on plasma from 36,000 Icelandic people2, for 1,514 of whom Olink data were also available. We found modest correlation between the two platforms. Although cis protein quantitative trait loci were detected for a similar absolute number of assays on the two platforms (2,101 on Olink versus 2,120 on SomaScan), the proportion of assays with such supporting evidence for assay performance was higher on the Olink platform (72% versus 43%). A considerable number of proteins had genomic associations that differed between the platforms. We provide examples where differences between platforms may influence conclusions drawn from the integration of protein levels with the study of diseases. We demonstrate how leveraging the diverse ancestries of participants in the UK Biobank helps to detect novel associations and refine genomic location. Our results show the value of the information provided by the two most commonly used high-throughput proteomics platforms and demonstrate the differences between them that at times provides useful complementarity.

Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis.

BACKGROUND: The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival. METHODS: Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH). RESULTS: Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis. CONCLUSIONS: Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.

Evaluation of Large-Scale Proteomics for Prediction of Cardiovascular Events.

Importance: Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain. Objective: To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations. Design, Setting, and Participants: The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals. Exposures: Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling. Main Outcomes and Measures: Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death. Results: In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population. Conclusions and Relevance: A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination.

Physical and cognitive impact following SARS-CoV-2 infection in a large population-based case-control study.

BACKGROUND: Persistent symptoms are common after SARS-CoV-2 infection but correlation with objective measures is unclear. METHODS: We invited all 3098 adults who tested SARS-CoV-2 positive in Iceland before October 2020 to the deCODE Health Study. We compared multiple symptoms and physical measures between 1706 Icelanders with confirmed prior infection (cases) who participated, and 619 contemporary and 13,779 historical controls. Cases participated in the study 5-18 months after infection. RESULTS: Here we report that 41 of 88 symptoms are associated with prior infection, most significantly disturbed smell and taste, memory disturbance, and dyspnea. Measured objectively, cases had poorer smell and taste results, less grip strength, and poorer memory recall. Differences in grip strength and memory recall were small. No other objective measure associated with prior infection including heart rate, blood pressure, postural orthostatic tachycardia, oxygen saturation, exercise tolerance, hearing, and traditional inflammatory, cardiac, liver, and kidney blood biomarkers. There was no evidence of more anxiety or depression among cases. We estimate the prevalence of long Covid to be 7% at a median of 8 months after infection. CONCLUSIONS: We confirm that diverse symptoms are common months after SARS-CoV-2 infection but find few differences between cases and controls in objective parameters measured. These discrepancies between symptoms and physical measures suggest a more complicated contribution to symptoms related to prior infection than is captured with conventional tests. Traditional clinical assessment is not expected to be particularly informative in relating symptoms to a past SARS-CoV-2 infection.

Persistent symptoms are commonly reported after SARS-CoV-2 infection, and this is often described as long Covid. We compared different symptoms reported following SARS-CoV- 2 infection with the results obtained during various medical evaluations that are often used to assess health, such as blood tests, smell tests, taste tests, hearing tests, etc. We compared symptoms and test results between 1,706 Icelanders who had been infected previously with SARS-CoV-2 infection (cases) and 14,398 individuals who had not been infected (controls). Out of 88 assessed symptoms, 41 were more common in cases than controls. However, relatively few differences were seen in the results obtained from the various medical evaluations (cases had poorer smell and taste test results, slightly less grip strength, and slightly poorer memory recall than controls). The differences seen between symptoms and results of medical evaluations suggests that conventional clinical tests may not be informative in relating symptoms to a past SARS-CoV-2 infection.

HLA alleles, disease severity, and age associate with T-cell responses following infection with SARS-CoV-2.

Memory T-cell responses following SARS-CoV-2 infection have been extensively investigated but many studies have been small with a limited range of disease severity. Here we analyze SARS-CoV-2 reactive T-cell responses in 768 convalescent SARS-CoV-2-infected (cases) and 500 uninfected (controls) Icelanders. The T-cell responses are stable three to eight months after SARS-CoV-2 infection, irrespective of disease severity and even those with the mildest symptoms induce broad and persistent T-cell responses. Robust CD4+ T-cell responses are detected against all measured proteins (M, N, S and S1) while the N protein induces strongest CD8+ T-cell responses. CD4+ T-cell responses correlate with disease severity, humoral responses and age, whereas CD8+ T-cell responses correlate with age and functional antibodies. Further, CD8+ T-cell responses associate with several class I HLA alleles. Our results, provide new insight into HLA restriction of CD8+ T-cell immunity and other factors contributing to heterogeneity of T-cell responses following SARS-CoV-2 infection.

Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles: a Mendelian randomization analysis.

BACKGROUND AND AIMS: The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration. METHOD AND RESULTS: We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N = 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses.In univariate MR analysis, both exposures associated with CAD (ßnon-HDL-C = 0.40, P = 2.8 × 10-48 and ßapoB = 0.38, P = 1.3 × 10-44). Adding effects on non-HDL-C into a model that already included those on apoB significantly improved the genetically predicted CAD effects (P = 3.9 × 10-5), while adding apoB into the model including non-HDL-C did not (P = 0.69). Thirty-five per cent (82/235) of the variants used as genetic instruments had discordant effects on the exposures, associating with non-HDL-C/apoB ratio at P < 2.1 × 10-4 (0.05/235). Fifty-one variants associated at genome-wide significance. CONCLUSION: Many sequence variants have discordant effects on non-HDL-C and apoB. These variants allowed us to show that the causal mechanism underlying the relationship between apolipoprotein B particles and CAD is more associated with non-HDL-C than apoB particle concentration.

The sequences of 150,119 genomes in the UK Biobank.

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data1,2. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank3. This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.

Genetic architecture of band neutrophil fraction in Iceland.

The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huët anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huët anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huët anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology.

Reconstruction of a large-scale outbreak of SARS-CoV-2 infection in Iceland informs vaccination strategies.

OBJECTIVES: The spread of SARS-CoV-2 is dependent on several factors, both biological and behavioural. The effectiveness of nonpharmaceutical interventions can be attributed largely to changes in human behaviour, but quantifying this effect remains challenging. Reconstructing the transmission tree of the third wave of SARS-CoV-2 infections in Iceland using contact tracing and viral sequence data from 2522 cases enables us to directly compare the infectiousness of distinct groups of persons. METHODS: The transmission tree enables us to model the effect that a given population prevalence of vaccination would have had on the third wave had one of three different vaccination strategies been implemented before that time. This allows us to compare the effectiveness of the strategies in terms of minimizing the number of cases, deaths, critical cases, and severe cases. RESULTS: We found that people diagnosed outside of quarantine (Rˆ=1.31) were 89% more infectious than those diagnosed while in quarantine (Rˆ=0.70) and that infectiousness decreased as a function of time spent in quarantine before diagnosis, with people diagnosed outside of quarantine being 144% more infectious than those diagnosed after ≥3 days in quarantine (Rˆ=0.54). People of working age, 16 to 66 years (Rˆ=1.08), were 46% more infectious than those outside of that age range (Rˆ=0.74). DISCUSSION: We found that vaccinating the population in order of ascending age or uniformly at random would have prevented more infections per vaccination than vaccinating in order of descending age, without significantly affecting the expected number of deaths, critical cases, or severe cases.

Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene.

Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.

Large-scale integration of the plasma proteome with genetics and disease.

The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.

Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

Malignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband's paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.

Predicting the probability of death using proteomics.

Predicting all-cause mortality risk is challenging and requires extensive medical data. Recently, large-scale proteomics datasets have proven useful for predicting health-related outcomes. Here, we use measurements of levels of 4,684 plasma proteins in 22,913 Icelanders to develop all-cause mortality predictors both for short- and long-term risk. The participants were 18-101 years old with a mean follow up of 13.7 (sd. 4.7) years. During the study period, 7,061 participants died. Our proposed predictor outperformed, in survival prediction, a predictor based on conventional mortality risk factors. We could identify the 5% at highest risk in a group of 60-80 years old, where 88% died within ten years and 5% at the lowest risk where only 1% died. Furthermore, the predicted risk of death correlates with measures of frailty in an independent dataset. Our results show that the plasma proteome can be used to assess general health and estimate the risk of death.

Molecular benchmarks of a SARS-CoV-2 epidemic.

A pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures.

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR.

BACKGROUND: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. METHODS: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. RESULTS: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. CONCLUSIONS: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans.

Humoral Immune Response to SARS-CoV-2 in Iceland.

BACKGROUND: Little is known about the nature and durability of the humoral immune response to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We measured antibodies in serum samples from 30,576 persons in Iceland, using six assays (including two pan-immunoglobulin [pan-Ig] assays), and we determined that the appropriate measure of seropositivity was a positive result with both pan-Ig assays. We tested 2102 samples collected from 1237 persons up to 4 months after diagnosis by a quantitative polymerase-chain-reaction (qPCR) assay. We measured antibodies in 4222 quarantined persons who had been exposed to SARS-CoV-2 and in 23,452 persons not known to have been exposed. RESULTS: Of the 1797 persons who had recovered from SARS-CoV-2 infection, 1107 of the 1215 who were tested (91.1%) were seropositive; antiviral antibody titers assayed by two pan-Ig assays increased during 2 months after diagnosis by qPCR and remained on a plateau for the remainder of the study. Of quarantined persons, 2.3% were seropositive; of those with unknown exposure, 0.3% were positive. We estimate that 0.9% of Icelanders were infected with SARS-CoV-2 and that the infection was fatal in 0.3%. We also estimate that 56% of all SARS-CoV-2 infections in Iceland had been diagnosed with qPCR, 14% had occurred in quarantined persons who had not been tested with qPCR (or who had not received a positive result, if tested), and 30% had occurred in persons outside quarantine and not tested with qPCR. CONCLUSIONS: Our results indicate that antiviral antibodies against SARS-CoV-2 did not decline within 4 months after diagnosis. We estimate that the risk of death from infection was 0.3% and that 44% of persons infected with SARS-CoV-2 in Iceland were not diagnosed by qPCR.

Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = -1.61 SD, CI95 = [-1.98, -1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.

Spread of SARS-CoV-2 in the Icelandic Population.

BACKGROUND: During the current worldwide pandemic, coronavirus disease 2019 (Covid-19) was first diagnosed in Iceland at the end of February. However, data are limited on how SARS-CoV-2, the virus that causes Covid-19, enters and spreads in a population. METHODS: We targeted testing to persons living in Iceland who were at high risk for infection (mainly those who were symptomatic, had recently traveled to high-risk countries, or had contact with infected persons). We also carried out population screening using two strategies: issuing an open invitation to 10,797 persons and sending random invitations to 2283 persons. We sequenced SARS-CoV-2 from 643 samples. RESULTS: As of April 4, a total of 1221 of 9199 persons (13.3%) who were recruited for targeted testing had positive results for infection with SARS-CoV-2. Of those tested in the general population, 87 (0.8%) in the open-invitation screening and 13 (0.6%) in the random-population screening tested positive for the virus. In total, 6% of the population was screened. Most persons in the targeted-testing group who received positive tests early in the study had recently traveled internationally, in contrast to those who tested positive later in the study. Children under 10 years of age were less likely to receive a positive result than were persons 10 years of age or older, with percentages of 6.7% and 13.7%, respectively, for targeted testing; in the population screening, no child under 10 years of age had a positive result, as compared with 0.8% of those 10 years of age or older. Fewer females than males received positive results both in targeted testing (11.0% vs. 16.7%) and in population screening (0.6% vs. 0.9%). The haplotypes of the sequenced SARS-CoV-2 viruses were diverse and changed over time. The percentage of infected participants that was determined through population screening remained stable for the 20-day duration of screening. CONCLUSIONS: In a population-based study in Iceland, children under 10 years of age and females had a lower incidence of SARS-CoV-2 infection than adolescents or adults and males. The proportion of infected persons identified through population screening did not change substantially during the screening period, which was consistent with a beneficial effect of containment efforts. (Funded by deCODE Genetics-Amgen.).