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7 results on '"Sigurdsson, Jon K"'

1. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Author

Steinthorsdottir V, McGinnis R, Williams NO, Stefansdottir L, Thorleifsson G, Shooter S, Fadista J, Sigurdsson JK, Auro KM, Berezina G, Borges MC, Bumpstead S, Bybjerg-Grauholm J, Colgiu I, Dolby VA, Dudbridge F, Engel SM, Franklin CS, Frigge ML, Frisbaek Y, Geirsson RT, Geller F, Gretarsdottir S, Gudbjartsson DF, Harmon Q, Hougaard DM, Hegay T, Helgadottir A, Hjartardottir S, Jääskeläinen T, Johannsdottir H, Jonsdottir I, Juliusdottir T, Kalsheker N, Kasimov A, Kemp JP, Kivinen K, Klungsøyr K, Lee WK, Melbye M, Miedzybrodska Z, Moffett A, Najmutdinova D, Nishanova F, Olafsdottir T, Perola M, Pipkin FB, Poston L, Prescott G, Saevarsdottir S, Salimbayeva D, Scaife PJ, Skotte L, Staines-Urias E, Stefansson OA, Sørensen KM, Thomsen LCV, Tragante V, Trogstad L, Simpson NAB, Aripova T, Casas JP, Dominiczak AF, Walker JJ, Thorsteinsdottir U, Iversen AC, Feenstra B, Lawlor DA, Boyd HA, Magnus P, Laivuori H, Zakhidova N, Svyatova G, Stefansson K, and Morgan L

Subjects
Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Asia, Central epidemiology, Blood Pressure genetics, Case-Control Studies, Datasets as Topic, Europe epidemiology, Female, Fibroblast Growth Factor 5 genetics, Genetic Loci genetics, Genome-Wide Association Study, Humans, Hypertension, Pregnancy-Induced epidemiology, MDS1 and EVI1 Complex Locus Protein genetics, Middle Aged, Pre-Eclampsia epidemiology, Pregnancy, Prospective Studies, Genetic Predisposition to Disease, Hypertension, Pregnancy-Induced genetics, Multifactorial Inheritance, Pre-Eclampsia genetics
Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

Published
2020
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2. Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.

Author

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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3. Associations of autozygosity with a broad range of human phenotypes.

Author

Clark DW, Okada Y, Moore KHS, Mason D, Pirastu N, Gandin I, Mattsson H, Barnes CLK, Lin K, Zhao JH, Deelen P, Rohde R, Schurmann C, Guo X, Giulianini F, Zhang W, Medina-Gomez C, Karlsson R, Bao Y, Bartz TM, Baumbach C, Biino G, Bixley MJ, Brumat M, Chai JF, Corre T, Cousminer DL, Dekker AM, Eccles DA, van Eijk KR, Fuchsberger C, Gao H, Germain M, Gordon SD, de Haan HG, Harris SE, Hofer E, Huerta-Chagoya A, Igartua C, Jansen IE, Jia Y, Kacprowski T, Karlsson T, Kleber ME, Li SA, Li-Gao R, Mahajan A, Matsuda K, Meidtner K, Meng W, Montasser ME, van der Most PJ, Munz M, Nutile T, Palviainen T, Prasad G, Prasad RB, Priyanka TDS, Rizzi F, Salvi E, Sapkota BR, Shriner D, Skotte L, Smart MC, Smith AV, van der Spek A, Spracklen CN, Strawbridge RJ, Tajuddin SM, Trompet S, Turman C, Verweij N, Viberti C, Wang L, Warren HR, Wootton RE, Yanek LR, Yao J, Yousri NA, Zhao W, Adeyemo AA, Afaq S, Aguilar-Salinas CA, Akiyama M, Albert ML, Allison MA, Alver M, Aung T, Azizi F, Bentley AR, Boeing H, Boerwinkle E, Borja JB, de Borst GJ, Bottinger EP, Broer L, Campbell H, Chanock S, Chee ML, Chen G, Chen YI, Chen Z, Chiu YF, Cocca M, Collins FS, Concas MP, Corley J, Cugliari G, van Dam RM, Damulina A, Daneshpour MS, Day FR, Delgado GE, Dhana K, Doney ASF, Dörr M, Doumatey AP, Dzimiri N, Ebenesersdóttir SS, Elliott J, Elliott P, Ewert R, Felix JF, Fischer K, Freedman BI, Girotto G, Goel A, Gögele M, Goodarzi MO, Graff M, Granot-Hershkovitz E, Grodstein F, Guarrera S, Gudbjartsson DF, Guity K, Gunnarsson B, Guo Y, Hagenaars SP, Haiman CA, Halevy A, Harris TB, Hedayati M, van Heel DA, Hirata M, Höfer I, Hsiung CA, Huang J, Hung YJ, Ikram MA, Jagadeesan A, Jousilahti P, Kamatani Y, Kanai M, Kerrison ND, Kessler T, Khaw KT, Khor CC, de Kleijn DPV, Koh WP, Kolcic I, Kraft P, Krämer BK, Kutalik Z, Kuusisto J, Langenberg C, Launer LJ, Lawlor DA, Lee IT, Lee WJ, Lerch MM, Li L, Liu J, Loh M, London SJ, Loomis S, Lu Y, Luan J, Mägi R, Manichaikul AW, Manunta P, Másson G, Matoba N, Mei XW, Meisinger C, Meitinger T, Mezzavilla M, Milani L, Millwood IY, Momozawa Y, Moore A, Morange PE, Moreno-Macías H, Mori TA, Morrison AC, Muka T, Murakami Y, Murray AD, de Mutsert R, Mychaleckyj JC, Nalls MA, Nauck M, Neville MJ, Nolte IM, Ong KK, Orozco L, Padmanabhan S, Pálsson G, Pankow JS, Pattaro C, Pattie A, Polasek O, Poulter N, Pramstaller PP, Quintana-Murci L, Räikkönen K, Ralhan S, Rao DC, van Rheenen W, Rich SS, Ridker PM, Rietveld CA, Robino A, van Rooij FJA, Ruggiero D, Saba Y, Sabanayagam C, Sabater-Lleal M, Sala CF, Salomaa V, Sandow K, Schmidt H, Scott LJ, Scott WR, Sedaghati-Khayat B, Sennblad B, van Setten J, Sever PJ, Sheu WH, Shi Y, Shrestha S, Shukla SR, Sigurdsson JK, Sikka TT, Singh JR, Smith BH, Stančáková A, Stanton A, Starr JM, Stefansdottir L, Straker L, Sulem P, Sveinbjornsson G, Swertz MA, Taylor AM, Taylor KD, Terzikhan N, Tham YC, Thorleifsson G, Thorsteinsdottir U, Tillander A, Tracy RP, Tusié-Luna T, Tzoulaki I, Vaccargiu S, Vangipurapu J, Veldink JH, Vitart V, Völker U, Vuoksimaa E, Wakil SM, Waldenberger M, Wander GS, Wang YX, Wareham NJ, Wild S, Yajnik CS, Yuan JM, Zeng L, Zhang L, Zhou J, Amin N, Asselbergs FW, Bakker SJL, Becker DM, Lehne B, Bennett DA, van den Berg LH, Berndt SI, Bharadwaj D, Bielak LF, Bochud M, Boehnke M, Bouchard C, Bradfield JP, Brody JA, Campbell A, Carmi S, Caulfield MJ, Cesarini D, Chambers JC, Chandak GR, Cheng CY, Ciullo M, Cornelis M, Cusi D, Smith GD, Deary IJ, Dorajoo R, van Duijn CM, Ellinghaus D, Erdmann J, Eriksson JG, Evangelou E, Evans MK, Faul JD, Feenstra B, Feitosa M, Foisy S, Franke A, Friedlander Y, Gasparini P, Gieger C, Gonzalez C, Goyette P, Grant SFA, Griffiths LR, Groop L, Gudnason V, Gyllensten U, Hakonarson H, Hamsten A, van der Harst P, Heng CK, Hicks AA, Hochner H, Huikuri H, Hunt SC, Jaddoe VWV, De Jager PL, Johannesson M, Johansson Å, Jonas JB, Jukema JW, Junttila J, Kaprio J, Kardia SLR, Karpe F, Kumari M, Laakso M, van der Laan SW, Lahti J, Laudes M, Lea RA, Lieb W, Lumley T, Martin NG, März W, Matullo G, McCarthy MI, Medland SE, Merriman TR, Metspalu A, Meyer BF, Mohlke KL, Montgomery GW, Mook-Kanamori D, Munroe PB, North KE, Nyholt DR, O'connell JR, Ober C, Oldehinkel AJ, Palmas W, Palmer C, Pasterkamp GG, Patin E, Pennell CE, Perusse L, Peyser PA, Pirastu M, Polderman TJC, Porteous DJ, Posthuma D, Psaty BM, Rioux JD, Rivadeneira F, Rotimi C, Rotter JI, Rudan I, Den Ruijter HM, Sanghera DK, Sattar N, Schmidt R, Schulze MB, Schunkert H, Scott RA, Shuldiner AR, Sim X, Small N, Smith JA, Sotoodehnia N, Tai ES, Teumer A, Timpson NJ, Toniolo D, Tregouet DA, Tuomi T, Vollenweider P, Wang CA, Weir DR, Whitfield JB, Wijmenga C, Wong TY, Wright J, Yang J, Yu L, Zemel BS, Zonderman AB, Perola M, Magnusson PKE, Uitterlinden AG, Kooner JS, Chasman DI, Loos RJF, Franceschini N, Franke L, Haley CS, Hayward C, Walters RG, Perry JRB, Esko T, Helgason A, Stefansson K, Joshi PK, Kubo M, and Wilson JF

Subjects
Alleles, Haplotypes, Homozygote, Humans, Body Size genetics, Cognition, Consanguinity, Fertility genetics, Health Status, Inbreeding Depression genetics, Risk-Taking
Abstract

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

Published
2019
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4. Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.

Author

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

Author

Rafnar T, Gunnarsson B, Stefansson OA, Sulem P, Ingason A, Frigge ML, Stefansdottir L, Sigurdsson JK, Tragante V, Steinthorsdottir V, Styrkarsdottir U, Stacey SN, Gudmundsson J, Arnadottir GA, Oddsson A, Zink F, Halldorsson G, Sveinbjornsson G, Kristjansson RP, Davidsson OB, Salvarsdottir A, Thoroddsen A, Helgadottir EA, Kristjansdottir K, Ingthorsson O, Gudmundsson V, Geirsson RT, Arnadottir R, Gudbjartsson DF, Masson G, Asselbergs FW, Jonasson JG, Olafsson K, Thorsteinsdottir U, Halldorsson BV, Thorleifsson G, and Stefansson K

Subjects
Case-Control Studies, Endometriosis genetics, Female, Genome-Wide Association Study, Humans, White People genetics, Leiomyoma genetics, Uterine Neoplasms genetics
Abstract

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

Published
2018
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6. A genome-wide association study yields five novel thyroid cancer risk loci.

Author

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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7. Epigenetic and genetic components of height regulation.

Author

Benonisdottir S, Oddsson A, Helgason A, Kristjansson RP, Sveinbjornsson G, Oskarsdottir A, Thorleifsson G, Davidsson OB, Arnadottir GA, Sulem G, Jensson BO, Holm H, Alexandersson KF, Tryggvadottir L, Walters GB, Gudjonsson SA, Ward LD, Sigurdsson JK, Iordache PD, Frigge ML, Rafnar T, Kong A, Masson G, Helgason H, Thorsteinsdottir U, Gudbjartsson DF, Sulem P, and Stefansson K

Subjects
Adult, Genetic Loci, Genetic Variation, Genotype, Humans, Iceland, Models, Genetic, Body Height genetics, Epigenesis, Genetic, Genetic Association Studies
Abstract

Adult height is a highly heritable trait. Here we identified 31.6 million sequence variants by whole-genome sequencing of 8,453 Icelanders and tested them for association with adult height by imputing them into 88,835 Icelanders. Here we discovered 13 novel height associations by testing four different models including parent-of-origin (|β|=0.4-10.6 cm). The minor alleles of three parent-of-origin signals associate with less height only when inherited from the father and are located within imprinted regions (IGF2-H19 and DLK1-MEG3). We also examined the association of these sequence variants in a set of 12,645 Icelanders with birth length measurements. Two of the novel variants, (IGF2-H19 and TET1), show significant association with both adult height and birth length, indicating a role in early growth regulation. Among the parent-of-origin signals, we observed opposing parental effects raising questions about underlying mechanisms. These findings demonstrate that common variations affect human growth by parental imprinting., Competing Interests: The following authors affiliated with deCODE genetics/Amgen are employed by the company: S.B., A.O., A.H., R.P.K., G.S., A.O., G.T., O.B.D., G.A.A, G.S., B.O.J., H.H., K.F.A., G.B.W., S.A.G., P.D.I. L.D.W., J.K.S., M.L.F., T.R., A.K., G.M., H. Helgason, U.T., D.F.G., P.S. and K.S.

Published
2016
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