50 results on '"Sigurdardottir O"'
Search Results
2. The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms
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Oddsson, A, Kristinsson, S Y, Helgason, H, Gudbjartsson, D F, Masson, G, Sigurdsson, A, Jonasdottir, A, Steingrimsdottir, H, Vidarsson, B, Reykdal, S, Eyjolfsson, G I, Olafsson, I, Onundarson, P T, Runarsson, G, Sigurdardottir, O, Kong, A, Rafnar, T, Sulem, P, Thorsteinsdottir, U, and Stefansson, K
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- 2014
- Full Text
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3. Characterization of the interaction of plasminogen activator inhibitor type 1 with vitronectin by surface plasmon resonance
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Ehnebom, J., Björquist, P., Sigurdardottir, O., and Deinum, J.
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- 2000
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- View/download PDF
4. A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease.
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Bjornsson, E., Halldorsson, G., Helgadottir, A., Gylfason, A, Kehr, B., Jonasdottir, A., Sigurdsson, A., Oddsson, A., Thorleifsson, G., Magnusson, O.T., Gretarsdottir, S., Kristjansson, R.P., Asgeirsdottir, M., Swinkels, D.W., Kiemeney, L.A., Eyjolfsson, G.I., Sigurdardottir, O., Masson, G., Olafsson, I., Thorgeirsson, G., Holm, H., Thorsteinsdottir, U., Gudbjartsson, D.F., Sulem, P., Stefansson, K., Bjornsson, E., Halldorsson, G., Helgadottir, A., Gylfason, A, Kehr, B., Jonasdottir, A., Sigurdsson, A., Oddsson, A., Thorleifsson, G., Magnusson, O.T., Gretarsdottir, S., Kristjansson, R.P., Asgeirsdottir, M., Swinkels, D.W., Kiemeney, L.A., Eyjolfsson, G.I., Sigurdardottir, O., Masson, G., Olafsson, I., Thorgeirsson, G., Holm, H., Thorsteinsdottir, U., Gudbjartsson, D.F., Sulem, P., and Stefansson, K.
- Abstract
Contains fulltext : 174137.pdf (publisher's version ) (Closed access)
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- 2017
5. A genome-wide association study yields five novel thyroid cancer risk loci
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Gudmundsson, J., Thorleifsson, G., Sigurdsson, J.K., Stefansdottir, L., Jonasson, J.G., Gudjonsson, S.A., Gudbjartsson, D.F., Masson, G., Johannsdottir, H., Halldorsson, G.H., Stacey, S.N., Helgason, H., Sulem, P., Senter, L., He, H., Liyanarachchi, S., Ringel, M.D., Aguillo, E., Panadero, A., Prats, E., Garcia-Castano, A., Juan, A. de, Rivera, F., Xu, L., Kiemeney, L.A.L.M., Eyjolfsson, G.I., Sigurdardottir, O., Olafsson, I., Kristvinsson, H., Netea-Maier, R.T., Jonsson, T., Mayordomo, J.I., Plantinga, T.S., Hjartarson, H., Hrafnkelsson, J., Sturgis, E.M., Thorsteinsdottir, U., Rafnar, T., Chapelle, A. de la, Stefansson, K., Gudmundsson, J., Thorleifsson, G., Sigurdsson, J.K., Stefansdottir, L., Jonasson, J.G., Gudjonsson, S.A., Gudbjartsson, D.F., Masson, G., Johannsdottir, H., Halldorsson, G.H., Stacey, S.N., Helgason, H., Sulem, P., Senter, L., He, H., Liyanarachchi, S., Ringel, M.D., Aguillo, E., Panadero, A., Prats, E., Garcia-Castano, A., Juan, A. de, Rivera, F., Xu, L., Kiemeney, L.A.L.M., Eyjolfsson, G.I., Sigurdardottir, O., Olafsson, I., Kristvinsson, H., Netea-Maier, R.T., Jonsson, T., Mayordomo, J.I., Plantinga, T.S., Hjartarson, H., Hrafnkelsson, J., Sturgis, E.M., Thorsteinsdottir, U., Rafnar, T., Chapelle, A. de la, and Stefansson, K.
- Abstract
Contains fulltext : 169947.pdf (publisher's version ) (Open Access), The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with Pcombined<3 x 10-8): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 x 10-7) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.
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- 2017
6. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease
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Helgadottir, A., Gretarsdottir, S., Thorleifsson, G., Hjartarson, E., Sigurdsson, A., Magnusdottir, A., Jonasdottir, A., Kristjansson, H., Sulem, P., Oddsson, A., Sveinbjornsson, G., Steinthorsdottir, V., Rafnar, T., Masson, G., Jonsdottir, I., Olafsson, I., Eyjolfsson, G.I., Sigurdardottir, O., Daneshpour, M.S., Khalili, D., Azizi, F., Swinkels, D.W., Kiemeney, L.A., Quyyumi, A.A., Levey, A.I., Patel, R.S., Hayek, S.S., Gudmundsdottir, I.J., Thorgeirsson, G., Thorsteinsdottir, U., Gudbjartsson, D.F., Holm, H., Stefansson, K., Helgadottir, A., Gretarsdottir, S., Thorleifsson, G., Hjartarson, E., Sigurdsson, A., Magnusdottir, A., Jonasdottir, A., Kristjansson, H., Sulem, P., Oddsson, A., Sveinbjornsson, G., Steinthorsdottir, V., Rafnar, T., Masson, G., Jonsdottir, I., Olafsson, I., Eyjolfsson, G.I., Sigurdardottir, O., Daneshpour, M.S., Khalili, D., Azizi, F., Swinkels, D.W., Kiemeney, L.A., Quyyumi, A.A., Levey, A.I., Patel, R.S., Hayek, S.S., Gudmundsdottir, I.J., Thorgeirsson, G., Thorsteinsdottir, U., Gudbjartsson, D.F., Holm, H., and Stefansson, K.
- Abstract
Contains fulltext : 171919.pdf (publisher's version ) (Closed access), Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 x 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 x 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
- Published
- 2016
7. Identification of common genetic variants influencing spontaneous dizygotic twinning and female fertility
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Mbarek, H., Steinberg, S., Nyholt, D.R., Gordon, S.D., Miller, M.B., McRae, A.F., Hottenga, J.J., Day, F.R., Willemsen, G., Geus, E.J.C. de, Davies, G.E., Martin, H.C., Penninx, B.W.J.H., Jansen, R., McAloney, K., Vink, J.M., Kaprio, J., Plomin, R., Spector, T.D., Magnusson, P.K.E., Reversade, B., Harris, R.A., Aagaard, K., Kristjansson, R.P., Olafsson, I., Eyjolfsson, G.I., Sigurdardottir, O., Iacono, W.G., Lambalk, C.B., Montgomery, G.W., McGue, M.K., Ong, K.K., Perry, J.R.B., Martin, N.G., Stefánsson, H., Stefánsson, K., Boomsma, D.I., Mbarek, H., Steinberg, S., Nyholt, D.R., Gordon, S.D., Miller, M.B., McRae, A.F., Hottenga, J.J., Day, F.R., Willemsen, G., Geus, E.J.C. de, Davies, G.E., Martin, H.C., Penninx, B.W.J.H., Jansen, R., McAloney, K., Vink, J.M., Kaprio, J., Plomin, R., Spector, T.D., Magnusson, P.K.E., Reversade, B., Harris, R.A., Aagaard, K., Kristjansson, R.P., Olafsson, I., Eyjolfsson, G.I., Sigurdardottir, O., Iacono, W.G., Lambalk, C.B., Montgomery, G.W., McGue, M.K., Ong, K.K., Perry, J.R.B., Martin, N.G., Stefánsson, H., Stefánsson, K., and Boomsma, D.I.
- Abstract
Contains fulltext : 157507.pdf (publisher's version ) (Closed access), Spontaneous dizygotic (DZ) twinning occurs in 1%–4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10−9, and rs17293443 in SMAD3, p = 1.57 × 10−8) and replicated (p = 3 × 10−3 and p = 1.44 × 10−4, respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.
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- 2016
8. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease
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Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A.B., Norddahl, G.L., Helgadottir, A., Magnusdottir, A., Jonasdottir, A., Gretarsdottir, S., Jonsdottir, I., Steinthorsdottir, V., Rafnar, T., Swinkels, D.W., Galesloot, T.E., Grarup, N., Jorgensen, T., Vestergaard, H., Hansen, T., Lauritzen, T., Linneberg, A., Friedrich, N., Krarup, N.T., Fenger, M., Abildgaard, U., Hansen, P.R., Galloe, A.M., Braund, P.S., Nelson, C.P., Hall, A.S., Williams, M.J., Rij, A.M. van, Jones, G.T., Patel, R.S., Levey, A.I., Hayek, S., Shah, S.H., Reilly, M., Eyjolfsson, G.I., Sigurdardottir, O., Olafsson, I., Kiemeney, L.A.L.M., Quyyumi, A.A., Rader, D.J., Kraus, W.E., Samani, N.J., Pedersen, O., Thorgeirsson, G., Masson, G., Holm, H., Gudbjartsson, D., Sulem, P., Thorsteinsdottir, U., Stefansson, K., Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A.B., Norddahl, G.L., Helgadottir, A., Magnusdottir, A., Jonasdottir, A., Gretarsdottir, S., Jonsdottir, I., Steinthorsdottir, V., Rafnar, T., Swinkels, D.W., Galesloot, T.E., Grarup, N., Jorgensen, T., Vestergaard, H., Hansen, T., Lauritzen, T., Linneberg, A., Friedrich, N., Krarup, N.T., Fenger, M., Abildgaard, U., Hansen, P.R., Galloe, A.M., Braund, P.S., Nelson, C.P., Hall, A.S., Williams, M.J., Rij, A.M. van, Jones, G.T., Patel, R.S., Levey, A.I., Hayek, S., Shah, S.H., Reilly, M., Eyjolfsson, G.I., Sigurdardottir, O., Olafsson, I., Kiemeney, L.A.L.M., Quyyumi, A.A., Rader, D.J., Kraus, W.E., Samani, N.J., Pedersen, O., Thorgeirsson, G., Masson, G., Holm, H., Gudbjartsson, D., Sulem, P., Thorsteinsdottir, U., and Stefansson, K.
- Abstract
Item does not contain fulltext, BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0x10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0x10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8x10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health
- Published
- 2016
9. Factors affecting the herd level of antibodies against Mycobacterium avium subspecies paratuberculosis in dairy cattle
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Sigurdardottir O, Bente Fredriksen, Jarp J, Jorun Tharaldsen, Berit Djønne, and Nyberg O
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Veterinary medicine ,animal diseases ,Cattle Diseases ,Paratuberculosis ,Enzyme-Linked Immunosorbent Assay ,Pasture ,Serology ,Birds ,Feces ,Seroepidemiologic Studies ,Surveys and Questionnaires ,medicine ,Animals ,Animal Husbandry ,Dairy cattle ,geography ,geography.geographical_feature_category ,General Veterinary ,biology ,Norway ,Deer ,General Medicine ,medicine.disease ,biology.organism_classification ,Animal Feed ,Antibodies, Bacterial ,Mycobacterium avium subspecies paratuberculosis ,Mycobacterium avium subsp. paratuberculosis ,Dairying ,Case-Control Studies ,Herd ,biology.protein ,Cervus elaphus ,Cattle ,Antibody - Abstract
A case-control study was made of Norwegian dairy herds with high and low herd levels of antibodies against Mycobacterium avium subspecies paratuberculosis. A high proportion of the herds had a considerable number of seropositive cows, and environmental and management factors were examined for possible associations with the high serological levels of antibodies. The most important appeared to be: geographical location, red deer (Cervus elaphus) gaining access to the pastures for cattle, the observation of wild birds in the feed storage, and herds sharing common pasture with other herds of cattle. However, diagnostic tests showed that none of the animals in the case herds was infected with M a paratuberculosis.
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- 2004
10. A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease
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Gretarsdottir, S., Helgason, H., Helgadottir, A., Sigurdsson, A., Thorleifsson, G., Magnusdottir, A., Oddsson, A., Steinthorsdottir, V., Rafnar, T., Graaf, J. de, Daneshpour, M.S., Hedayati, M., Azizi, F., Grarup, N., Jorgensen, T., Vestergaard, H., Hansen, T., Eyjolfsson, G., Sigurdardottir, O., Olafsson, I., Kiemeney, B., Pedersen, O., Sulem, P., Thorgeirsson, G., Gudbjartsson, D.F., Holm, H., Thorsteinsdottir, U., Stefansson, K., Gretarsdottir, S., Helgason, H., Helgadottir, A., Sigurdsson, A., Thorleifsson, G., Magnusdottir, A., Oddsson, A., Steinthorsdottir, V., Rafnar, T., Graaf, J. de, Daneshpour, M.S., Hedayati, M., Azizi, F., Grarup, N., Jorgensen, T., Vestergaard, H., Hansen, T., Eyjolfsson, G., Sigurdardottir, O., Olafsson, I., Kiemeney, B., Pedersen, O., Sulem, P., Thorgeirsson, G., Gudbjartsson, D.F., Holm, H., Thorsteinsdottir, U., and Stefansson, K.
- Abstract
Contains fulltext : 154823.pdf (publisher's version ) (Open Access), Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 x 10-80 and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 x 10-12) and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 x 10-8 and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.
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- 2015
11. Studies on the interaction between plasminogen activator inhibitor-1 and vitronectin
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Sigurdardottir, O., primary and Wiman, B., additional
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- 1992
- Full Text
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12. Systemic release of thrombomodulin, but not from the cardioplegic, reperfused heart during open heart surgery
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Valen, G., Sigurdardottir, O., and Vaage, J.
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- 1996
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13. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis
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Ferkingstad, E., Magnusson, Magnus K., Bell, S., Rigas, A. S., Allara, E., Bjornsdottir, G., Ramond, A., Sorensen, E., Halldorsson, G. H., Paul, D. S., Burgdorf, K. S., Eggertsson, H. P., Kristmundsdottir, S., Astle, W. J., Erikstrup, C., Sigurdsson, J. K., Vuckovic, D., Tragante, V., Surendran, P., Vidarsson, B., Jonsdottir, I., Torben Hansen, Sigurdardottir, O., Stefansson, H., Rye, D., Peters, J. E., Westergaard, D., Holm, H., Soranzo, N., Karina Banasik, Thorleifsson, G., Ouwehand, W. H., Thorsteinsdottir, U., Sulem, P., Butterworth, A. S., Gudbjartsson, D. F., Danesh, J., Søren Brunak, Di Angelantonio, E., Henrik Ullum, Stefansson, K., and Dbds, Genomic Consortium
14. The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms.
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Amgen Inc, DeCODE Genet, Reykjavik, Iceland, Univ Iceland, Fac Med, Reykjavik, Iceland, Natl Univ Hosp Iceland, Landspitali, Dept Hematol, Reykjavik, Iceland, Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland, RAM, Lab Mjodd, Reykjavik, Iceland, Natl Univ Hosp Iceland, Landspitali, Dept Clin Biochem, Reykjavik, Iceland, Akureyri Hosp, Dept Clin Biochem, Akureyri, Iceland, Oddsson, A, Kristinsson, S Y, Helgason, H, Gudbjartsson, D F, Masson, G, Sigurdsson, A, Jonasdottir, A, Steingrimsdottir, H, Vidarsson, B, Reykdal, S, Eyjolfsson, G I, Olafsson, I, Onundarson, P T, Runarsson, G, Sigurdardottir, O, Kong, A, Rafnar, T, Sulem, P, Thorsteinsdottir, U, Stefansson, K, Amgen Inc, DeCODE Genet, Reykjavik, Iceland, Univ Iceland, Fac Med, Reykjavik, Iceland, Natl Univ Hosp Iceland, Landspitali, Dept Hematol, Reykjavik, Iceland, Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland, RAM, Lab Mjodd, Reykjavik, Iceland, Natl Univ Hosp Iceland, Landspitali, Dept Clin Biochem, Reykjavik, Iceland, Akureyri Hosp, Dept Clin Biochem, Akureyri, Iceland, Oddsson, A, Kristinsson, S Y, Helgason, H, Gudbjartsson, D F, Masson, G, Sigurdsson, A, Jonasdottir, A, Steingrimsdottir, H, Vidarsson, B, Reykdal, S, Eyjolfsson, G I, Olafsson, I, Onundarson, P T, Runarsson, G, Sigurdardottir, O, Kong, A, Rafnar, T, Sulem, P, Thorsteinsdottir, U, and Stefansson, K
- Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.
15. A partial loss-of-function variant in STAT6 protects against T2 asthma.
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Kristjansdottir K, Norddahl GL, Ivarsdottir EV, Halldorsson GH, Einarsson G, Bjarnadóttir K, Rutsdottir G, Arnthorsson AO, Erikstrup C, Gudmundsdottir S, Gunnarsdottir K, Gunnbjornsdottir MI, Halldorsson BV, Holm H, Ludviksdottir D, Ludviksson BR, Brunak S, Bruun MT, Mikkelsen C, Mikkelsen S, Jensen BA, Sørensen E, Thomsen SF, Ullum H, Olafsson I, Onundarson PT, Ostrowski SR, Saevarsdottir S, Sigurdardottir O, Sigurgeirsson B, Snaebjarnarson AS, Sveinbjornsson G, Thorlacius GE, Thorleifsson G, Tragante V, Vidarsson B, Porsbjerg C, Bjornsdottir US, Sulem P, Gudbjartsson DF, Melsted P, Pedersen OB, Jonsdóttir I, Olafsdottir TA, and Stefansson K
- Abstract
Background: Signal Transducer and Activator of Transcription 6 (STAT6) is central to Type 2 (T2) inflammation and common non-coding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment., Objective: To test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture., Methods: We tested association of p.L406P with plasma protein levels, white blood cell counts and the risk of asthma and allergic phenotypes. We tested significant associations in other cohorts using a burden test. The effects of p.L406P on STAT6 protein function were examined in cell lines and by comparing CD4
+ T-cell responses from carriers and non-carriers of the variant., Results: p.L406P associated with reduced plasma levels of STAT6 and IgE as well as with lower eosinophil and basophil counts in blood. It also protected against asthma, mostly driven by severe T2 high asthma. We showed that p.L406P led to lower IL-4-induced activation in luciferase reporter assays and lower levels of STAT6 in CD4+ T cells. We identified multiple genes with expression that was affected by the p.L406P genotype upon IL-4 treatment of CD4+ T cells; the effect was consistent with a weaker IL-4 response in carriers than non-carriers of p.L406P., Conclusions: We report a partial loss-of-function variant in STAT6, resulting in dampened IL-4 responses and protection from T2 high asthma, implicating STAT6 as an attractive therapeutic target., (Copyright © 2024. Published by Elsevier Inc.)- Published
- 2024
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16. Sequence variants influencing the regulation of serum IgG subclass levels.
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Olafsdottir TA, Thorleifsson G, Lopez de Lapuente Portilla A, Jonsson S, Stefansdottir L, Niroula A, Jonasdottir A, Eggertsson HP, Halldorsson GH, Thorlacius GE, Arnthorsson AO, Bjornsdottir US, Asselbergs FW, Bentlage AEH, Eyjolfsson GI, Gudmundsdottir S, Gunnarsdottir K, Halldorsson BV, Holm H, Ludviksson BR, Melsted P, Norddahl GL, Olafsson I, Saevarsdottir S, Sigurdardottir O, Sigurdsson A, Temming R, Önundarson PT, Thorsteinsdottir U, Vidarsson G, Sulem P, Gudbjartsson DF, Jonsdottir I, Nilsson B, and Stefansson K
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- Humans, Adult, Female, Male, Child, Adolescent, Receptors, IgG genetics, Middle Aged, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains blood, Alleles, Young Adult, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Autoimmune Diseases blood, Chromosomes, Human, Pair 17 genetics, Genetic Predisposition to Disease, HLA Antigens genetics, HLA Antigens immunology, Membrane Proteins, Immunoglobulin G blood, Immunoglobulin G immunology, Immunoglobulin G genetics, Genome-Wide Association Study, Asthma genetics, Asthma immunology, Asthma blood, Polymorphism, Single Nucleotide
- Abstract
Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics., (© 2024. The Author(s).)
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- 2024
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17. Genetic architecture of band neutrophil fraction in Iceland.
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Oskarsson GR, Magnusson MK, Oddsson A, Jensson BO, Fridriksdottir R, Arnadottir GA, Katrinardottir H, Rognvaldsson S, Halldorsson GH, Sveinbjornsson G, Ivarsdottir EV, Stefansdottir L, Ferkingstad E, Norland K, Tragante V, Saemundsdottir J, Jonasdottir A, Jonasdottir A, Sigurjonsdottir S, Petursdottir KO, Davidsson OB, Rafnar T, Holm H, Olafsson I, Onundarson PT, Vidarsson B, Sigurdardottir O, Masson G, Gudbjartsson DF, Jonsdottir I, Norddahl GL, Thorsteinsdottir U, Sulem P, and Stefansson K
- Subjects
- Genome-Wide Association Study, Granulocytes metabolism, Humans, Iceland, Neutrophils metabolism, Pelger-Huet Anomaly genetics
- Abstract
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., (© 2022. The Author(s).)
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- 2022
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18. Genetic variants associated with platelet count are predictive of human disease and physiological markers.
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Mikaelsdottir E, Thorleifsson G, Stefansdottir L, Halldorsson G, Sigurdsson JK, Lund SH, Tragante V, Melsted P, Rognvaldsson S, Norland K, Helgadottir A, Magnusson MK, Ragnarsson GB, Kristinsson SY, Reykdal S, Vidarsson B, Gudmundsdottir IJ, Olafsson I, Onundarson PT, Sigurdardottir O, Sigurdsson EL, Grondal G, Geirsson AJ, Geirsson G, Gudmundsson J, Holm H, Saevarsdottir S, Jonsdottir I, Thorgeirsson G, Gudbjartsson DF, Thorsteinsdottir U, Rafnar T, and Stefansson K
- Subjects
- Female, Humans, Male, Biomarkers analysis, Genetic Variation, Phenotype, Platelet Count, Quantitative Trait Loci
- Abstract
Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease., (© 2021. The Author(s).)
- Published
- 2021
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19. Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits.
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Beyter D, Ingimundardottir H, Oddsson A, Eggertsson HP, Bjornsson E, Jonsson H, Atlason BA, Kristmundsdottir S, Mehringer S, Hardarson MT, Gudjonsson SA, Magnusdottir DN, Jonasdottir A, Jonasdottir A, Kristjansson RP, Sverrisson ST, Holley G, Palsson G, Stefansson OA, Eyjolfsson G, Olafsson I, Sigurdardottir O, Torfason B, Masson G, Helgason A, Thorsteinsdottir U, Holm H, Gudbjartsson DF, Sulem P, Magnusson OT, Halldorsson BV, and Stefansson K
- Subjects
- Alleles, Cholesterol, LDL metabolism, Chromosomes, Human genetics, Female, Gene Frequency genetics, Humans, Iceland, Linear Models, Male, Proprotein Convertase 9 genetics, Recombination, Genetic genetics, Sequence Deletion genetics, Disease genetics, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Quantitative Trait, Heritable
- Abstract
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.
- Published
- 2021
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20. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis.
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Bell S, Rigas AS, Magnusson MK, Ferkingstad E, Allara E, Bjornsdottir G, Ramond A, Sørensen E, Halldorsson GH, Paul DS, Burgdorf KS, Eggertsson HP, Howson JMM, Thørner LW, Kristmundsdottir S, Astle WJ, Erikstrup C, Sigurdsson JK, Vuckovic D, Dinh KM, Tragante V, Surendran P, Pedersen OB, Vidarsson B, Jiang T, Paarup HM, Onundarson PT, Akbari P, Nielsen KR, Lund SH, Juliusson K, Magnusson MI, Frigge ML, Oddsson A, Olafsson I, Kaptoge S, Hjalgrim H, Runarsson G, Wood AM, Jonsdottir I, Hansen TF, Sigurdardottir O, Stefansson H, Rye D, Peters JE, Westergaard D, Holm H, Soranzo N, Banasik K, Thorleifsson G, Ouwehand WH, Thorsteinsdottir U, Roberts DJ, Sulem P, Butterworth AS, Gudbjartsson DF, Danesh J, Brunak S, Di Angelantonio E, Ullum H, and Stefansson K
- Subjects
- Humans, Biomarkers blood, Denmark, Ferritins blood, Genome-Wide Association Study, Genotype, Homeostasis, Iceland, Phenotype, Risk Assessment, Risk Factors, Transferrin metabolism, United Kingdom, Anemia, Iron-Deficiency blood, Anemia, Iron-Deficiency diagnosis, Anemia, Iron-Deficiency genetics, Genetic Loci, Genetic Variation, Iron blood, Iron Overload blood, Iron Overload diagnosis, Iron Overload genetics
- Abstract
Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.
- Published
- 2021
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21. Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR .
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Bjornsson E, Gunnarsdottir K, Halldorsson GH, Sigurdsson A, Arnadottir GA, Jonsson H, Olafsdottir EF, Niehus S, Kehr B, Sveinbjörnsson G, Gudmundsdottir S, Helgadottir A, Andersen K, Thorleifsson G, Eyjolfsson GI, Olafsson I, Sigurdardottir O, Saemundsdottir J, Jonsdottir I, Magnusson OT, Masson G, Stefansson H, Gudbjartsson DF, Thorgeirsson G, Holm H, Halldorsson BV, Melsted P, Norddahl GL, Sulem P, Thorsteinsdottir U, and Stefansson K
- Subjects
- 3' Untranslated Regions, Alternative Splicing, Gain of Function Mutation, Gene Deletion, Genetic Vectors genetics, Genetic Vectors metabolism, Herpesvirus 4, Human genetics, Heterozygote, Humans, Hyperlipoproteinemia Type II genetics, Hyperlipoproteinemia Type II pathology, Iceland, Lymphocytes cytology, Lymphocytes metabolism, MicroRNAs metabolism, Pedigree, Protein Isoforms genetics, RNA, Messenger metabolism, Cholesterol, LDL blood, Receptors, LDL genetics
- Abstract
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.- Published
- 2021
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22. Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease.
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Helgadottir A, Thorleifsson G, Alexandersson KF, Tragante V, Thorsteinsdottir M, Eiriksson FF, Gretarsdottir S, Björnsson E, Magnusson O, Sveinbjornsson G, Jonsdottir I, Steinthorsdottir V, Ferkingstad E, Jensson BÖ, Stefansson H, Olafsson I, Christensen AH, Torp-Pedersen C, Køber L, Pedersen OB, Erikstrup C, Sørensen E, Brunak S, Banasik K, Hansen TF, Nyegaard M, Eyjolfssson GI, Sigurdardottir O, Thorarinsson BL, Matthiasson SE, Steingrimsdottir T, Bjornsson ES, Danielsen R, Asselbergs FW, Arnar DO, Ullum H, Bundgaard H, Sulem P, Thorsteinsdottir U, Thorgeirsson G, Holm H, Gudbjartsson DF, and Stefansson K
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 5 genetics, Humans, Iceland, Sterols, Coronary Artery Disease epidemiology, Coronary Artery Disease genetics, Phytosterols
- Abstract
Aims: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols., Methods and Results: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4)., Conclusions: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2020
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23. Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.
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Olafsdottir TA, Theodors F, Bjarnadottir K, Bjornsdottir US, Agustsdottir AB, Stefansson OA, Ivarsdottir EV, Sigurdsson JK, Benonisdottir S, Eyjolfsson GI, Gislason D, Gislason T, Guðmundsdóttir S, Gylfason A, Halldorsson BV, Halldorsson GH, Juliusdottir T, Kristinsdottir AM, Ludviksdottir D, Ludviksson BR, Masson G, Norland K, Onundarson PT, Olafsson I, Sigurdardottir O, Stefansdottir L, Sveinbjornsson G, Tragante V, Gudbjartsson DF, Thorleifsson G, Sulem P, Thorsteinsdottir U, Norddahl GL, Jonsdottir I, and Stefansson K
- Subjects
- 3' Untranslated Regions genetics, Airway Remodeling immunology, Asthma immunology, Eosinophils, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Iceland, Ki-1 Antigen immunology, Ki-1 Antigen metabolism, Leukocyte Count, MicroRNAs metabolism, Polymorphism, Single Nucleotide immunology, Quantitative Trait Loci immunology, Receptor, Transforming Growth Factor-beta Type I immunology, Receptor, Transforming Growth Factor-beta Type I metabolism, United Kingdom, Airway Remodeling genetics, Asthma genetics, Ki-1 Antigen genetics, Receptor, Transforming Growth Factor-beta Type I genetics, T-Lymphocytes immunology
- Abstract
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.
- Published
- 2020
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24. Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.
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Olafsson S, Alexandersson KF, Gizurarson JGK, Hauksdottir K, Gunnarsson O, Olafsson K, Gudmundsson J, Stacey SN, Sveinbjornsson G, Saemundsdottir J, Bjornsson ES, Olafsson S, Bjornsson S, Orvar KB, Vikingsson A, Geirsson AJ, Arinbjarnarson S, Bjornsdottir G, Thorgeirsson TE, Sigurdsson S, Halldorsson GH, Magnusson OT, Masson G, Holm H, Jonsdottir I, Sigurdardottir O, Eyjolfsson GI, Olafsson I, Sulem P, Thorsteinsdottir U, Jonsson T, Rafnar T, Gudbjartsson DF, and Stefansson K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Child, Child, Preschool, Female, Gene Frequency, Genome-Wide Association Study, Humans, Iceland epidemiology, Infant, Infant, Newborn, Male, Middle Aged, Neoplasms blood, Neoplasms diagnosis, Neoplasms genetics, Polymorphism, Single Nucleotide, Predictive Value of Tests, Reference Values, Registries statistics & numerical data, Sequence Analysis, RNA, Whole Genome Sequencing, Young Adult, Biomarkers, Tumor blood, Neoplasms epidemiology
- Abstract
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 ( N = 22,686), carcinoembryonic antigen ( N = 22,309), cancer antigens 15.3 ( N = 7,107), 19.9 ( N = 9,945), and 125 ( N = 9,824), and ALP ( N = 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., (©2019 American Association for Cancer Research.)
- Published
- 2020
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25. Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes.
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Gudbjartsson DF, Thorgeirsson G, Sulem P, Helgadottir A, Gylfason A, Saemundsdottir J, Bjornsson E, Norddahl GL, Jonasdottir A, Jonasdottir A, Eggertsson HP, Gretarsdottir S, Thorleifsson G, Indridason OS, Palsson R, Jonasson F, Jonsdottir I, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Danielsen R, Matthiasson SE, Kristmundsdottir S, Halldorsson BV, Hreidarsson AB, Valdimarsson EM, Gudnason T, Benediktsson R, Steinthorsdottir V, Thorsteinsdottir U, Holm H, and Stefansson K
- Subjects
- Case-Control Studies, Coronary Artery Disease genetics, Diabetes Mellitus, Type 2 genetics, Humans, Iceland, Kringles, Lipoprotein(a) genetics, Mendelian Randomization Analysis, Molecular Weight, Protein Isoforms blood, Risk Factors, Coronary Artery Disease blood, DNA Copy Number Variations, Diabetes Mellitus, Type 2 blood, Lipoprotein(a) blood
- Abstract
Background: Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D)., Objectives: This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal., Methods: This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D., Results: Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D., Conclusions: Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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26. A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.
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Kristjansson RP, Benonisdottir S, Davidsson OB, Oddsson A, Tragante V, Sigurdsson JK, Stefansdottir L, Jonsson S, Jensson BO, Arthur JG, Arnadottir GA, Sulem G, Halldorsson BV, Gunnarsson B, Halldorsson GH, Stefansson OA, Oskarsson GR, Deaton AM, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Onundarson PT, Gislason D, Gislason T, Ludviksson BR, Ludviksdottir D, Olafsdottir TA, Rafnar T, Masson G, Zink F, Bjornsdottir G, Magnusson OT, Bjornsdottir US, Thorleifsson G, Norddahl GL, Gudbjartsson DF, Thorsteinsdottir U, Jonsdottir I, Sulem P, and Stefansson K
- Subjects
- Adult, Asthma genetics, Chronic Disease, Eosinophils pathology, Female, Genome-Wide Association Study methods, Humans, Iceland, Leukocyte Count methods, Male, Nasal Polyps pathology, Sinusitis pathology, Arachidonate 15-Lipoxygenase genetics, Genetic Variation genetics, Nasal Polyps genetics, Sinusitis genetics
- Abstract
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
-27 , odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8 , 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.- Published
- 2019
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27. Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.
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Ferkingstad E, Oddsson A, Gretarsdottir S, Benonisdottir S, Thorleifsson G, Deaton AM, Jonsson S, Stefansson OA, Norddahl GL, Zink F, Arnadottir GA, Gunnarsson B, Halldorsson GH, Helgadottir A, Jensson BO, Kristjansson RP, Sveinbjornsson G, Sverrisson DA, Masson G, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Holm H, Jonsdottir I, Olafsson S, Steingrimsdottir T, Rafnar T, Bjornsson ES, Thorsteinsdottir U, Gudbjartsson DF, Sulem P, and Stefansson K
- Subjects
- Gallstones genetics, Hepatocyte Nuclear Factor 4 genetics, Humans, Mutation, Missense genetics, Organic Anion Transporters, Sodium-Dependent genetics, Symporters genetics, alpha 1-Antitrypsin genetics, Gallstones metabolism, Genome-Wide Association Study methods
- Abstract
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
-12 , MAF = 1%; Val98Ile: OR = 1.15 [1.10-1.20], P = 1.8 × 10-10 , 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.- Published
- 2018
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28. Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.
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Gudmundsson J, Sigurdsson JK, Stefansdottir L, Agnarsson BA, Isaksson HJ, Stefansson OA, Gudjonsson SA, Gudbjartsson DF, Masson G, Frigge ML, Stacey SN, Sulem P, Halldorsson GH, Tragante V, Holm H, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Jonsson T, Jonsson E, Barkardottir RB, Hilmarsson R, Asselbergs FW, Geirsson G, Thorsteinsdottir U, Rafnar T, Thorleifsson G, and Stefansson K
- Subjects
- Acetylation, Aged, Computational Biology, Genetic Predisposition to Disease, Histones metabolism, Humans, Iceland, Lower Urinary Tract Symptoms blood, Lower Urinary Tract Symptoms genetics, Lysine metabolism, Male, Meta-Analysis as Topic, Multifactorial Inheritance genetics, Mutation genetics, Phenotype, Quantitative Trait Loci genetics, Risk Factors, United Kingdom, Genome-Wide Association Study, Prostate-Specific Antigen blood, Prostatic Hyperplasia blood, Prostatic Hyperplasia genetics
- Abstract
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
g = 0.77 (P = 2.6 × 10-11 ), 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 = 1.6×10-55 ). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.- Published
- 2018
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29. Insights into imprinting from parent-of-origin phased methylomes and transcriptomes.
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Zink F, Magnusdottir DN, Magnusson OT, Walker NJ, Morris TJ, Sigurdsson A, Halldorsson GH, Gudjonsson SA, Melsted P, Ingimundardottir H, Kristmundsdottir S, Alexandersson KF, Helgadottir A, Gudmundsson J, Rafnar T, Jonsdottir I, Holm H, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Masson G, Gudbjartsson DF, Thorsteinsdottir U, Halldorsson BV, Stacey SN, and Stefansson K
- Subjects
- Angelman Syndrome genetics, Case-Control Studies, Chromosomes, Human, Pair 15, Cohort Studies, CpG Islands genetics, Female, Genetic Loci, Humans, Iceland, Male, Polymorphism, Single Nucleotide, Prader-Willi Syndrome genetics, Quantitative Trait Loci genetics, DNA Methylation genetics, Genome, Human, Genomic Imprinting physiology, Inheritance Patterns genetics, Parents, Transcriptome genetics
- Abstract
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.
- Published
- 2018
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30. Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease.
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Helgadottir A, Sulem P, Thorgeirsson G, Gretarsdottir S, Thorleifsson G, Jensson BÖ, Arnadottir GA, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Thorsteinsdottir U, Gudbjartsson DF, Holm H, and Stefansson K
- Subjects
- Humans, Iceland, Liver metabolism, Mutation, Cholesterol, HDL metabolism, Coronary Artery Disease genetics, Scavenger Receptors, Class B genetics
- Abstract
Aims: Scavenger receptor Class B Type 1 (SR-BI) is a major receptor for high-density lipoprotein (HDL) that promotes hepatic uptake of cholesterol from HDL. A rare mutation p.P376L, in the gene encoding SR-BI, SCARB1, was recently reported to associate with elevated HDL cholesterol (HDL-C) and increased risk of coronary artery disease (CAD), suggesting that increased HDL-C caused by SR-BI impairment might be an independent marker of cardiovascular risk. We tested the hypothesis that alleles in or close to SCARB1 that associate with elevated levels of HDL-C also associate with increased risk of CAD in the relatively homogeneous population of Iceland., Methods and Results: Using a large resource of whole-genome sequenced Icelanders, we identified thirteen SCARB1 coding mutations that we examined for association with HDL-C (n = 136 672). Three rare SCARB1 mutations, encoding p.G319V, p.V111M, and p.V32M (combined allelic frequency = 0.2%) associate with elevated levels of HDL-C (p.G319V: β = 11.1 mg/dL, P = 8.0 × 10-7; p.V111M: β = 8.3 mg/dL, P = 1.1 × 10-6; p.V32M: β = 10.2 mg/dL, P = 8.1 × 10-4). These mutations do not associate with CAD (36 886 cases/306 268 controls) (odds ratio = 0.90, 95% confidence interval 0.67-1.22, P = 0.49), despite effects on HDL-C comparable to that reported for p.P376L, both in terms of direction and magnitude. Furthermore, HDL-C raising alleles of three common SCARB1 non-coding variants, including one previously unreported (rs61941676-C: β = 1.25 mg/dL, P = 1.7 × 10-18), and of one low frequency coding variant (p.V135I) that independently associate with higher HDL-C, do not confer increased risk of CAD., Conclusion: Elevated HDL-C due to genetically compromised SR-BI function is not a marker of CAD risk.
- Published
- 2018
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31. A rare missense variant in NR1H4 associates with lower cholesterol levels.
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Deaton AM, Sulem P, Nioi P, Benonisdottir S, Ward LD, Davidsson OB, Lao S, Helgadottir A, Fan F, Jensson BO, Norddahl GL, Jonasdottir A, Jonasdottir A, Sigurdsson A, Kristjansson RP, Oddsson A, Arnadottir GA, Jonsson H, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Bjornsson ES, Olafsson S, Steingrimsdottir T, Rafnar T, Thorgeirsson G, Masson G, Thorleifsson G, Gudbjartsson DF, Holm H, Thorsteinsdottir U, and Stefansson K
- Abstract
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 NR1H4 (R436H) associating with lower levels of total cholesterol (effect = -0.47 standard deviations or -0.55 mmol L
-1 , p = 4.21 × 10-10 , N = 150,211). Importantly, NR1H4 R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. NR1H4 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., Competing Interests: A.M.D., P.S., P.N, S.B., L.D.W., O.B.D., S.L., A.H., F.F., B.O.J., G.L.N., As.J., Ad.J., A.S., R.P.K., A.O., G.A.A., H.J., T.R., G.Thorg., G.M., G.Thorl., D.F.G., H.H., U.T. and K.S. who are affiliated with deCODE genetics/Amgen declare competing financial interests as employees. The remaining authors declare no competing financial interests.- Published
- 2018
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32. Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability.
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Ivarsdottir EV, Steinthorsdottir V, Daneshpour MS, Thorleifsson G, Sulem P, Holm H, Sigurdsson S, Hreidarsson AB, Sigurdsson G, Bjarnason R, Thorsson AV, Benediktsson R, Eyjolfsson G, Sigurdardottir O, Olafsson I, Zeinali S, Azizi F, Thorsteinsdottir U, Gudbjartsson DF, and Stefansson K
- Subjects
- Alleles, Body Mass Index, Diabetes Mellitus, Type 2 blood, Fasting, Female, Gene Frequency, Glucokinase genetics, Glucose-6-Phosphatase genetics, Glycated Hemoglobin metabolism, Humans, Iceland, Male, Penetrance, Polymorphism, Single Nucleotide, Risk Factors, Transcription Factor 7-Like 2 Protein genetics, Blood Glucose metabolism, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease genetics, Genetic Variation
- Abstract
Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10
-10 ), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10-11 and 7.3% per allele, P = 7.5 × 10-18 , respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r2 = 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.- Published
- 2017
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33. Identification of sequence variants influencing immunoglobulin levels.
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Jonsson S, Sveinbjornsson G, de Lapuente Portilla AL, Swaminathan B, Plomp R, Dekkers G, Ajore R, Ali M, Bentlage AEH, Elmér E, Eyjolfsson GI, Gudjonsson SA, Gullberg U, Gylfason A, Halldorsson BV, Hansson M, Holm H, Johansson Å, Johnsson E, Jonasdottir A, Ludviksson BR, Oddsson A, Olafsson I, Olafsson S, Sigurdardottir O, Sigurdsson A, Stefansdottir L, Masson G, Sulem P, Wuhrer M, Wihlborg AK, Thorleifsson G, Gudbjartsson DF, Thorsteinsdottir U, Vidarsson G, Jonsdottir I, Nilsson B, and Stefansson K
- Subjects
- Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Hematopoiesis genetics, Humans, Iceland, Immunity, Humoral genetics, Immunoglobulin Class Switching genetics, Immunoglobulin Isotypes genetics, Male, Polymorphism, Single Nucleotide, Sweden, Genetic Variation, Immunoglobulins genetics
- Abstract
Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10
-55 , β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10-8 , β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.- Published
- 2017
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34. A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease.
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Bjornsson E, Helgason H, Halldorsson G, Helgadottir A, Gylfason A, Kehr B, Jonasdottir A, Jonasdottir A, Sigurdsson A, Oddsson A, Thorleifsson G, Magnusson OT, Gretarsdottir S, Zink F, Kristjansson RP, Asgeirsdottir M, Swinkels DW, Kiemeney LA, Eyjolfsson GI, Sigurdardottir O, Masson G, Olafsson I, Thorgeirsson G, Holm H, Thorsteinsdottir U, Gudbjartsson DF, Sulem P, and Stefansson K
- Subjects
- Adult, Alleles, Base Sequence, Coronary Artery Disease metabolism, DNA Copy Number Variations genetics, Female, Gene Frequency genetics, Genetic Association Studies methods, Genetic Variation, Haptoglobins metabolism, Humans, Iceland, Lipids blood, Lipids genetics, Lipoproteins genetics, Male, Mutation, Odds Ratio, RNA Splice Sites genetics, Risk Factors, Coronary Artery Disease genetics, Haptoglobins genetics
- Abstract
Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2017
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35. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.
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Smith D, Helgason H, Sulem P, Bjornsdottir US, Lim AC, Sveinbjornsson G, Hasegawa H, Brown M, Ketchem RR, Gavala M, Garrett L, Jonasdottir A, Jonasdottir A, Sigurdsson A, Magnusson OT, Eyjolfsson GI, Olafsson I, Onundarson PT, Sigurdardottir O, Gislason D, Gislason T, Ludviksson BR, Ludviksdottir D, Boezen HM, Heinzmann A, Krueger M, Porsbjerg C, Ahluwalia TS, Waage J, Backer V, Deichmann KA, Koppelman GH, Bønnelykke K, Bisgaard H, Masson G, Thorsteinsdottir U, Gudbjartsson DF, Johnston JA, Jonsdottir I, and Stefansson K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Alternative Splicing, Animals, Binding Sites, Biological Assay, Child, Child, Preschool, Denmark, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Heterozygote, Humans, Iceland, Infant, Infant, Newborn, Introns, Male, Mice, Mice, Transgenic, Middle Aged, Netherlands, Young Adult, Asthma genetics, Eosinophils metabolism, Interleukin-33 genetics, Mutation
- Abstract
IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.
- Published
- 2017
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36. A genome-wide association study yields five novel thyroid cancer risk loci.
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Gudmundsson J, Thorleifsson G, Sigurdsson JK, Stefansdottir L, Jonasson JG, Gudjonsson SA, Gudbjartsson DF, Masson G, Johannsdottir H, Halldorsson GH, Stacey SN, Helgason H, Sulem P, Senter L, He H, Liyanarachchi S, Ringel MD, Aguillo E, Panadero A, Prats E, Garcia-Castaño A, De Juan A, Rivera F, Xu L, Kiemeney LA, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Kristvinsson H, Netea-Maier RT, Jonsson T, Mayordomo JI, Plantinga TS, Hjartarson H, Hrafnkelsson J, Sturgis EM, Thorsteinsdottir U, Rafnar T, de la Chapelle A, and Stefansson K
- Subjects
- Adult, Asian People genetics, Case-Control Studies, Chromosomes, Human genetics, Female, Gene Expression Regulation, Neoplastic, Gene Frequency genetics, Genetic Predisposition to Disease, Genomic Structural Variation, Genotype, Humans, Male, Middle Aged, Pituitary Hormones analysis, Risk Factors, Thyroid Cancer, Papillary, Thyroid Gland metabolism, Thyroid Neoplasms metabolism, White People genetics, Whole Genome Sequencing, Carcinoma, Papillary genetics, Genetic Loci, Genome-Wide Association Study, Thyroid Neoplasms genetics
- Abstract
The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with P
combined <3 × 10-8 ): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10-7 ) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.- Published
- 2017
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37. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.
- Author
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Nioi P, Sigurdsson A, Thorleifsson G, Helgason H, Agustsdottir AB, Norddahl GL, Helgadottir A, Magnusdottir A, Jonasdottir A, Gretarsdottir S, Jonsdottir I, Steinthorsdottir V, Rafnar T, Swinkels DW, Galesloot TE, Grarup N, Jørgensen T, Vestergaard H, Hansen T, Lauritzen T, Linneberg A, Friedrich N, Krarup NT, Fenger M, Abildgaard U, Hansen PR, Galløe AM, Braund PS, Nelson CP, Hall AS, Williams MJ, van Rij AM, Jones GT, Patel RS, Levey AI, Hayek S, Shah SH, Reilly M, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Kiemeney LA, Quyyumi AA, Rader DJ, Kraus WE, Samani NJ, Pedersen O, Thorgeirsson G, Masson G, Holm H, Gudbjartsson D, Sulem P, Thorsteinsdottir U, and Stefansson K
- Subjects
- Adult, Aged, Aged, 80 and over, Base Sequence, Female, Genetic Predisposition to Disease, Humans, Iceland, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Sequence Data, Myocardial Infarction genetics, Risk, Sequence Analysis, DNA, White People genetics, Asialoglycoprotein Receptor genetics, Cholesterol blood, Coronary Artery Disease genetics, Haploinsufficiency
- Abstract
Background: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease., Methods: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability., Results: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3))., Conclusions: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).
- Published
- 2016
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38. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease.
- Author
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Helgadottir A, Gretarsdottir S, Thorleifsson G, Hjartarson E, Sigurdsson A, Magnusdottir A, Jonasdottir A, Kristjansson H, Sulem P, Oddsson A, Sveinbjornsson G, Steinthorsdottir V, Rafnar T, Masson G, Jonsdottir I, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Daneshpour MS, Khalili D, Azizi F, Swinkels DW, Kiemeney L, Quyyumi AA, Levey AI, Patel RS, Hayek SS, Gudmundsdottir IJ, Thorgeirsson G, Thorsteinsdottir U, Gudbjartsson DF, Holm H, and Stefansson K
- Subjects
- Coronary Artery Disease blood, Coronary Artery Disease diagnosis, Humans, Cholesterol blood, Coronary Artery Disease genetics, Lipids blood, Triglycerides blood
- Abstract
Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
- Published
- 2016
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39. Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility.
- Author
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Mbarek H, Steinberg S, Nyholt DR, Gordon SD, Miller MB, McRae AF, Hottenga JJ, Day FR, Willemsen G, de Geus EJ, Davies GE, Martin HC, Penninx BW, Jansen R, McAloney K, Vink JM, Kaprio J, Plomin R, Spector TD, Magnusson PK, Reversade B, Harris RA, Aagaard K, Kristjansson RP, Olafsson I, Eyjolfsson GI, Sigurdardottir O, Iacono WG, Lambalk CB, Montgomery GW, McGue M, Ong KK, Perry JRB, Martin NG, Stefánsson H, Stefánsson K, and Boomsma DI
- Subjects
- Anxiety genetics, Case-Control Studies, Depression genetics, Family, Female, Follicle Stimulating Hormone blood, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Mothers, Polycystic Ovary Syndrome blood, Pregnancy, Fertility genetics, Genetic Variation genetics, Polycystic Ovary Syndrome genetics, Twins, Dizygotic genetics
- Abstract
Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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40. Common and rare variants associating with serum levels of creatine kinase and lactate dehydrogenase.
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Kristjansson RP, Oddsson A, Helgason H, Sveinbjornsson G, Arnadottir GA, Jensson BO, Jonasdottir A, Jonasdottir A, Bragi Walters G, Sulem G, Oskarsdottir A, Benonisdottir S, Davidsson OB, Masson G, Magnusson OT, Holm H, Sigurdardottir O, Jonsdottir I, Eyjolfsson GI, Olafsson I, Gudbjartsson DF, Thorsteinsdottir U, Sulem P, and Stefansson K
- Subjects
- Anoctamins, Antigens, CD genetics, Antigens, Differentiation, Myelomonocytic genetics, Biomarkers blood, Cell Adhesion Molecules, Neuronal genetics, Chloride Channels genetics, Complement Factor H genetics, Female, Gene Frequency, Genetic Variation, HLA-DQ beta-Chains genetics, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Iceland, Isoenzymes genetics, L-Lactate Dehydrogenase genetics, Lactate Dehydrogenase 5, Macrophage Colony-Stimulating Factor genetics, Male, Membrane Glycoproteins, Nerve Growth Factors genetics, Polymorphism, Single Nucleotide, Receptors, Cell Surface genetics, Receptors, Immunologic genetics, Receptors, Lymphocyte Homing genetics, Receptors, Scavenger, Regression Analysis, Creatine Kinase blood, Creatine Kinase, MM Form genetics, L-Lactate Dehydrogenase blood
- Abstract
Creatine kinase (CK) and lactate dehydrogenase (LDH) are widely used markers of tissue damage. To search for sequence variants influencing serum levels of CK and LDH, 28.3 million sequence variants identified through whole-genome sequencing of 2,636 Icelanders were imputed into 63,159 and 98,585 people with CK and LDH measurements, respectively. Here we describe 13 variants associating with serum CK and 16 with LDH levels, including four that associate with both. Among those, 15 are non-synonymous variants and 12 have a minor allele frequency below 5%. We report sequence variants in genes encoding the enzymes being measured (CKM and LDHA), as well as in genes linked to muscular (ANO5) and immune/inflammatory function (CD163/CD163L1, CSF1, CFH, HLA-DQB1, LILRB5, NINJ1 and STAB1). A number of the genes are linked to the mononuclear/phagocyte system and clearance of enzymes from the serum. This highlights the variety in the sources of normal diversity in serum levels of enzymes.
- Published
- 2016
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41. A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease.
- Author
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Gretarsdottir S, Helgason H, Helgadottir A, Sigurdsson A, Thorleifsson G, Magnusdottir A, Oddsson A, Steinthorsdottir V, Rafnar T, de Graaf J, Daneshpour MS, Hedayati M, Azizi F, Grarup N, Jørgensen T, Vestergaard H, Hansen T, Eyjolfsson G, Sigurdardottir O, Olafsson I, Kiemeney LA, Pedersen O, Sulem P, Thorgeirsson G, Gudbjartsson DF, Holm H, Thorsteinsdottir U, and Stefansson K
- Subjects
- Humans, RNA, Messenger genetics, Cholesterol blood, Coronary Artery Disease prevention & control, RNA Splicing, Receptors, LDL genetics
- Abstract
Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 × 10⁻⁸⁰ and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 × 10⁻¹²) and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 × 10⁻⁸ and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527:c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.
- Published
- 2015
- Full Text
- View/download PDF
42. Common and rare variants associated with kidney stones and biochemical traits.
- Author
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Oddsson A, Sulem P, Helgason H, Edvardsson VO, Thorleifsson G, Sveinbjörnsson G, Haraldsdottir E, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Masson G, Holm H, Gudbjartsson DF, Thorsteinsdottir U, Indridason OS, Palsson R, and Stefansson K
- Subjects
- Genome, Human, Genome-Wide Association Study, Humans, Iceland epidemiology, Kidney Calculi epidemiology, Odds Ratio, Quantitative Trait Loci, Genetic Predisposition to Disease, Genetic Variation, Kidney Calculi genetics
- Abstract
Kidney stone disease is a complex disorder with a strong genetic component. We conducted a genome-wide association study of 28.3 million sequence variants detected through whole-genome sequencing of 2,636 Icelanders that were imputed into 5,419 kidney stone cases, including 2,172 cases with a history of recurrent kidney stones, and 279,870 controls. We identify sequence variants associating with kidney stones at ALPL (rs1256328[T], odds ratio (OR)=1.21, P=5.8 × 10(-10)) and a suggestive association at CASR (rs7627468[A], OR=1.16, P=2.0 × 10(-8)). Focusing our analysis on coding sequence variants in 63 genes with preferential kidney expression we identify two rare missense variants SLC34A1 p.Tyr489Cys (OR=2.38, P=2.8 × 10(-5)) and TRPV5 p.Leu530Arg (OR=3.62, P=4.1 × 10(-5)) associating with recurrent kidney stones. We also observe associations of the identified kidney stone variants with biochemical traits in a large population set, indicating potential biological mechanism.
- Published
- 2015
- Full Text
- View/download PDF
43. Large-scale whole-genome sequencing of the Icelandic population.
- Author
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Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E, Sigurdsson GT, Stacey SN, Frigge ML, Holm H, Saemundsdottir J, Helgadottir HT, Johannsdottir H, Sigfusson G, Thorgeirsson G, Sverrisson JT, Gretarsdottir S, Walters GB, Rafnar T, Thjodleifsson B, Bjornsson ES, Olafsson S, Thorarinsdottir H, Steingrimsdottir T, Gudmundsdottir TS, Theodors A, Jonasson JG, Sigurdsson A, Bjornsdottir G, Jonsson JJ, Thorarensen O, Ludvigsson P, Gudbjartsson H, Eyjolfsson GI, Sigurdardottir O, Olafsson I, Arnar DO, Magnusson OT, Kong A, Masson G, Thorsteinsdottir U, Helgason A, Sulem P, and Stefansson K
- Subjects
- Aged, Aged, 80 and over, Atrial Fibrillation genetics, Bulbar Palsy, Progressive genetics, Chromogranins, Female, Frameshift Mutation, Gene Frequency, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Hearing Loss, Sensorineural genetics, Humans, INDEL Mutation, Iceland, Liver Diseases genetics, Male, Middle Aged, Molecular Sequence Annotation, Phylogeography, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled genetics, Risk, Sequence Analysis, DNA, Thyrotropin blood, ATP Binding Cassette Transporter, Subfamily B genetics, GTP-Binding Protein alpha Subunits, Gs genetics, Myosin Light Chains genetics
- Abstract
Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.
- Published
- 2015
- Full Text
- View/download PDF
44. Rare mutations associating with serum creatinine and chronic kidney disease.
- Author
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Sveinbjornsson G, Mikaelsdottir E, Palsson R, Indridason OS, Holm H, Jonasdottir A, Helgason A, Sigurdsson S, Jonasdottir A, Sigurdsson A, Eyjolfsson GI, Sigurdardottir O, Magnusson OT, Kong A, Masson G, Sulem P, Olafsson I, Thorsteinsdottir U, Gudbjartsson DF, and Stefansson K
- Subjects
- Adolescent, Adult, Aged, Alleles, Case-Control Studies, Female, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Genotype, Glomerular Filtration Rate, Humans, INDEL Mutation, Iceland, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic pathology, Amino Acid Transport Systems, Neutral genetics, Creatinine blood, Membrane Proteins genetics, Mitochondrial Proteins genetics, Organic Cation Transport Proteins genetics, Renal Insufficiency, Chronic genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. The large set of sequenced individuals allowed accurate imputation of variants to a minor allele frequency (MAF) of 0.1%. We tested the imputed variants for association with SCr. In addition to replicating established loci, we discovered missense and loss-of-function variants associating with SCr in three solute carriers (SLC6A19, SLC25A45 and SLC47A1) and two E3 ubiquitin ligases (RNF186 and RNF128). All the variants are within coding sequences and all but one are rare (MAF <2%) with SCr effects between 0.085 and 0.129 standard deviations. These rare variants have a larger effect on SCr than previously reported common variants, explaining 0.5% of the variability of SCr in Icelanders in addition to the 1% already accounted for. We tested the five variants associating with SCr for association with CKD in an Icelandic sample of 15 594 cases and 291 428 controls. Three of the variants also associated with CKD. These variants may either affect kidney function or creatinine synthesis and excretion. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2014
- Full Text
- View/download PDF
45. Mycobacterium avium subspecies paratuberculosis--a review of present research in Norway.
- Author
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Holstad G, Sigurdardottir O, Valheim M, Storset A, Olsen L, Halldorsdottir S, Djønne B, and Fredriksen B
- Subjects
- Animals, Goats, Norway epidemiology, Paratuberculosis epidemiology, Paratuberculosis immunology, Mycobacterium avium subsp. paratuberculosis immunology, Mycobacterium avium subsp. paratuberculosis pathogenicity, Paratuberculosis pathology, Research
- Published
- 2003
46. Sarcoidosis patients have bronchial hyperreactivity and signs of mast cell activation in their bronchoalveolar lavage.
- Author
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Ohrn MB, Sköld CM, van Hage-Hamsten M, Sigurdardottir O, Zetterström O, and Eklund A
- Subjects
- Adolescent, Adult, Cell Count, Chymases, Extracellular Matrix Proteins analysis, Female, Histamine pharmacology, Humans, Hyaluronic Acid analysis, Inflammation metabolism, Inflammation Mediators metabolism, Macrophages, Alveolar cytology, Male, Mast Cells enzymology, Middle Aged, Sarcoidosis, Pulmonary complications, Sarcoidosis, Pulmonary pathology, Serine Endopeptidases metabolism, Tryptases, Bronchial Hyperreactivity etiology, Bronchoalveolar Lavage Fluid immunology, Mast Cells immunology, Sarcoidosis, Pulmonary immunology
- Abstract
An increased (p < 0.001) frequency of bronchial hyperreactivity (BHR) was found in sarcoidosis patients as compared with healthy volunteers. The patients had more mast cells (p < 0.001) and tryptase (p < 0.001) in their bronchoalveolar lavage fluid, but there were no differences between BHR-positive and BHR-negative patients. Furthermore, the bronchoalveolar lavage fluid concentrations of macrophages, lymphocytes, and of the soluble components albumin, fibronectin, and vitronectin were also elevated in the sarcoidosis patients, indicating an ongoing inflammation in the airways and/or in the interstitium. We observed no significant differences in the parameters when the sarcoidosis patients were subdivided into BHR, clinical activity, or chest X-ray stages. Our findings may indicate a multifactorial background to the hyperreactivity.
- Published
- 1995
- Full Text
- View/download PDF
47. Identification of a PAI-1 binding site in vitronectin.
- Author
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Sigurdardottir O and Wiman B
- Subjects
- Amino Acid Sequence, Binding Sites, Chloramines pharmacology, Chromatography, Gel, Chromatography, High Pressure Liquid, Drug Stability, Glycoproteins chemistry, Glycoproteins pharmacology, Humans, Molecular Sequence Data, Oxidation-Reduction, Peptide Fragments chemistry, Peptide Fragments metabolism, Peptide Fragments pharmacology, Tosyl Compounds pharmacology, Trypsin metabolism, Vitronectin, Glycoproteins metabolism, Plasminogen Activator Inhibitor 1 metabolism
- Abstract
Active PAI-1 (plasminogen activator inhibitor 1) is bound to vitronectin in plasma and in the extracellular matrix. In this study we aimed at identifying the PAI-1 binding site in vitronectin, which at present is a matter of dispute. Vitronectin was cleaved with trypsin and the fragments were tested for inhibitory effect on the PAI-1/vitronectin interaction using vitronectin-coated microtiter plates. Intact vitronectin and the tryptic digest of vitronectin both caused a 50% reduction in PAI-1 binding at a concentration of about 2 nmol/I. Gel-filtration on Sephadex G-50 superfine of the tryptic peptides resulted in one main peak of inhibitory activity. The elution volume, Kav, was 0.55 indicating (a) medium-size peptide(s). The peptide was further purified by reverse-phase HPLC. Structural analysis revealed that it constituted the 45 NH2-terminal amino-acid residues in vitronectin. The NH2-terminal vitronectin peptide caused a 50% decrease in PAI-1 binding to the vitronectin-coated microtiter plates at a concentration of about 13 nmol/l. Thus, the peptide is a little less effective in this respect than intact vitronectin. Reduced and S-carboxymethylated peptide had no effect on the interaction. The NH2-terminal vitronectin fragment increased the stability of active PAI-1 by about 60%, which is a little less than with intact vitronectin. The peptide also prevented PAI-1 from oxidation with chloramine T. The half-life was prolonged about 4-fold as compared to about 30-fold with intact vitronectin.
- Published
- 1994
- Full Text
- View/download PDF
48. Vitronectin and its relationship to other extracellular matrix components in bronchoalveolar lavage fluid in sarcoidosis.
- Author
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Eklund AG, Sigurdardottir O, and Ohrn M
- Subjects
- Adult, Female, Fibronectins analysis, Humans, Hyaluronic Acid analysis, Male, Middle Aged, Vitronectin, Bronchoalveolar Lavage Fluid chemistry, Extracellular Matrix Proteins analysis, Glycoproteins analysis, Lung Diseases metabolism, Sarcoidosis metabolism
- Abstract
There is a need to find markers that can be used as indicators of early fibrotic changes in the lung in patients with sarcoidosis. The fibrotic reaction is accompanied by an increase in the connective tissue components, and the extracellular matrix molecules are characterized by an ability to interact with each other. We found increased concentrations of three components of the extracellular matrix, vitronectin (VN), fibronectin (FN), and hyaluronan (HA), in bronchoalveolar lavage (BAL) fluid from 56 patients with sarcoidosis compared with 38 healthy control subjects (p less than 0.001 for all). Using an enzyme-linked immunosorbent assay, the median value for VN in BAL fluid from sarcoid patients was 74 micrograms/L (interquartile range, 47 to 138) compared with 38 micrograms/L (IQR, 22 to 55) in control subjects. The median VN concentration in serum was 0.25 g/L in both groups. VN consists of various functional domains, and it may, together with FN and HA, contribute to repair or exaggeration of the interstitial changes that occur when sarcoidosis affects the lungs. VN correlated to the concentration of albumin in the BAL fluid (p less than 0.01) but even closer to the concentrations of FN and HA (p less than 0.001 for both). The extracellular matrix components did not show any correlation to the disease activity, roentgenographic stage, or functional signs of developed fibrosis. In conclusion, the increased concentrations of VN, FN, and HA may predict only an ongoing inflammation and not necessarily a fibrotic process.
- Published
- 1992
- Full Text
- View/download PDF
49. Stability of plasminogen activator inhibitor 1 (PAI-1).
- Author
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Lindahl TL, Sigurdardottir O, and Wiman B
- Subjects
- Antigens analysis, Blood Proteins isolation & purification, Chloramines, Glycoproteins isolation & purification, Half-Life, Humans, Hydrogen-Ion Concentration, Oxidation-Reduction, Plasminogen Inactivators immunology, Temperature, Vitronectin, Plasminogen Inactivators metabolism, Tosyl Compounds
- Abstract
The stability of PAI-activity has been studied at different conditions. The inactivation followed first order kinetics. Lowering the temperature and decreasing the pH both, increased the stability of PAI-1 dramatically. Addition of the PAI-1 binding protein, vitronectin, to reactivated PAI-1, about doubled the half-life of PAI-1 at all conditions studied. In the presence of chloramine T, the inactivation of reactivated PAI-1 was very rapid. In this case the protective effect of purified vitronectin, human plasma or fetal calf serum, but not of bovine serum albumin, was pronounced. The stability of the spontaneously active high Mr form of PAI-1 (partially purified or in plasma), constituting a complex between PAI-1 and vitronectin, was quite similar to reactivated PAI-1 in the presence of vitronectin. Addition of pure vitronectin, human plasma or fetal calf serum to such material had no further stabilizing effect. Reactivated PAI-1, which was inactivated by incubation at physiological conditions could again be fully reactivated, in contrast to chloramine T-oxidized PAI-1, which was irreversibly inactivated.
- Published
- 1989
50. Plasminogen activator inhibitor 1 (PAI) is bound to vitronectin in plasma.
- Author
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Wiman B, Almquist A, Sigurdardottir O, and Lindahl T
- Subjects
- Amino Acid Sequence, Blood Proteins, Chromatography, Electrophoresis, Polyacrylamide Gel, Glycoproteins isolation & purification, Humans, Immunoblotting, Molecular Sequence Data, Molecular Weight, Plasminogen Activators antagonists & inhibitors, Plasminogen Inactivators, Vitronectin, Glycoproteins blood
- Abstract
Functionally active plasminogen activator inhibitor 1 (PAI) is bound to a discrete binding protein in plasma [(1988) Thromb. Haemost. 59, 392-395]. The binding protein has now been partially purified using conventional chromatographic techniques. After addition of active PAI its complex with the binding protein was purified by chromatography on insolubilized monoclonal antibodies towards PAI. Dodecylsulphate (polyacrylamide gel electrophoresis revealed two main compounds with molecular masses of 50 and 75 kDa respectively. NH2-terminal amino acid sequence analysis and immunoblotting analysis suggested that the two compounds were PAI (50 kDa) and vitronectin (75 kDa). We conclude that the PAI-binding protein is identical to vitronectin.
- Published
- 1988
- Full Text
- View/download PDF
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