Publications by authors named "Gisli Masson"

107 Publications

Molecular benchmarks of a SARS-CoV-2 epidemic.

Nat Commun 2021 06 15;12(1):3633. Epub 2021 Jun 15.

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.

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.
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http://dx.doi.org/10.1038/s41467-021-23883-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206085PMC
June 2021

Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits.

Nat Genet 2021 06 10;53(6):779-786. Epub 2021 May 10.

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.

Long-read sequencing (LRS) promises to improve the characterization of structural variants (SVs). We generated LRS data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions). We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association of a rare deletion in PCSK9 with lower low-density lipoprotein (LDL) cholesterol levels, compared to the population average. We also discovered an association of a multiallelic SV in ACAN with height; we found 11 alleles that differed in the number of a 57-bp-motif repeat and observed a linear relationship between the number of repeats carried and height. These results show that SVs can be accurately characterized at the population scale using LRS data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.
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http://dx.doi.org/10.1038/s41588-021-00865-4DOI Listing
June 2021

Differences between germline genomes of monozygotic twins.

Nat Genet 2021 01 7;53(1):27-34. Epub 2021 Jan 7.

deCODE genetics/Amgen, Reykjavik, Iceland.

Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.
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http://dx.doi.org/10.1038/s41588-020-00755-1DOI Listing
January 2021

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

Circ Genom Precis Med 2021 02 14;14(1):e003029. Epub 2020 Dec 14.

deCODE genetics/Amgen, Inc (E.B., K.G., G.H.H., A.S., G.A.A., H.J., G.S., S.G., A.H., G. Thorleifsson, J.S., I.J., O.T.M., G.M., H.S., D.F.G., G. Thorgeirsson, H.H., B.V.H., P.M., G.L.N., P.S., U.T., K.S.), University of Iceland.

Background: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene () cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in 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 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; =8.4×10). 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 . 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 (=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (=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 causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of mRNA as a potent regulator of LDL receptor expression in humans.
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http://dx.doi.org/10.1161/CIRCGEN.120.003029DOI Listing
February 2021

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

N Engl J Med 2020 10 1;383(18):1724-1734. Epub 2020 Sep 1.

From deCODE Genetics/Amgen (D.F.G., G.L.N., P.M., K.G., H.H., A.O.A., K. Bjarnadottir, B. Thorsteinsdottir, S.K., K. Birgisdottir, A.M.K., G.A.A., E.V.I., M.A., F.J., A.B.A., J.B., B.E., R.F., E.E.G., S.G., K.R.G., A.G., A.H., B.O.J., A.J., H.J., T.K., D.N.M., O.T.M., S.R., L.R., A.S., G. Sveinbjornsson, K.E.S., E.A.T., B. Thorbjornsson, J.S., G.M., G.G., U.T., I.J., P.S., K.S.), the School of Engineering and Natural Sciences (D.F.G., P.M.), the Department of Anthropology (A.H.), the BioMedical Center (K.G.K.), and the Faculty of Medicine, School of Health Sciences (M.I.S., M.G., K.G.K., R.P., U.T., I.J., K.S.), University of Iceland, Internal Medicine and Rehabilitation Services (E.E., D.H., R.F.I., M.G., L.B.O., M.K., R.P.), the Division of Anesthesia and Intensive Care Medicine (M.I.S.), and the Department of Clinical Microbiology (O.S.G., T.R.G., K.G.K., M.S.), Landspitali-the National University Hospital, and the Directorate of Health (G. Sigmundsdottir, M.T., K.S.J., A.M., T.G.), Reykjavik, and the Health Care Institution of South Iceland, Selfoss (S.H.K.) - all 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.
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http://dx.doi.org/10.1056/NEJMoa2026116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494247PMC
October 2020

FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.

Nature 2020 08 24;584(7822):619-623. Epub 2020 Jun 24.

Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10) and coeliac disease (OR = 1.62, P = 1.20 × 10). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.
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http://dx.doi.org/10.1038/s41586-020-2436-0DOI Listing
August 2020

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

Commun Biol 2020 04 23;3(1):189. Epub 2020 Apr 23.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

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 (Effect = -1.61 SD, CI = [-1.98, -1.35]; Effect = 0.63 SD, CI = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
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http://dx.doi.org/10.1038/s42003-020-0921-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181819PMC
April 2020

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

N Engl J Med 2020 06 14;382(24):2302-2315. Epub 2020 Apr 14.

From deCODE Genetics-Amgen (D.F.G., A.H., H.J., O.T.M., P.M., G.L.N., J.S., A.S., P.S., A.B.A., B.E., R.F., E.E.G., G.G., K.R.G., A.G., H.H., B.O.J., A.J., F.J., T.K., D.N.M., L.R., G. Sveinbjornsson, K.E.S., E.A.T., B.T., G.M., I.J., U.T., K.S.), the School of Engineering and Natural Sciences (D.F.G., P.M.), the Department of Anthropology (A.H.), the Faculty of Medicine, School of Health Sciences (A.L., I.J., K.G.K., U.T., K.S.), and the BioMedical Center of the University of Iceland (K.G.K.), University of Iceland, the Department of Clinical Microbiology, Landspitali-National University Hospital (O.S.G., T.R.G., M.S., A.L., K.G.K.) and the Directorate of Health (K.S.J., G. Sigmundsdottir, A.D.M., T.G.) - all in Reykjavik, Iceland.

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.).
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http://dx.doi.org/10.1056/NEJMoa2006100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175425PMC
June 2020

Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.

Nat Commun 2020 01 20;11(1):393. Epub 2020 Jan 20.

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.

Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.
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http://dx.doi.org/10.1038/s41467-019-14144-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971247PMC
January 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.

Cancer Epidemiol Biomarkers Prev 2020 01 30;29(1):225-235. Epub 2019 Oct 30.

deCODE genetics/AMGEN, Reykjavik, Iceland.

Background: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects.

Methods: We performed genome-wide association studies of serum levels of AFP ( = 22,686), carcinoembryonic antigen ( = 22,309), cancer antigens 15.3 ( = 7,107), 19.9 ( = 9,945), and 125 ( = 9,824), and ALP ( = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry.

Results: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels.

Conclusions: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood.

Impact: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954334PMC
January 2020

Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.

Nat Commun 2019 May 24;10(1):2358. Epub 2019 May 24.

Bone Biology Division, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.

The original HTML version of this Article was updated shortly after publication to add links to the Peer Review file.In addition, affiliations 16 and 17 incorrectly read 'School of Medicine Sydney, University of Notre Dame Australia, Sydney, WA, 6160, Australia' and 'St Vincent's Clinical School, University of New South Wales Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.' This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-10425-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534558PMC
May 2019

GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures.

Nat Commun 2019 05 3;10(1):2054. Epub 2019 May 3.

Bone Biology Division, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.

Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10, β = -0.090) and confers risk of hip fracture (P = 1.0 × 10, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.
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http://dx.doi.org/10.1038/s41467-019-09860-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499783PMC
May 2019

A PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy.

Nat Commun 2019 04 16;10(1):1777. Epub 2019 Apr 16.

deCODE Genetics/Amgen, Inc., 101 Reykjavik, Iceland.

Nerve conduction (NC) studies generate measures of peripheral nerve function that can reveal underlying pathology due to axonal loss, demyelination or both. We perform a genome-wide association study of sural NC amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH (c.996+1G>A; MAF = 1.32%) associating with decreased NC amplitude but not velocity. PRPH encodes peripherin, an intermediate filament (IF) protein involved in cytoskeletal development and maintenance of neurons. Through RNA and protein studies, we show that the variant leads to loss-of-function (LoF), as when over-expressed in a cell line devoid of other IFs, it does not allow formation of the normal filamentous structure of peripherin, yielding instead punctate protein inclusions. Recall of carriers for neurological assessment confirms that from an early age, homozygotes have significantly lower sural NC amplitude than non-carriers and are at risk of a mild, early-onset, sensory-negative, axonal polyneuropathy.
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http://dx.doi.org/10.1038/s41467-019-09719-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468012PMC
April 2019

Characterizing mutagenic effects of recombination through a sequence-level genetic map.

Science 2019 Jan;363(6425)

deCODE genetics, Amgen, Sturlugata 8, Reykjavik, Iceland.

Genetic diversity arises from recombination and de novo mutation (DNM). Using a combination of microarray genotype and whole-genome sequence data on parent-child pairs, we identified 4,531,535 crossover recombinations and 200,435 DNMs. The resulting genetic map has a resolution of 682 base pairs. Crossovers exhibit a mutagenic effect, with overrepresentation of DNMs within 1 kilobase of crossovers in males and females. In females, a higher mutation rate is observed up to 40 kilobases from crossovers, particularly for complex crossovers, which increase with maternal age. We identified 35 loci associated with the recombination rate or the location of crossovers, demonstrating extensive genetic control of meiotic recombination, and our results highlight genes linked to the formation of the synaptonemal complex as determinants of crossovers.
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http://dx.doi.org/10.1126/science.aau1043DOI Listing
January 2019

A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.

Nat Genet 2019 02 14;51(2):267-276. Epub 2019 Jan 14.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.
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http://dx.doi.org/10.1038/s41588-018-0314-6DOI Listing
February 2019

Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.

Nat Commun 2018 11 30;9(1):5101. Epub 2018 Nov 30.

deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.

Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR = 1.36 [1.25-1.49], P = 2.1 × 10, MAF = 1%; Val98Ile: OR = 1.15 [1.10-1.20], P = 1.8 × 10, MAF = 4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.
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http://dx.doi.org/10.1038/s41467-018-07460-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269469PMC
November 2018

Sequence variants associating with urinary biomarkers.

Hum Mol Genet 2019 04;28(7):1199-1211

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context.
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http://dx.doi.org/10.1093/hmg/ddy409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423415PMC
April 2019

Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.

Nat Commun 2018 11 8;9(1):4568. Epub 2018 Nov 8.

deCODE genetics/AMGEN, 101, Reykjavik, Iceland.

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, r = 0.77 (P = 2.6 × 10), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.
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http://dx.doi.org/10.1038/s41467-018-06920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224563PMC
November 2018

Multiple transmissions of de novo mutations in families.

Nat Genet 2018 12 5;50(12):1674-1680. Epub 2018 Nov 5.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

De novo mutations (DNMs) cause a large proportion of severe rare diseases of childhood. DNMs that occur early may result in mosaicism of both somatic and germ cells. Such early mutations can cause recurrence of disease. We scanned 1,007 sibling pairs from 251 families and identified 878 DNMs shared by siblings (ssDNMs) at 448 genomic sites. We estimated DNM recurrence probability based on parental mosaicism, sharing of DNMs among siblings, parent-of-origin, mutation type and genomic position. We detected 57.2% of ssDNMs in the parental blood. The recurrence probability of a DNM decreases by 2.27% per year for paternal DNMs and 1.78% per year for maternal DNMs. Maternal ssDNMs are more likely to be T>C mutations than paternal ssDNMs, and less likely to be C>T mutations. Depending on the properties of the DNM, the recurrence probability ranges from 0.011% to 28.5%. We have launched an online calculator to allow estimation of DNM recurrence probability for research purposes.
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http://dx.doi.org/10.1038/s41588-018-0259-9DOI Listing
December 2018

Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis.

Nat Genet 2018 12 29;50(12):1681-1687. Epub 2018 Oct 29.

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.

Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10, p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10, p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10, OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL (rs117018441, P = 1.8 × 10, OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis.
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http://dx.doi.org/10.1038/s41588-018-0247-0DOI Listing
December 2018

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease.

Nat Commun 2018 10 25;9(1):4447. Epub 2018 Oct 25.

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase's main subunit (gp91) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10; OR = 67.6), as well as reduced height (P = 3.3 × 10; -8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.
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http://dx.doi.org/10.1038/s41467-018-06964-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202333PMC
October 2018

Insights into imprinting from parent-of-origin phased methylomes and transcriptomes.

Nat Genet 2018 11 22;50(11):1542-1552. Epub 2018 Oct 22.

deCODE genetics/AMGEN, Reykjavik, Iceland.

Imprinting is the preferential expression of one parental allele over the other. It is controlled primarily through differential methylation of cytosine at CpG dinucleotides. Here we combine 285 methylomes and 11,617 transcriptomes from peripheral blood samples with parent-of-origin phased haplotypes, to produce a new map of imprinted methylation and gene expression patterns across the human genome. We demonstrate how imprinted methylation is a continuous rather than a binary characteristic. We describe at high resolution the parent-of-origin methylation pattern at the 15q11.2 Prader-Willi/Angelman syndrome locus, with nearly confluent stochastic paternal methylation punctuated by 'spikes' of maternal methylation. We find examples of polymorphic imprinted methylation unrelated (at VTRNA2-1 and PARD6G) or related (at CHRNE) to nearby SNP genotypes. We observe RNA isoform-specific imprinted expression patterns suggestive of a methylation-sensitive transcriptional elongation block. Finally, we gain new insights into parent-of-origin-specific effects on phenotypes at the DLK1/MEG3 and GNAS loci.
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http://dx.doi.org/10.1038/s41588-018-0232-7DOI Listing
November 2018

A truncating mutation in EPOR leads to hypo-responsiveness to erythropoietin with normal haemoglobin.

Commun Biol 2018 17;1:49. Epub 2018 May 17.

deCODE genetics/Amgen, Inc, 101, Reykjavik, Iceland.

The cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells. We performed a genome-wide association study (GWAS) testing 32.5 million sequence variants for association with serum EPO levels in a set of 4187 individuals. We detect an association between a rare and well imputed stop-gained variant rs370865377[A] (p.Gln82Ter) in , carried by 1 in 550 Icelanders, and increased serum EPO levels (MAF = 0.09%, Effect = 1.47 SD,  = 3.3 × 10). We validated these findings by measuring serum EPO levels in 34 additional pairs of carriers and matched controls and found carriers to have 3.23-fold higher EPO levels than controls ( = 1.7 × 10;  = 1.6 × 10). In contrast to previously reported EPOR mutations, p.Gln82Ter does not associate with haemoglobin levels (Effect = -0.045 SD,  = 0.32,  = 273,160), probably due to a compensatory EPO upregulation in response to EPO-R hypo-responsiveness.
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http://dx.doi.org/10.1038/s42003-018-0053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123817PMC
May 2018

A rare missense variant in associates with lower cholesterol levels.

Commun Biol 2018 8;1:14. Epub 2018 Feb 8.

deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.

Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in (R436H) associating with lower levels of total cholesterol (effect = -0.47 standard deviations or -0.55 mmol L,  = 4.21 × 10,  = 150,211). Importantly, R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans.
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http://dx.doi.org/10.1038/s42003-018-0015-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123719PMC
February 2018

Author Correction: The rate of meiotic gene conversion varies by sex and age.

Nat Genet 2018 11;50(11):1616

deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

In the version of this article published, statements about the impact of insertions and deletions on gene conversions were incorrect. We reported a bias toward deletions, whereas in fact the bias was toward insertions. We are deeply indebted to Laurent Duret and Brice Letcher for noticing this mistake in our manuscript. The following statements are incorrect in the published manuscript.
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http://dx.doi.org/10.1038/s41588-018-0228-3DOI Listing
November 2018

Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits.

Nat Commun 2018 09 7;9(1):3636. Epub 2018 Sep 7.

deCODE Genetics/Amgen, Sturlugata 8, 101, Reykjavik, Iceland.

Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth.
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http://dx.doi.org/10.1038/s41467-018-05428-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128903PMC
September 2018

Relatedness disequilibrium regression estimates heritability without environmental bias.

Nat Genet 2018 09 13;50(9):1304-1310. Epub 2018 Aug 13.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Heritability measures the proportion of trait variation that is due to genetic inheritance. Measurement of heritability is important in the nature-versus-nurture debate. However, existing estimates of heritability may be biased by environmental effects. Here, we introduce relatedness disequilibrium regression (RDR), a novel method for estimating heritability. RDR avoids most sources of environmental bias by exploiting variation in relatedness due to random Mendelian segregation. We used a sample of 54,888 Icelanders who had both parents genotyped to estimate the heritability of 14 traits, including height (55.4%, s.e. 4.4%) and educational attainment (17.0%, s.e. 9.4%). Our results suggest that some other estimates of heritability may be inflated by environmental effects.
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http://dx.doi.org/10.1038/s41588-018-0178-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130754PMC
September 2018

Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

J Natl Cancer Inst 2018 09;110(9):967-974

Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland.

Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population.

Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database.

Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele.

Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.
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http://dx.doi.org/10.1093/jnci/djy002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924PMC
September 2018

The nature of nurture: Effects of parental genotypes.

Science 2018 Jan;359(6374):424-428

deCODE genetics/Amgen, 101 Reykjavik, Iceland.

Sequence variants in the parental genomes that are not transmitted to a child (the proband) are often ignored in genetic studies. Here we show that nontransmitted alleles can affect a child through their impacts on the parents and other relatives, a phenomenon we call "genetic nurture." Using results from a meta-analysis of educational attainment, we find that the polygenic score computed for the nontransmitted alleles of 21,637 probands with at least one parent genotyped has an estimated effect on the educational attainment of the proband that is 29.9% ( = 1.6 × 10) of that of the transmitted polygenic score. Genetic nurturing effects of this polygenic score extend to other traits. Paternal and maternal polygenic scores have similar effects on educational attainment, but mothers contribute more than fathers to nutrition- and heath-related traits.
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http://dx.doi.org/10.1126/science.aan6877DOI Listing
January 2018
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