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1. Sequence variants influencing the regulation of serum IgG subclass levels

Author

Thorunn A. Olafsdottir, Gudmar Thorleifsson, Aitzkoa Lopez de Lapuente Portilla, Stefan Jonsson, Lilja Stefansdottir, Abhishek Niroula, Aslaug Jonasdottir, Hannes P. Eggertsson, Gisli H. Halldorsson, Gudny E. Thorlacius, Asgeir O. Arnthorsson, Unnur S. Bjornsdottir, Folkert W. Asselbergs, Arthur E. H. Bentlage, Gudmundur I. Eyjolfsson, Steinunn Gudmundsdottir, Kristbjorg Gunnarsdottir, Bjarni V. Halldorsson, Hilma Holm, Bjorn R. Ludviksson, Pall Melsted, Gudmundur L. Norddahl, Isleifur Olafsson, Saedis Saevarsdottir, Olof Sigurdardottir, Asgeir Sigurdsson, Robin Temming, Pall T. Önundarson, Unnur Thorsteinsdottir, Gestur Vidarsson, Patrick Sulem, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Björn Nilsson, and Kari Stefansson

Subjects
Science
Abstract

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.

Published
2024
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2. Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Author

Molly Went, Laura Duran-Lozano, Gisli H. Halldorsson, Andrea Gunnell, Nerea Ugidos-Damboriena, Philip Law, Ludvig Ekdahl, Amit Sud, Gudmar Thorleifsson, Malte Thodberg, Thorunn Olafsdottir, Antton Lamarca-Arrizabalaga, Caterina Cafaro, Abhishek Niroula, Ram Ajore, Aitzkoa Lopez de Lapuente Portilla, Zain Ali, Maroulio Pertesi, Hartmut Goldschmidt, Lilja Stefansdottir, Sigurdur Y. Kristinsson, Simon N. Stacey, Thorvardur J. Love, Saemundur Rognvaldsson, Roman Hajek, Pavel Vodicka, Ulrika Pettersson-Kymmer, Florentin Späth, Carolina Schinke, Frits Van Rhee, Patrick Sulem, Egil Ferkingstad, Grimur Hjorleifsson Eldjarn, Ulf-Henrik Mellqvist, Ingileif Jonsdottir, Gareth Morgan, Pieter Sonneveld, Anders Waage, Niels Weinhold, Hauke Thomsen, Asta Försti, Markus Hansson, Annette Juul-Vangsted, Unnur Thorsteinsdottir, Kari Hemminki, Martin Kaiser, Thorunn Rafnar, Kari Stefansson, Richard Houlston, and Björn Nilsson

Subjects
Science
Abstract

Abstract Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

Published
2024
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3. Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease

Author

Saedis Saevarsdottir, Kristbjörg Bjarnadottir, Thorsteinn Markusson, Jonas Berglund, Thorunn A. Olafsdottir, Gisli H. Halldorsson, Gudrun Rutsdottir, Kristbjorg Gunnarsdottir, Asgeir Orn Arnthorsson, Sigrun H. Lund, Lilja Stefansdottir, Julius Gudmundsson, Ari J. Johannesson, Arni Sturluson, Asmundur Oddsson, Bjarni Halldorsson, Björn R. Ludviksson, Egil Ferkingstad, Erna V. Ivarsdottir, Gardar Sveinbjornsson, Gerdur Grondal, Gisli Masson, Grimur Hjorleifsson Eldjarn, Gudmundur A. Thorisson, Katla Kristjansdottir, Kirk U. Knowlton, Kristjan H. S. Moore, Sigurjon A. Gudjonsson, Solvi Rognvaldsson, Stacey Knight, Lincoln D. Nadauld, Hilma Holm, Olafur T. Magnusson, Patrick Sulem, Daniel F. Gudbjartsson, Thorunn Rafnar, Gudmar Thorleifsson, Pall Melsted, Gudmundur L. Norddahl, Ingileif Jonsdottir, and Kari Stefansson

Subjects
Science
Abstract

Abstract Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5’-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10−16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10−3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.

Published
2024
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4. GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis

Author

Astros Th. Skuladottir, Lilja Stefansdottir, Gisli H. Halldorsson, Olafur A. Stefansson, Anna Bjornsdottir, Palmi Jonsson, Vala Palmadottir, Thorgeir E. Thorgeirsson, G. Bragi Walters, Rosa S. Gisladottir, Gyda Bjornsdottir, Gudrun A. Jonsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Kirk U. Knowlton, David A. Jones, Aigar Ottas, Estonian Biobank, Ole B. Pedersen, Maria Didriksen, Søren Brunak, Karina Banasik, Thomas Folkmann Hansen, Christian Erikstrup, DBDS Genomic Consortium, Jan Haavik, Ole A. Andreassen, David Rye, Jannicke Igland, Sisse Rye Ostrowski, Lili A. Milani, Lincoln D. Nadauld, Hreinn Stefansson, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson’s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Published
2024
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5. Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria

Author

Ragnar P. Kristjansson, Gudjon R. Oskarsson, Astros Skuladottir, Asmundur Oddsson, Solvi Rognvaldsson, Gardar Sveinbjornsson, Sigrun H. Lund, Brynjar O. Jensson, Edda L. Styrmisdottir, Gisli H. Halldorsson, Egil Ferkingstad, Grimur Hjorleifsson Eldjarn, Doruk Beyter, Snædis Kristmundsdottir, Kristinn Juliusson, Run Fridriksdottir, Gudny A. Arnadottir, Hildigunnur Katrinardottir, Margret H. Snorradottir, Vinicius Tragante, Lilja Stefansdottir, Erna V. Ivarsdottir, Gyda Bjornsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Bjorn R. Ludviksson, Pall T. Onundarson, Saedis Saevarsdottir, Pall Melsted, Gudmundur L. Norddahl, Unnur S. Bjornsdottir, Thorunn Olafsdottir, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Patrick Sulem, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Urticaria is a skin disorder characterized by outbreaks of raised pruritic wheals. In order to identify sequence variants associated with urticaria, we performed a meta-analysis of genome-wide association studies for urticaria with a total of 40,694 cases and 1,230,001 controls from Iceland, the UK, Finland, and Japan. We also performed transcriptome- and proteome-wide analyses in Iceland and the UK. We found nine sequence variants at nine loci associating with urticaria. The variants are at genes participating in type 2 immune responses and/or mast cell biology (CBLB, FCER1A, GCSAML, STAT6, TPSD1, ZFPM1), the innate immunity (C4), and NF-κB signaling. The most significant association was observed for the splice-donor variant rs56043070[A] (hg38: chr1:247556467) in GCSAML (MAF = 6.6%, OR = 1.24 (95%CI: 1.20–1.28), P-value = 3.6 × 10-44). We assessed the effects of the variants on transcripts, and levels of proteins relevant to urticaria pathophysiology. Our results emphasize the role of type 2 immune response and mast cell activation in the pathogenesis of urticaria. Our findings may point to an IgE-independent urticaria pathway that could help address unmet clinical need.

Published
2023
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6. Genetic architecture of band neutrophil fraction in Iceland

Author

Gudjon R. Oskarsson, Magnus K. Magnusson, Asmundur Oddsson, Brynjar O. Jensson, Run Fridriksdottir, Gudny A. Arnadottir, Hildigunnur Katrinardottir, Solvi Rognvaldsson, Gisli H. Halldorsson, Gardar Sveinbjornsson, Erna V. Ivarsdottir, Lilja Stefansdottir, Egil Ferkingstad, Kristjan Norland, Vinicius Tragante, Jona Saemundsdottir, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Svanhvit Sigurjonsdottir, Karen O. Petursdottir, Olafur B. Davidsson, Thorunn Rafnar, Hilma Holm, Isleifur Olafsson, Pall T. Onundarson, Brynjar Vidarsson, Olof Sigurdardottir, Gisli Masson, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Gudmundur L. Norddahl, Unnur Thorsteinsdottir, Patrick Sulem, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

A GWAS in Iceland reveals that variants in inner nuclear membrane proteins are associated with nuclear morphology of granulocytes and band neutrophil fraction.

Published
2022
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7. A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome

Author

Astros Th. Skuladottir, Gyda Bjornsdottir, Egil Ferkingstad, Gudmundur Einarsson, Lilja Stefansdottir, Muhammad Sulaman Nawaz, Asmundur Oddsson, Thorunn A. Olafsdottir, Saedis Saevarsdottir, G. Bragi Walters, Sigurdur H. Magnusson, Anna Bjornsdottir, Olafur A. Sveinsson, Arnor Vikingsson, Thomas Folkmann Hansen, Rikke Louise Jacobsen, Christian Erikstrup, Michael Schwinn, Søren Brunak, Karina Banasik, Sisse Rye Ostrowski, Anders Troelsen, Cecilie Henkel, Ole Birger Pedersen, DBDS Genetic Consortium, Ingileif Jonsdottir, Daniel F. Gudbjartsson, Patrick Sulem, Thorgeir E. Thorgeirsson, Hreinn Stefansson, and Kari Stefansson

Subjects
Science
Abstract

The underlying genetics of carpal tunnel syndrome is not well understood. Here, the authors perform a GWAS meta-analysis for carpal tunnel syndrome finding variants at 50 loci with connections to the extracellular matrix discovered through various functional analyses.

Published
2022
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8. Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Author

Gyda Bjornsdottir, Lilja Stefansdottir, Gudmar Thorleifsson, Patrick Sulem, Kristjan Norland, Egil Ferkingstad, Asmundur Oddsson, Florian Zink, Sigrun H. Lund, Muhammad S. Nawaz, G. Bragi Walters, Astros Th. Skuladottir, Sigurjon A. Gudjonsson, Gudmundur Einarsson, Gisli H. Halldorsson, Valgerdur Bjarnadottir, Gardar Sveinbjornsson, Anna Helgadottir, Unnur Styrkarsdottir, Larus J. Gudmundsson, Ole B. Pedersen, Thomas Folkmann Hansen, Thomas Werge, Karina Banasik, Anders Troelsen, Soren T. Skou, Lise Wegner Thørner, Christian Erikstrup, Kaspar Rene Nielsen, Susan Mikkelsen, DBDS Genetic Consortium, GO Consortium, Ingileif Jonsdottir, Aron Bjornsson, Ingvar H. Olafsson, Elfar Ulfarsson, Josep Blondal, Arnor Vikingsson, Soren Brunak, Sisse R. Ostrowski, Henrik Ullum, Unnur Thorsteinsdottir, Hreinn Stefansson, Daniel F. Gudbjartsson, Thorgeir E. Thorgeirsson, and Kari Stefansson

Subjects
Science
Abstract

Little is known about the biology of back pain, a leading cause of disability. Here the authors report 30 new back pain loci, implicating genes involved in cartilage/bone biology, as well as neurological and inflammatory processes.

Published
2022
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9. A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

Author

Astros Th. Skuladottir, Gyda Bjornsdottir, Muhammad Sulaman Nawaz, Hannes Petersen, Solvi Rognvaldsson, Kristjan Helgi Swerford Moore, Pall I. Olafsson, Sigurður H. Magnusson, Anna Bjornsdottir, Olafur A. Sveinsson, Gudrun R. Sigurdardottir, Saedis Saevarsdottir, Erna V. Ivarsdottir, Lilja Stefansdottir, Bjarni Gunnarsson, Joseph B. Muhlestein, Kirk U. Knowlton, David A. Jones, Lincoln D. Nadauld, Annette M. Hartmann, Dan Rujescu, Michael Strupp, G. Bragi Walters, Thorgeir E. Thorgeirsson, Ingileif Jonsdottir, Hilma Holm, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Patrick Sulem, Hreinn Stefansson, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Astros Skuladottir et al. conducted a genome-wide association study on 48,072 vertigo cases and 894,541 controls from four populations with European ancestries. They identified six common variants associated with vertigo, thereby providing further insight into the etiology of vestibular disorders.

Published
2021
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10. Genetic variants associated with platelet count are predictive of human disease and physiological markers

Author

Evgenia Mikaelsdottir, Gudmar Thorleifsson, Lilja Stefansdottir, Gisli Halldorsson, Jon K. Sigurdsson, Sigrun H. Lund, Vinicius Tragante, Pall Melsted, Solvi Rognvaldsson, Kristjan Norland, Anna Helgadottir, Magnus K. Magnusson, Gunnar B. Ragnarsson, Sigurdur Y. Kristinsson, Sigrun Reykdal, Brynjar Vidarsson, Ingibjorg J. Gudmundsdottir, Isleifur Olafsson, Pall T. Onundarson, Olof Sigurdardottir, Emil L. Sigurdsson, Gerdur Grondal, Arni J. Geirsson, Gudmundur Geirsson, Julius Gudmundsson, Hilma Holm, Saedis Saevarsdottir, Ingileif Jonsdottir, Gudmundur Thorgeirsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Thorunn Rafnar, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Evgenia Mikaelsdottir et al. report a study of variants associated with platelet count among European individuals where they identify 577 associations. They also report a genetic overlap between platelet count and human diseases, including myeloproliferative neoplasms, rheumatoid arthritis, and hypertension, as well as a genetic overlap between platelet count and various physiological markers.

Published
2021
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11. Author Correction: Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Author

Gyda Bjornsdottir, Lilja Stefansdottir, Gudmar Thorleifsson, Patrick Sulem, Kristjan Norland, Egil Ferkingstad, Asmundur Oddsson, Florian Zink, Sigrun H. Lund, Muhammad S. Nawaz, G. Bragi Walters, Astros Th. Skuladottir, Sigurjon A. Gudjonsson, Gudmundur Einarsson, Gisli H. Halldorsson, Valgerdur Bjarnadottir, Gardar Sveinbjornsson, Anna Helgadottir, Unnur Styrkarsdottir, Larus J. Gudmundsson, Ole B. Pedersen, Thomas Folkmann Hansen, Thomas Werge, Karina Banasik, Anders Troelsen, Soren T. Skou, Lise Wegner Thørner, Christian Erikstrup, Kaspar Rene Nielsen, Susan Mikkelsen, DBDS Genetic Consortium, GO Consortium, Ingileif Jonsdottir, Aron Bjornsson, Ingvar H. Olafsson, Elfar Ulfarsson, Josep Blondal, Arnor Vikingsson, Soren Brunak, Sisse R. Ostrowski, Henrik Ullum, Unnur Thorsteinsdottir, Hreinn Stefansson, Daniel F. Gudbjartsson, Thorgeir E. Thorgeirsson, and Kari Stefansson

Subjects
Science
Published
2022
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12. Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor

Author

Joseph Dowsett, Egil Ferkingstad, Line Jee Hartmann Rasmussen, Lise Wegner Thørner, Magnús K. Magnússon, Karen Sugden, Gudmar Thorleifsson, Mike Frigge, Kristoffer Sølvsten Burgdorf, Sisse Rye Ostrowski, Erik Sørensen, Christian Erikstrup, Ole Birger Pedersen, Thomas Folkmann Hansen, Karina Banasik, Søren Brunak, DBDS Genomic Consortium, Vinicius Tragante, Sigrun Helga Lund, Lilja Stefansdottir, Bjarni Gunnarson, Richie Poulton, Louise Arseneault, Avshalom Caspi, Terrie E. Moffitt, Daníel Gudbjartsson, Jesper Eugen-Olsen, Hreinn Stefánsson, Kári Stefánsson, and Henrik Ullum

Subjects
Biology (General), QH301-705.5
Abstract

Dowsett and colleagues used a genome-wide association approach to investigate the genetic influence on soluble urokinase-type plasminogen activator receptor presence in the plasma of humans. Their findings indicate a 60% heritability factor in British twins, and using a wide sample of Northern European genome samples they identify eleven genetic loci associated with an increase or decrease of this chronic inflammation marker.

Published
2021
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13. The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

Author

Erna V. Ivarsdottir, Hilma Holm, Stefania Benonisdottir, Thorhildur Olafsdottir, Gardar Sveinbjornsson, Gudmar Thorleifsson, Hannes P. Eggertsson, Gisli H. Halldorsson, Kristjan E. Hjorleifsson, Pall Melsted, Arnaldur Gylfason, Gudny A. Arnadottir, Asmundur Oddsson, Brynjar O. Jensson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Thorhildur Juliusdottir, Lilja Stefansdottir, Vinicius Tragante, Bjarni V. Halldorsson, Hannes Petersen, Gudmundur Thorgeirsson, Unnur Thorsteinsdottir, Patrick Sulem, Ingibjorg Hinriksdottir, Ingileif Jonsdottir, Daniel F. Gudbjartsson, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Erna Ivarsdottir et al. report a genome-wide association meta-analysis for age-related hearing loss in the Icelandic and UK populations. They identify 21 novel variants, 13 of which are rare, and reveal a genetic correlation between age-related hearing loss and tinnitus.

Published
2021
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14. Germline variants at SOHLH2 influence multiple myeloma risk

Author

Laura Duran-Lozano, Gudmar Thorleifsson, Aitzkoa Lopez de Lapuente Portilla, Abhishek Niroula, Molly Went, Malte Thodberg, Maroulio Pertesi, Ram Ajore, Caterina Cafaro, Pall I. Olason, Lilja Stefansdottir, G. Bragi Walters, Gisli H. Halldorsson, Ingemar Turesson, Martin F. Kaiser, Niels Weinhold, Niels Abildgaard, Niels Frost Andersen, Ulf-Henrik Mellqvist, Anders Waage, Annette Juul-Vangsted, Unnur Thorsteinsdottir, Markus Hansson, Richard Houlston, Thorunn Rafnar, Kari Stefansson, and Björn Nilsson

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10−14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.

Published
2021
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15. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Valgerdur Steinthorsdottir, Ralph McGinnis, Nicholas O. Williams, Lilja Stefansdottir, Gudmar Thorleifsson, Scott Shooter, João Fadista, Jon K. Sigurdsson, Kirsi M. Auro, Galina Berezina, Maria-Carolina Borges, Suzannah Bumpstead, Jonas Bybjerg-Grauholm, Irina Colgiu, Vivien A. Dolby, Frank Dudbridge, Stephanie M. Engel, Christopher S. Franklin, Michael L. Frigge, Yr Frisbaek, Reynir T. Geirsson, Frank Geller, Solveig Gretarsdottir, Daniel F. Gudbjartsson, Quaker Harmon, David Michael Hougaard, Tatyana Hegay, Anna Helgadottir, Sigrun Hjartardottir, Tiina Jääskeläinen, Hrefna Johannsdottir, Ingileif Jonsdottir, Thorhildur Juliusdottir, Noor Kalsheker, Abdumadjit Kasimov, John P. Kemp, Katja Kivinen, Kari Klungsøyr, Wai K. Lee, Mads Melbye, Zosia Miedzybrodska, Ashley Moffett, Dilbar Najmutdinova, Firuza Nishanova, Thorunn Olafsdottir, Markus Perola, Fiona Broughton Pipkin, Lucilla Poston, Gordon Prescott, Saedis Saevarsdottir, Damilya Salimbayeva, Paula Juliet Scaife, Line Skotte, Eleonora Staines-Urias, Olafur A. Stefansson, Karina Meden Sørensen, Liv Cecilie Vestrheim Thomsen, Vinicius Tragante, Lill Trogstad, Nigel A. B. Simpson, FINNPEC Consortium, GOPEC Consortium, Tamara Aripova, Juan P. Casas, Anna F. Dominiczak, James J. Walker, Unnur Thorsteinsdottir, Ann-Charlotte Iversen, Bjarke Feenstra, Deborah A. Lawlor, Heather Allison Boyd, Per Magnus, Hannele Laivuori, Nodira Zakhidova, Gulnara Svyatova, Kari Stefansson, and Linda Morgan

Subjects
Science
Abstract

Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020
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16. Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Author

Maria Didriksen, Muhammad Sulaman Nawaz, Joseph Dowsett, Steven Bell, Christian Erikstrup, Ole B. Pedersen, Erik Sørensen, Poul J. Jennum, Kristoffer S. Burgdorf, Brendan Burchell, Adam S. Butterworth, Nicole Soranzo, David B. Rye, Lynn Marie Trotti, Prabhjyot Saini, Lilja Stefansdottir, Sigurdur H. Magnusson, Gudmar Thorleifsson, Thordur Sigmundsson, Albert P. Sigurdsson, Katja Van Den Hurk, Franke Quee, Michael W. T. Tanck, Willem H. Ouwehand, David J. Roberts, Eric J. Earley, Michael P. Busch, Alan E. Mast, Grier P. Page, John Danesh, Emanuele Di Angelantonio, Hreinn Stefansson, Henrik Ullum, and Kari Stefansson

Subjects
Biology (General), QH301-705.5
Abstract

Didriksen, Nawaz, et al. identify three novel genetic risk variants for restless legs syndrome and confirm 19 out of 20 previously reported variants through a genome-wide association meta-analysis including nearly half a million individuals. Using expression QTL analysis, they also find that a subset of these loci may have a causal effect on nearby gene expression.

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

Author

Thorunn A. Olafsdottir, Fannar Theodors, Kristbjorg Bjarnadottir, Unnur Steina Bjornsdottir, Arna B. Agustsdottir, Olafur A. Stefansson, Erna V. Ivarsdottir, Jon K. Sigurdsson, Stefania Benonisdottir, Gudmundur I. Eyjolfsson, David Gislason, Thorarinn Gislason, Steinunn Guðmundsdóttir, Arnaldur Gylfason, Bjarni V. Halldorsson, Gisli H. Halldorsson, Thorhildur Juliusdottir, Anna M. Kristinsdottir, Dora Ludviksdottir, Bjorn R. Ludviksson, Gisli Masson, Kristjan Norland, Pall T. Onundarson, Isleifur Olafsson, Olof Sigurdardottir, Lilja Stefansdottir, Gardar Sveinbjornsson, Vinicius Tragante, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Patrick Sulem, Unnur Thorsteinsdottir, Gudmundur L. Norddahl, Ingileif Jonsdottir, and Kari Stefansson

Subjects
Science
Abstract

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

Published
2020
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18. Associations of autozygosity with a broad range of human phenotypes

Author

David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson

Subjects
Science
Abstract

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

Published
2019
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19. GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Unnur Styrkarsdottir, Olafur A. Stefansson, Kristbjorg Gunnarsdottir, Gudmar Thorleifsson, Sigrun H. Lund, Lilja Stefansdottir, Kristinn Juliusson, Arna B. Agustsdottir, Florian Zink, Gisli H. Halldorsson, Erna V. Ivarsdottir, Stefania Benonisdottir, Hakon Jonsson, Arnaldur Gylfason, Kristjan Norland, Katerina Trajanoska, Cindy G. Boer, Lorraine Southam, Jason C. S. Leung, Nelson L. S. Tang, Timothy C. Y. Kwok, Jenny S. W. Lee, Suzanne C. Ho, Inger Byrjalsen, Jacqueline R. Center, Seung Hun Lee, Jung-Min Koh, L. Stefan Lohmander, Lan T. Ho-Pham, Tuan V. Nguyen, John A. Eisman, Jean Woo, Ping-C. Leung, John Loughlin, Eleftheria Zeggini, Claus Christiansen, Fernando Rivadeneira, Joyce van Meurs, Andre G. Uitterlinden, Brynjolfur Mogensen, Helgi Jonsson, Thorvaldur Ingvarsson, Gunnar Sigurdsson, Rafn Benediktsson, Patrick Sulem, Ingileif Jonsdottir, Gisli Masson, Hilma Holm, Gudmundur L. Norddahl, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, and Kari Stefansson

Subjects
Science
Abstract

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

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

Author

Julius Gudmundsson, Jon K. Sigurdsson, Lilja Stefansdottir, Bjarni A. Agnarsson, Helgi J. Isaksson, Olafur A. Stefansson, Sigurjon A. Gudjonsson, Daniel F. Gudbjartsson, Gisli Masson, Michael L. Frigge, Simon N. Stacey, Patrick Sulem, Gisli H. Halldorsson, Vinicius Tragante, Hilma Holm, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Thorvaldur Jonsson, Eirikur Jonsson, Rosa B. Barkardottir, Rafn Hilmarsson, Folkert W. Asselbergs, Gudmundur Geirsson, Unnur Thorsteinsdottir, Thorunn Rafnar, Gudmar Thorleifsson, and Kari Stefansson

Subjects
Science
Abstract

Elderly males are often affected by benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS), but their link to prostate cancer risk is not well defined. Here, a genome-wide association study of BPH/LUTS patients from Iceland and the UK found 23 significant variants at 14 loci, and 15 of these variants associate with prostate specific antigen, which is linked to prostate cancer risk.

Published
2018
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21. Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Author

Thorunn Rafnar, Bjarni Gunnarsson, Olafur A. Stefansson, Patrick Sulem, Andres Ingason, Michael L. Frigge, Lilja Stefansdottir, Jon K. Sigurdsson, Vinicius Tragante, Valgerdur Steinthorsdottir, Unnur Styrkarsdottir, Simon N. Stacey, Julius Gudmundsson, Gudny A. Arnadottir, Asmundur Oddsson, Florian Zink, Gisli Halldorsson, Gardar Sveinbjornsson, Ragnar P. Kristjansson, Olafur B. Davidsson, Anna Salvarsdottir, Asgeir Thoroddsen, Elisabet A. Helgadottir, Katrin Kristjansdottir, Orri Ingthorsson, Valur Gudmundsson, Reynir T. Geirsson, Ragnheidur Arnadottir, Daniel F. Gudbjartsson, Gisli Masson, Folkert W. Asselbergs, Jon G. Jonasson, Karl Olafsson, Unnur Thorsteinsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, and Kari Stefansson

Subjects
Science
Abstract

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

Published
2018
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22. Author Correction: Germline variants at SOHLH2 influence multiple myeloma risk

Author

Laura Duran-Lozano, Gudmar Thorleifsson, Aitzkoa Lopez de Lapuente Portilla, Abhishek Niroula, Molly Went, Malte Thodberg, Maroulio Pertesi, Ram Ajore, Caterina Cafaro, Pall I. Olason, Lilja Stefansdottir, G. Bragi Walters, Gisli H. Halldorsson, Ingemar Turesson, Martin F. Kaiser, Niels Weinhold, Niels Abildgaard, Niels Frost Andersen, Ulf-Henrik Mellqvist, Anders Waage, Annette Juul-Vangsted, Unnur Thorsteinsdottir, Markus Hansson, Richard Houlston, Thorunn Rafnar, Kari Stefansson, and Björn Nilsson

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2021
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23. A genome-wide association study yields five novel thyroid cancer risk loci

Author

Julius Gudmundsson, Gudmar Thorleifsson, Jon K. Sigurdsson, Lilja Stefansdottir, Jon G. Jonasson, Sigurjon A. Gudjonsson, Daniel F. Gudbjartsson, Gisli Masson, Hrefna Johannsdottir, Gisli H. Halldorsson, Simon N. Stacey, Hannes Helgason, Patrick Sulem, Leigha Senter, Huiling He, Sandya Liyanarachchi, Matthew D. Ringel, Esperanza Aguillo, Angeles Panadero, Enrique Prats, Almudena Garcia-Castaño, Ana De Juan, Fernando Rivera, Li Xu, Lambertus A. Kiemeney, Gudmundur I. Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Hoskuldur Kristvinsson, Romana T. Netea-Maier, Thorvaldur Jonsson, Jose I. Mayordomo, Theo S. Plantinga, Hannes Hjartarson, Jon Hrafnkelsson, Erich M. Sturgis, Unnur Thorsteinsdottir, Thorunn Rafnar, Albert de la Chapelle, and Kari Stefansson

Subjects
Science
Abstract

Non-medullary thyroid cancers include papillary and follicular subtypes, and are the most common type of thyroid cancer. Here, the authors extend previous work by performing a large genome-wide association study and find five novel loci associated with this disease.

Published
2017
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24. Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis

Author

Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Kristrun Aradottir, Bjarke Feenstra, Asgeir Sigurdsson, Lilja Stefansdottir, Anna M. Kristinsdottir, Florian Zink, Gisli H. Halldorsson, Nete Munk Nielsen, Frank Geller, Mads Melbye, Daniel F. Gudbjartsson, Reynir T. Geirsson, Unnur Thorsteinsdottir, and Kari Stefansson

Subjects
Science
Abstract

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

Published
2016
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25. Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Unnur Styrkarsdottir, Olafur A. Stefansson, Kristbjorg Gunnarsdottir, Gudmar Thorleifsson, Sigrun H. Lund, Lilja Stefansdottir, Kristinn Juliusson, Arna B. Agustsdottir, Florian Zink, Gisli H. Halldorsson, Erna V. Ivarsdottir, Stefania Benonisdottir, Hakon Jonsson, Arnaldur Gylfason, Kristjan Norland, Katerina Trajanoska, Cindy G. Boer, Lorraine Southam, Jason C. S. Leung, Nelson L. S. Tang, Timothy C. Y. Kwok, Jenny S. W. Lee, Suzanne C. Ho, Inger Byrjalsen, Jacqueline R. Center, Seung Hun Lee, Jung-Min Koh, L. Stefan Lohmander, Lan T. Ho-Pham, Tuan V. Nguyen, John A. Eisman, Jean Woo, Ping-C. Leung, John Loughlin, Eleftheria Zeggini, Claus Christiansen, Fernando Rivadeneira, Joyce van Meurs, Andre G. Uitterlinden, Brynjolfur Mogensen, Helgi Jonsson, Thorvaldur Ingvarsson, Gunnar Sigurdsson, Rafn Benediktsson, Patrick Sulem, Ingileif Jonsdottir, Gisli Masson, Hilma Holm, Gudmundur L. Norddahl, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, and Kari Stefansson

Subjects
Science
Abstract

The original HTML version of this Article was updated shortly after publication to add links to the Peer Review file. In addition, affiliations 16 and 17 incorrectly read ‘School of Medicine Sydney, University of Notre Dame Australia, Sydney, WA, 6160, Australia’ and ‘St Vincent’s Clinical School, University of New South Wales Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.’ This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019
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26. Supplementary Material from Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk

Author

Kari Stefansson, Daniel F. Gudbjartsson, Thorunn Rafnar, Patrick Sulem, Jon H. Olafsson, Karl Olafsson, Tomas T. Agustsson, Unnur Thorsteinsdottir, Bjarni V. Halldorsson, Hannes P. Eggertsson, Lilja Stefansdottir, Pall I. Olason, Evgenia Mikaelsdottir, Julius Gudmundsson, Valgerdur Steinthorsdottir, Pall Melsted, Solvi Rognvaldsson, Sigrun H. Lund, Florian Zink, Sigurjon A. Gudjonsson, Run Fridriksdottir, Asmundur Oddsson, Arnaldur Gylfason, Hakon Jonsson, Snaedis Kristmundsdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Jon G. Jonasson, Rafn Benediktsson, Kavita Y. Sarin, Laufey Tryggvadottir, Arni Kjalar Kristjansson, Kristin Thorisdottir, Bardur Sigurgeirsson, Kristjan Norland, Gudmar Thorleifsson, Gardar Sveinbjornsson, Simon N. Stacey, and Thorhildur Olafsdottir

Abstract

Supplementary Methods, Supplementary Tables 1-18 and Supplementary Figures 1-5.

Published
2023

27. Data from Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk

Author

Kari Stefansson, Daniel F. Gudbjartsson, Thorunn Rafnar, Patrick Sulem, Jon H. Olafsson, Karl Olafsson, Tomas T. Agustsson, Unnur Thorsteinsdottir, Bjarni V. Halldorsson, Hannes P. Eggertsson, Lilja Stefansdottir, Pall I. Olason, Evgenia Mikaelsdottir, Julius Gudmundsson, Valgerdur Steinthorsdottir, Pall Melsted, Solvi Rognvaldsson, Sigrun H. Lund, Florian Zink, Sigurjon A. Gudjonsson, Run Fridriksdottir, Asmundur Oddsson, Arnaldur Gylfason, Hakon Jonsson, Snaedis Kristmundsdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Jon G. Jonasson, Rafn Benediktsson, Kavita Y. Sarin, Laufey Tryggvadottir, Arni Kjalar Kristjansson, Kristin Thorisdottir, Bardur Sigurgeirsson, Kristjan Norland, Gudmar Thorleifsson, Gardar Sveinbjornsson, Simon N. Stacey, and Thorhildur Olafsdottir

Abstract

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10−12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10−4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis.Significance:This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.

Published
2023

28. Distinction between the effects of parental and fetal genomes on fetal growth

Author

Daniel F. Gudbjartsson, Vinicius Tragante, Kari Stefansson, Hilma Holm, Gudmar Thorleifsson, Emil L. Sigurdsson, Gudmundur Thorgeirsson, Rafn Benediktsson, Rosa B. Thorolfsdottir, Erna V. Ivarsdottir, Thora Steingrimsdottir, Unnur Thorsteinsdottir, Ingileif Jonsdottir, Kristjan E. Hjorleifsson, David O. Arnar, Gardar Sveinbjornsson, Michael L. Frigge, Valgerdur Steinthorsdottir, Lilja Stefansdottir, Thorhildur Juliusdottir, Jon K. Sigurdsson, and Anna Helgadottir

Subjects
Adult, Blood Glucose, Male, Offspring, Birth weight, Iceland, Blood Pressure, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Genome, Fetal Development, Genetics, Birth Weight, Humans, Allele, Genetic association, Fetus, Models, Genetic, Haplotype, Infant, Newborn, Body Height, Haplotypes, Cardiovascular Diseases, Female, Genome-Wide Association Study
Abstract

Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome. Genome-wide association analyses using parental and offspring genotypes provide insights into fetal and maternal genetic effects on fetal growth. The results show that maternal and fetal genomes influence birth weight through distinct mechanisms.

Published
2021

29. The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

Author

Aslaug Jonasdottir, Gudny A. Arnadottir, Daniel F. Gudbjartsson, Vinicius Tragante, Asmundur Oddsson, Kari Stefansson, I. Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Brynjar O. Jensson, Gudmundur Thorgeirsson, Páll Melsted, Stefania Benonisdottir, Erna V. Ivarsdottir, Hilma Holm, Thorhildur Juliusdottir, Gardar Sveinbjornsson, Hannes Petersen, Hannes P. Eggertsson, Gisli H. Halldorsson, Lilja Stefansdottir, Patrick Sulem, Ingibjorg Hinriksdottir, Thorhildur Ólafsdóttir, Arnaldur Gylfason, Adalbjorg Jonasdottir, Kristjan E. Hjorleifsson, and Unnur Thorsteinsdottir

Subjects
0301 basic medicine, Adult, Male, Aging, Hearing loss, QH301-705.5, Medicine (miscellaneous), Genome-wide association study, Biology, Genetic correlation, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Risk Factors, medicine, otorhinolaryngologic diseases, Missense mutation, Humans, Genetic Predisposition to Disease, Biology (General), Hearing Loss, Aged, Genetic association study, Genetics, Aged, 80 and over, Genetic Variation, Middle Aged, Genetic architecture, Ageing, 030104 developmental biology, Genes, Mendelian inheritance, symbols, Female, Tandem exon duplication, medicine.symptom, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery, Tinnitus, Genome-Wide Association Study
Abstract

Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10−22 and OR = 4.2 for heterozygotes, P = 5.7 × 10−27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing., Erna Ivarsdottir et al. report a genome-wide association meta-analysis for age-related hearing loss in the Icelandic and UK populations. They identify 21 novel variants, 13 of which are rare, and reveal a genetic correlation between age-related hearing loss and tinnitus.

Published
2021

30. Loss-of-Function Variants in the Tumor-Suppressor Gene PTPN14 Confer Increased Cancer Risk

Author

Unnur Thorsteinsdottir, Asgeir Sigurdsson, Bjarni V. Halldorsson, Asmundur Oddsson, Kari Stefansson, Tomas Thor Agustsson, Hannes P. Eggertsson, Rafn Benediktsson, Gudmar Thorleifsson, Páll Melsted, Thorunn Rafnar, Arni Kristjansson, Patrick Sulem, Lilja Stefansdottir, Karl Olafsson, Kristjan Norland, Julius Gudmundsson, Jón Ólafsson, Laufey Tryggvadottir, Kavita Y. Sarin, Solvi Rognvaldsson, Gardar Sveinbjornsson, Hakon Jonsson, Arnaldur Gylfason, Sigurjon A. Gudjonsson, Sigrun H. Lund, Kristin Thorisdottir, Daniel F. Gudbjartsson, Florian Zink, Aslaug Jonasdottir, Jon G. Jonasson, Evgenia Mikaelsdottir, Bardur Sigurgeirsson, Thorhildur Ólafsdóttir, Valgerdur Steinthorsdottir, Pall I. Olason, Snaedis Kristmundsdottir, Run Fridriksdottir, and Simon N. Stacey

Subjects
0301 basic medicine, Genetics, Cancer Research, Cancer-Predisposing Gene, Tumor suppressor gene, Cancer, Locus (genetics), Genome-wide association study, Biology, medicine.disease, medicine.disease_cause, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Genotype, medicine, Basal cell carcinoma, Carcinogenesis
Abstract

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in PTPN14 conferred substantial risks of BCC (OR, 8.0; P = 1.9 × 10−12), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the PTPN14 locus were associated with BCC, suggesting PTPN14 as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, P = 1.6 × 10−4) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. Significance: This study identifies the tumor-suppressor gene PTPN14 as a high-impact BCC predisposition gene and indicates that inactivation of PTPN14 by germline sequence variants may also lead to increased risk of cervical cancer.

Published
2021

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

Author

Bjorn R. Ludviksson, Daniel F. Gudbjartsson, Vinicius Tragante, Pall T. Onundarson, Arnaldur Gylfason, Thorarinn Gislason, Olafur A. Stefansson, Olof Sigurdardottir, Stefania Benonisdottir, Gudmundur L. Norddahl, Arna B Agustsdottir, Fannar Theodors, Bjarni V. Halldorsson, Patrick Sulem, Lilja Stefansdottir, Gardar Sveinbjornsson, Erna V. Ivarsdottir, Thorunn A. Olafsdottir, Unnur Thorsteinsdottir, Gisli Masson, Gudmar Thorleifsson, Gudmundur I. Eyjolfsson, Steinunn Guðmundsdóttir, Thorhildur Juliusdottir, David Gislason, Ingileif Jonsdottir, Jon K. Sigurdsson, Kristjan Norland, Kristbjorg Bjarnadottir, Kari Stefansson, Unnur S. Bjornsdottir, Gisli H. Halldorsson, Anna M. Kristinsdottir, Dora Ludviksdottir, Isleifur Olafsson, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræðideild (HR), Department of Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Tæknisvið (HR), School of Technology (RU), Háskóli Íslands, University of Iceland, Háskólinn í Reykjavík, and Reykjavik University

Subjects
0301 basic medicine, T-Lymphocytes, Iceland, Receptor, Transforming Growth Factor-beta Type I, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, Genome-wide association studies, Pathogenesis, Leukocyte Count, Missense mutation, lcsh:Science, 3' Untranslated Regions, Multidisciplinary, Gen, 021001 nanoscience & nanotechnology, Phenotype, Astmi, 3. Good health, medicine.anatomical_structure, Airway Remodeling, 0210 nano-technology, Erfðarannsóknir, T cell, Science, Quantitative Trait Loci, T cells, Ki-1 Antigen, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immunogenetics, medicine, Humans, Genetic Predisposition to Disease, Loss function, Asthma, business.industry, General Chemistry, medicine.disease, United Kingdom, respiratory tract diseases, Eosinophils, MicroRNAs, Meta-analysis, Genarannsóknir, 030104 developmental biology, Expression quantitative trait loci, Immunology, lcsh:Q, Gene expression, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), 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., We thank the individuals who participated in this study and the staff at the Icelandic Patient Recruitment Center and the deCODE genetics core facilities. Further to all our colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK biobank Resource under Application Number ‘24711’.

Published
2020

32. A genome-wide meta-analysis identifies 53 sequence variants associating with carpal tunnel syndrome

Author

Astros Skuladottir, Gyda Bjornsdottir, Egil Ferkingstad, Gudmundur Einarsson, Lilja Stefansdottir, Muhammad Sulaman Nawaz, Thorunn Olafsdottir, Saedis Saevarsdottir, G. Walters, Sigurdur Magnusson, Asmundur Oddson, Anna Bjornsdottir, Olafur Sveinsson, Arnor Vikingsson, Thomas Hansen, Rikke Jacobsen, Christian Erikstrup, Michael Schwinn, Søren Brunak, Karina Banasik, Sisse Ostrowski, Anders Troelsen, Cecilie Henkel, Ole Pedersen, Ingileif Jonsdottir, Daniel Gudbjartsson, Patrick Sulem, Thorgeir Thorgeirsson, Hreinn Stefansson, and Kari Stefansson

Subjects
nervous system diseases
Abstract

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (Ncases = 48,843, Ncontrols = 1,190,837), we found 53 sequence variants at 50 loci that associate with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10−24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in recurrent/persistent cases than nonrecurrent/nonresistant cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

Published
2022

33. Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Author

Saedis, Saevarsdottir, Lilja, Stefansdottir, Patrick, Sulem, Gudmar, Thorleifsson, Egil, Ferkingstad, Gudrun, Rutsdottir, Bente, Glintborg, Helga, Westerlind, Gerdur, Grondal, Isabella C, Loft, Signe Bek, Sorensen, Benedicte A, Lie, Mikael, Brink, Lisbeth, Ärlestig, Asgeir Orn, Arnthorsson, Eva, Baecklund, Karina, Banasik, Steffen, Bank, Lena I, Bjorkman, Torkell, Ellingsen, Christian, Erikstrup, Oleksandr, Frei, Inger, Gjertsson, Daniel F, Gudbjartsson, Sigurjon A, Gudjonsson, Gisli H, Halldorsson, Oliver, Hendricks, Jan, Hillert, Estrid, Hogdall, Søren, Jacobsen, Dorte Vendelbo, Jensen, Helgi, Jonsson, Alf, Kastbom, Ingrid, Kockum, Salome, Kristensen, Helga, Kristjansdottir, Margit H, Larsen, Asta, Linauskas, Ellen-Margrethe, Hauge, Anne G, Loft, Bjorn R, Ludviksson, Sigrun H, Lund, Thorsteinn, Markusson, Gisli, Masson, Pall, Melsted, Kristjan H S, Moore, Heidi, Munk, Kaspar R, Nielsen, Gudmundur L, Norddahl, Asmundur, Oddsson, Thorunn A, Olafsdottir, Pall I, Olason, Tomas, Olsson, Sisse Rye, Ostrowski, Kim, Hørslev-Petersen, Solvi, Rognvaldsson, Helga, Sanner, Gilad N, Silberberg, Hreinn, Stefansson, Erik, Sørensen, Inge J, Sørensen, Carl, Turesson, Thomas, Bergman, Lars, Alfredsson, Tore K, Kvien, Søren, Brunak, Kristján, Steinsson, Vibeke, Andersen, Ole A, Andreassen, Solbritt, Rantapää-Dahlqvist, Merete Lund, Hetland, Lars, Klareskog, Johan, Askling, Leonid, Padyukov, Ole Bv, Pedersen, Unnur, Thorsteinsdottir, Ingileif, Jonsdottir, and Kari, Stefansson

Subjects
Proteomics, rheumatoid arthritis, autoantibodies, Janus Kinases/genetics, Immunology, polymorphism, genetic, General Biochemistry, Genetics and Molecular Biology, polymorphism, Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics, Arthritis, Rheumatoid, Rheumatology, genetic, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Medicinsk genetik, Rheumatology and Autoimmunity, Janus Kinases, Reumatologi och inflammation, Genetic Predisposition to Disease/genetics, Biochemistry and Molecular Biology, Interferon-alpha, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Arthritis, Rheumatoid/genetics, STAT Transcription Factors/genetics, STAT Transcription Factors, Signal Transduction/genetics, Medical Genetics, Biokemi och molekylärbiologi, Genome-Wide Association Study, Signal Transduction
Abstract

Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce. Funding Agencies|NORDFORSK [90825]; Swedish Research Council [2018-02803]; Swedish innovation Agency (Vinnova); Innovationsfonden; The Research Council of Norway; Region Stockholm-Karolinska Institutet; Region Vasterbotten (ALF); Danish Rheumatism Association [R194-A6956, A1923, A3037, A3570]; Swedish Brain Foundation; Nils and Bibbi Jensens Foundation; Knut and Alice Wallenberg Foundation; Margaretha af Ugglas Foundation; South-Eastern Heath Region of Norway; Health Research Fund of Central Denmark Region; Region of Southern Denmark; A.P. Moller Foundation for the Advancement of Medical Science; Colitis-Crohn Foreningen; Novo Nordisk Foundation [NNF15OC0016932]; Aase og Ejnar Danielsens Fond; Beckett-Fonden; Augustinus Fonden; Knud and Edith Eriksens Mindefond; Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis Legat; Psoriasis Forskningsfonden; University of Aarhus; Region of Southern Denmarks PhD Fund [12/7725]; Department of Rheumatology, Frederiksberg Hospital; Research Council of Norway [229624, 223273]; South East and Western Norway Health Authorities; ERC AdG project SELECTionPREDISPOSED; Stiftelsen Kristian Gerhard Jebsen; Trond Mohn Foundation; Novo Nordisk Foundation; University of Bergen

Published
2022

34. Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor

Author

Line Jee Hartmann Rasmussen, Henrik Ullum, Avshalom Caspi, Joseph Dowsett, Søren Brunak, Karina Banasik, Louise Arseneault, Mike Frigge, Kari Stefansson, Erik Sørensen, Karen Sugden, Gudmar Thorleifsson, Sigrun H. Lund, Daniel F. Gudbjartsson, Vinicius Tragante, Kristoffer Sølvsten Burgdorf, Terrie E. Moffitt, Christian Erikstrup, Richie Poulton, Sisse R. Ostrowski, Bjarni Gunnarson, Egil Ferkingstad, Hreinn Stefansson, Lise Wegner Thørner, Lilja Stefansdottir, Thomas Hansen, Magnus K. Magnusson, Jesper Eugen-Olsen, and Ole Birger Pedersen

Subjects
0301 basic medicine, Adult, Male, Multifactorial Inheritance, Adolescent, QH301-705.5, Medicine (miscellaneous), Inflammation, Genome-wide association study, Biology, Inflammatory diseases, Quantitative trait, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Receptors, Urokinase Plasminogen Activator, Cohort Studies, 03 medical and health sciences, Prognostic markers, 0302 clinical medicine, Quantitative Trait, Heritable, medicine, Humans, Biology (General), Receptor, Receptors, Urokinase Plasminogen Activator/blood, Urokinase, Chromosome Mapping, Urokinase receptor, C-Reactive Protein, 030104 developmental biology, SuPAR, Genetic marker, 030220 oncology & carcinogenesis, Inflammation Mediators/blood, Immunology, Genetic markers, Female, Inflammation Mediators, medicine.symptom, General Agricultural and Biological Sciences, C-Reactive Protein/genetics, Plasminogen activator, Biomarkers, Biomarkers/blood, medicine.drug, Genome-Wide Association Study
Abstract

Soluble urokinase-type plasminogen activator receptor (suPAR) is a chronic inflammation marker associated with the development of a range of diseases, including cancer and cardiovascular disease. The genetics of suPAR remain unexplored but may shed light on the biology of the marker and its connection to outcomes. We report a heritability estimate of 60% for the variation in suPAR and performed a genome-wide association meta-analysis on suPAR levels measured in Iceland (N = 35,559) and in Denmark (N = 12,177). We identified 13 independently genome-wide significant sequence variants associated with suPAR across 11 distinct loci. Associated variants were found in and around genes encoding uPAR (PLAUR), its ligand uPA (PLAU), the kidney-disease-associated gene PLA2R1 as well as genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response. These findings provide new insight into the causes of variation in suPAR plasma levels, which may clarify suPAR’s potential role in associated diseases, as well as the underlying mechanisms that give suPAR its prognostic value as a unique marker of chronic inflammation., Dowsett and colleagues used a genome-wide association approach to investigate the genetic influence on soluble urokinase-type plasminogen activator receptor presence in the plasma of humans. Their findings indicate a 60% heritability factor in British twins, and using a wide sample of Northern European genome samples they identify eleven genetic loci associated with an increase or decrease of this chronic inflammation marker.

Published
2021

35. Genetic insight into sick sinus syndrome

Author

Jon K. Sigurdsson, Gudmundur Thorgeirsson, Ingileif Jonsdottir, Søren Brunak, Mette Nyegaard, Bjarni Torfason, Henrik Ullum, Hildur M Aegisdottir, Gudmundur L. Norddahl, Stefan Jonsson, Hilma Holm, Lilja Stefansdottir, Christian Torp-Pedersen, Ben Michael Brumpton, Asmundur Oddsson, Daniel F. Gudbjartsson, Vinicius Tragante, Kristoffer Sølvsten Burgdorf, Kari Stefansson, Erna V. Ivarsdottir, Stefania Benonisdottir, Kristjan E. Hjorleifsson, Cristen J. Willer, Kristian Hveem, David O. Arnar, Gardar Sveinbjornsson, Sridharan Rajamani, Rosa B. Thorolfsdottir, Karina Banasik, Ole Birger Pedersen, Solveig Gretarsdottir, Atli S Valgardsson, David Westergaard, Erik Sørensen, Gudmar Thorleifsson, Peter Weeke, Unnur Thorsteinsdottir, Olafur B. Davidsson, Gisli H. Halldorsson, Michael L. Frigge, Anna Helgadottir, Wei Zhou, Patrick Sulem, Henning Bundgaard, and Kaspar René Nielsen

Subjects
Pacemaker, Artificial, KERATIN-8 MUTATIONS, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Electrocardiography, Sick Sinus Syndrome/genetics, 0302 clinical medicine, Atrial Fibrillation, SEQUENCE VARIANTS, Missense mutation, GWAS, AcademicSubjects/MED00200, Precision Medicine, Sick Sinus Syndrome, MYOSIN HEAVY-CHAIN, 0303 health sciences, Mendelian Randomization Analysis, RARE VARIANTS, Atrial Fibrillation/genetics, NODE DYSFUNCTION, Cardiology and Cardiovascular Medicine, Sick sinus syndrome, GANGLIONATED PLEXUS ABLATION, NAV1.8 Voltage-Gated Sodium Channel, 03 medical and health sciences, Clinical Research, Mendelian randomization, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, PULMONARY VEIN ISOLATION, Triglycerides, 030304 developmental biology, INTERMEDIATE-FILAMENTS, KRT8, business.industry, Keratin-8, Odds ratio, medicine.disease, Atrial fibrillation, Human genetics, SSS, Diabetes Mellitus, Type 2, ATRIAL-FIBRILLATION, business, Genome-Wide Association Study
Abstract

Aims The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10−20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS., Graphical Abstract Summary of genetic insight into the pathogenesis of SSS and the role of risk factors in its development. Variants at six loci (named by corresponding gene names) were identified through GWAS and their unique phenotypic associations provide insight into distinct pathways underlying SSS. Investigation of the role of risk factors in SSS development supported a causal role for AF and heart rate and provided convincing evidence against causality for BMI, cholesterol (HDL and non-HDL), triglycerides and T2D. Mendelian randomization did not support causality for CAD, ischaemic stroke, heart failure, PR interval or QRS duration (not shown in figure). Red and blue arrows represent positive and negative associations, respectively.

Published
2021

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

Author

Cindy G. Boer, Timothy Kwok, Kristbjorg Gunnarsdottir, Tuan V. Nguyen, Jenny S.W. Lee, Seung-Hun Lee, Stefania Benonisdottir, Helgi Jonsson, Gunnar Sigurdsson, Unnur Styrkarsdottir, Kristinn Juliusson, Gudmundur L. Norddahl, Lan T. Ho-Pham, Jung Min Koh, Inger Byrjalsen, Daniel F. Gudbjartsson, Lilja Stefansdottir, Claus Christiansen, Unnur Thorsteinsdottir, Jason Leung, Thorvaldur Ingvarsson, Brynjolfur Mogensen, Eleftheria Zeggini, Olafur A. Stefansson, John Loughlin, Gisli Masson, Kari Stefansson, Arnaldur Gylfason, Lorraine Southam, Arna B Agustsdottir, Rafn Benediktsson, Fernando Rivadeneira, Gisli H. Halldorsson, Suzanne C. Ho, Hilma Holm, Katerina Trajanoska, Hakon Jonsson, Sigrun H. Lund, Joyce B. J. van Meurs, Florian Zink, Kristjan Norland, Nelson L.S. Tang, L. Stefan Lohmander, Erna V. Ivarsdottir, Gudmar Thorleifsson, Ingileif Jonsdottir, P. C. Leung, André G. Uitterlinden, John A. Eisman, Jean Woo, Patrick Sulem, Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HA), School of Health Sciences (UA), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands, University of Iceland, Háskólinn á Akureyri, University of Akureyri, Heilbrigðisvísindastofnun (HA), and Research Centre for Health Science (UA)

Subjects
Male, 0301 basic medicine, Oncology, Bone density, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, Osteoarthritis, Collagen Type XI, Genome-wide association studies, Absorptiometry, Photon, Risk Factors, Bone Density, Growth Differentiation Factor 5, lcsh:Science, 10. No inequality, Aged, 80 and over, Bone mineral, Hip fracture, Multidisciplinary, Middle Aged, 021001 nanoscience & nanotechnology, Publisher Correction, Slitgigt, 3. Good health, Female, Erfðarannsóknir, 0210 nano-technology, Adult, musculoskeletal diseases, Beinin, medicine.medical_specialty, Science, Bone and Bones, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Gene expression analysis, Internal medicine, Genetics, medicine, Erfðafræði, Humans, Genetic Predisposition to Disease, Allele, Bone, Alleles, Aged, Hip Fractures, business.industry, Case-control study, General Chemistry, medicine.disease, Body Height, MicroRNAs, 030104 developmental biology, Genetic Loci, Case-Control Studies, Orthopedic surgery, lcsh:Q, Beinbrot, business, Fractures, Follow-Up Studies, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein)., Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10−42, β = −0.090) and confers risk of hip fracture (P = 1.0 × 10−8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density., We thank all the study subjects for their valuable participation, the staff from all studies and the participating physicians. A part of this research has been conducted using the UK Biobank Resource under Application Number 23359. arcOGEN (http://www.arcogen.org.uk/) was funded by a special purpose grant from Arthritis Research UK (grant 18030).

Published
2019

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

Author

Sigurjon A. Gudjonsson, Kari Stefansson, Gisli H. Halldorsson, Julius Gudmundsson, Gudmundur Geirsson, Thorunn Rafnar, Isleifur Olafsson, Thorvaldur Jonsson, Unnur Thorsteinsdottir, Olafur A. Stefansson, Eirikur Jonsson, Gudmundur I. Eyjolfsson, Bjarni A. Agnarsson, Daniel F. Gudbjartsson, Vinicius Tragante, Rosa B. Barkardottir, Rafn Hilmarsson, Gudmar Thorleifsson, Lilja Stefansdottir, Hilma Holm, Gisli Masson, Helgi J Isaksson, Folkert W. Asselbergs, Olof Sigurdardottir, Michael L. Frigge, Patrick Sulem, Simon N. Stacey, Jon K. Sigurdsson, Faculty of Medicine (UI), Læknadeild (HÍ), Biomedical Center (UI), Lífvísindasetur (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), and University of Iceland (UI)

Subjects
Male, 0301 basic medicine, Multifactorial Inheritance, Iceland, Prostatic Hyperplasia, General Physics and Astronomy, Genome-wide association study, urologic and male genital diseases, Histones, 0302 clinical medicine, Risk Factors, Non-U.S. Gov't, lcsh:Science, Cancer, Prostate cancer risk, Multidisciplinary, Research Support, Non-U.S. Gov't, Acetylation, Hyperplasia, humanities, 3. Good health, Prostate-specific antigen, Phenotype, 030220 oncology & carcinogenesis, medicine.medical_specialty, Science, Quantitative Trait Loci, Urology, Blöðruhálskirtilskrabbamein, Research Support, Genetic correlation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Lower Urinary Tract Symptoms, Meta-Analysis as Topic, Lower urinary tract symptoms, Genetics, Journal Article, medicine, Erfðafræði, Humans, Genetic Predisposition to Disease, Krabbamein, Aged, business.industry, Lysine, Computational Biology, Rannsóknir, General Chemistry, Prostate-Specific Antigen, medicine.disease, United Kingdom, 030104 developmental biology, Mutation, Polygenic risk score, lcsh:Q, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein) Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., 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., We thank the individuals that participated in the study and whose contribution made this work possible. This research has been conducted using the UK Biobank Resource under Application Number 24711. Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the cancer patients.

Published
2018

38. Germline variants at SOHLH2 influence multiple myeloma risk

Author

G. Bragi Walters, Niels Abildgaard, Caterina Cafaro, Gisli H. Halldorsson, Markus Hansson, Anders Waage, Ulf-Henrik Mellqvist, Richard S. Houlston, Kari Stefansson, Martin Kaiser, Gudmar Thorleifsson, Thorunn Rafnar, Annette Juul-Vangsted, Aitzkoa Lopez de Lapuente Portilla, Niels Weinhold, Laura Duran-Lozano, Abhishek Niroula, Malte Thodberg, Pall I. Olason, Molly Went, Björn Nilsson, Lilja Stefansdottir, Niels Frost Andersen, Unnur Thorsteinsdottir, Maroulio Pertesi, Ram Ajore, and Ingemar Turesson

Subjects
0301 basic medicine, Male, Linkage disequilibrium, medicine.medical_specialty, Cell type, Biology, Polymorphism, Single Nucleotide, Germline, Article, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Internal medicine, Genetics research, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Genetic Predisposition to Disease, Author Correction, Gene, Transcription factor, Multiple myeloma, RC254-282, Germ-Line Mutation, Aged, Genetics, Hematology, Disease genetics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Chromatin, 030104 developmental biology, Germ Cells, Oncology, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, Genome-Wide Association Study
Abstract

Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10−14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.

Published
2021

39. A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo

Author

Ingileif Jonsdottir, Saedis Saevarsdottir, Lincoln Nadauld, Kirk U. Knowlton, Dan Rujescu, Kristjan H. S. Moore, Patrick Sulem, Gudmar Thorleifsson, Annette M. Hartmann, Michael Strupp, Hannes Petersen, Astros Skuladottir, Pall I. Olafsson, Lilja Stefansdottir, Olafur A. Sveinsson, Muhammad Sulaman Nawaz, Joseph B. Muhlestein, Solvi Rognvaldsson, Kari Stefansson, David A. Jones, Hreinn Stefansson, G. Bragi Walters, Thorgeir E. Thorgeirsson, Erna V. Ivarsdottir, Bjarni Gunnarsson, Sigurður H. Magnusson, Daniel F. Gudbjartsson, Hilma Holm, Gyda Bjornsdottir, Gudrun R. Sigurdardottir, and Anna Bjornsdottir

Subjects
Genetics of the nervous system, Benign paroxysmal positional vertigo, Hearing loss, QH301-705.5, Labyrinth Diseases, Mutation, Missense, Medicine (miscellaneous), Disease, Bioinformatics, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Article, Vertigo, otorhinolaryngologic diseases, Medicine, Humans, Risk factor, TECTA, Biology (General), Transcriptomics, Vestibular system, biology, business.industry, Genome, Human, Rare variants, biology.organism_classification, medicine.disease, Ear, Inner, Etiology, Genetic markers, sense organs, medicine.symptom, General Agricultural and Biological Sciences, business, Genome-Wide Association Study
Abstract

Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease., Astros Skuladottir et al. conducted a genome-wide association study on 48,072 vertigo cases and 894,541 controls from four populations with European ancestries. They identified six common variants associated with vertigo, thereby providing further insight into the etiology of vestibular disorders.

Published
2021
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40. Genetic variants associated with platelet count are predictive of human disease and physiological markers

Author

Lilja Stefansdottir, Arni Jon Geirsson, Sigurdur Y. Kristinsson, Daniel F. Gudbjartsson, Vinicius Tragante, Brynjar Vidarsson, Gunnar B Ragnarsson, Anna Helgadottir, Solvi Rognvaldsson, Gudmundur Geirsson, Magnus K. Magnusson, Pall T. Onundarson, Gudmundur Thorgeirsson, Sigrun Reykdal, Kari Stefansson, Thorunn Rafnar, Isleifur Olafsson, Julius Gudmundsson, Evgenia Mikaelsdottir, Gerdur Grondal, Ingileif Jonsdottir, Hilma Holm, Kristjan Norland, Emil L. Sigurdsson, Saedis Saevarsdottir, Páll Melsted, Jon K. Sigurdsson, Olof Sigurdardottir, Gisli H. Halldorsson, Sigrun H. Lund, Unnur Thorsteinsdottir, Gudmar Thorleifsson, and Ingibjorg J. Gudmundsdottir

Subjects
Male, QH301-705.5, Quantitative Trait Loci, Medicine (miscellaneous), Genome-wide association study, Disease, Quantitative trait locus, Bioinformatics, Quantitative trait, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Article, medicine, Humans, Platelet, Biology (General), Ankylosing spondylitis, business.industry, Platelet Count, Genetic Variation, Hyperplasia, medicine.disease, Phenotype, Hemostasis, Rheumatoid arthritis, Female, Gene expression, General Agricultural and Biological Sciences, business, Biomarkers
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., Evgenia Mikaelsdottir et al. report a study of variants associated with platelet count among European individuals where they identify 577 associations. They also report a genetic overlap between platelet count and human diseases, including myeloproliferative neoplasms, rheumatoid arthritis, and hypertension, as well as a genetic overlap between platelet count and various physiological markers.

Published
2020

41. Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Author

Thordur Sigmundsson, Erik Sørensen, David B. Rye, Katja van den Hurk, Franke A. Quee, Poul Jennum, Muhammad Nawaz, Willem H. Ouwehand, Michael W.T. Tanck, Steven Bell, Sigurdur H. Magnusson, Hreinn Stefansson, Gudmar Thorleifsson, Nicole Soranzo, Prabhjyot Saini, Maria Didriksen, Joseph Dowsett, Emanuele Di Angelantonio, Lynn Marie Trotti, Henrik Ullum, Eric J. Earley, Alan E. Mast, Michael P. Busch, David J. Roberts, Christian Erikstrup, Kari Stefansson, Kristoffer Sølvsten Burgdorf, Albert P. Sigurdsson, Ole Birger Pedersen, John Danesh, Grier P. Page, Lilja Stefansdottir, Brendan Burchell, Adam S. Butterworth, Didriksen, Maria [0000-0002-4856-496X], Nawaz, Muhammad Sulaman [0000-0002-5576-9007], Dowsett, Joseph [0000-0001-5381-2633], Bell, Steven [0000-0001-6774-3149], Erikstrup, Christian [0000-0001-6551-6647], Pedersen, Ole B [0000-0003-2312-5976], Burchell, Brendan [0000-0002-8243-937X], Butterworth, Adam S [0000-0002-6915-9015], Tanck, Michael WT [0000-0001-9828-4459], Ouwehand, Willem H [0000-0002-7744-1790], Earley, Eric J [0000-0001-6576-1319], Busch, Michael P [0000-0002-1446-125X], Page, Grier P [0000-0003-2582-3786], Stefansson, Hreinn [0000-0002-9331-6666], Stefansson, Kari [0000-0003-1676-864X], Apollo - University of Cambridge Repository, Pedersen, Ole B. [0000-0003-2312-5976], Butterworth, Adam S. [0000-0002-6915-9015], Tanck, Michael W. T. [0000-0001-9828-4459], Ouwehand, Willem H. [0000-0002-7744-1790], Earley, Eric J. [0000-0001-6576-1319], Busch, Michael P. [0000-0002-1446-125X], Page, Grier P. [0000-0003-2582-3786], Epidemiology and Data Science, APH - Methodology, and Public and occupational health

Subjects
0301 basic medicine, Adult, medicine.medical_specialty, Linkage disequilibrium, QH301-705.5, 692/617/375/1816, 631/208/205/2138, Medicine (miscellaneous), Genome-wide association study, Disease, Bioinformatics, Genome-wide association studies, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Linkage Disequilibrium, 38, 38/43, 03 medical and health sciences, 0302 clinical medicine, Restless Legs Syndrome, Epidemiology, 38/23, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Restless legs syndrome, Biology (General), health care economics and organizations, Genetic association, Aged, business.industry, article, Sleep disorders, Middle Aged, medicine.disease, Obesity, 631/208/199, 030104 developmental biology, Meta-analysis, 38/39, Gene expression, General Agricultural and Biological Sciences, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Funder: Scottish Government; doi: https://doi.org/10.13039/100012095, Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.

Published
2020

42. Loss-of-Function Variants in the Tumor-Suppressor Gene

Author

Thorhildur, Olafsdottir, Simon N, Stacey, Gardar, Sveinbjornsson, Gudmar, Thorleifsson, Kristjan, Norland, Bardur, Sigurgeirsson, Kristin, Thorisdottir, Arni Kjalar, Kristjansson, Laufey, Tryggvadottir, Kavita Y, Sarin, Rafn, Benediktsson, Jon G, Jonasson, Asgeir, Sigurdsson, Aslaug, Jonasdottir, Snaedis, Kristmundsdottir, Hakon, Jonsson, Arnaldur, Gylfason, Asmundur, Oddsson, Run, Fridriksdottir, Sigurjon A, Gudjonsson, Florian, Zink, Sigrun H, Lund, Solvi, Rognvaldsson, Pall, Melsted, Valgerdur, Steinthorsdottir, Julius, Gudmundsson, Evgenia, Mikaelsdottir, Pall I, Olason, Lilja, Stefansdottir, Hannes P, Eggertsson, Bjarni V, Halldorsson, Unnur, Thorsteinsdottir, Tomas T, Agustsson, Karl, Olafsson, Jon H, Olafsson, Patrick, Sulem, Thorunn, Rafnar, Daniel F, Gudbjartsson, and Kari, Stefansson

Subjects
Male, Skin Neoplasms, Genotype, Whole Genome Sequencing, Age Factors, Iceland, Uterine Cervical Neoplasms, Penetrance, Tissue Banks, Protein Tyrosine Phosphatases, Non-Receptor, United Kingdom, Gene Frequency, Carcinoma, Basal Cell, Loss of Function Mutation, Case-Control Studies, Exome Sequencing, Odds Ratio, Humans, Female, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Genome-Wide Association Study
Abstract

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in

Published
2020

43. Species richness in North Atlantic fish: Process concealed by pattern

Author

Jón Sólmundsson, Didier Gascuel, Jónas P. Jonasson, Luis Gil de Sola, Jakov Dulčić, Jákup Reinert, Melita Peharda, Jan G. Hiddink, Heino O. Fock, Henrik Gislason, Mark R. Payne, Sanja Matić-Skoko, Lilja Stefansdottir, Nedo Vrgoč, F. Velasco, Corina Chaves, Cristina Silva, Remment ter Hofstede, Igor Isajlović, Andrey V. Dolgov, Hicham Masski, Gudrun Marteinsdottir, Maria de Fátima Borges, Anders Nielsen, Jeremy S. Collie, Teresa Bottari, Ole A Jørgensen, Kristján Kristinsson, Daniel E. Duplisea, Brian R. MacKenzie, DTU Aqua, National Institute of Aquatic Resources, Technical University of Denmark [Lyngby] (DTU), Graduate School of Oceanography [Narragansett], University of Rhode Island (URI), Instituto Português de Investigação do Mar e da Atmosfera (IPMA), Institute for Biological Resources and Marine Biotechnology (IRBIM), RUSSIAN FEDERAL RESEARCH INSTITUTE OF FISHERIES AND OCEANOGRAPHY MOSCOW RUS, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Institute of Oceanography, Fisheries, Maurice-Lamontagne Institute, Fisheries and Oceans Canada (DFO), Thünen-Institute of Sea Fisheries, Écologie et santé des écosystèmes (ESE), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Instituto Español de Oceanografía (IEO). Centro Costero de Málaga, Muelle Pesquero s/n. 29.640 Fuengirola (Málaga), Spain, School of Ocean Sciences [Menai Bridge], Bangor University, MARINE AND FRESHWATER RESEARCH INSTITUTE REYKJAVIK ISL, Institute of Life and Environmental Sciences, University of Iceland, INRH, Faroe Marine Research Institute, INSTITUTO ESPANOL DE OCEANOGRAFIA SANTANDER ESP, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
0106 biological sciences, Centro Oceanográfico de Santander, abundance, biodiversity, density, marine fish, species size, temperature, Biodiversity, 010603 evolutionary biology, 01 natural sciences, Latitude, Abundance (ecology), SDG 14 - Life Below Water, 14. Life underwater, Pesquerías, Ecology, Evolution, Behavior and Systematics, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Global and Planetary Change, Extinction, Ecology, 010604 marine biology & hydrobiology, Generalized additive model, [SDV.SA.STP]Life Sciences [q-bio]/Agricultural sciences/Sciences and technics of fishery, Environmental science, Species richness, Neutral theory of molecular evolution, Global biodiversity
Abstract

Aim: Previous analyses of marine fish species richness based on presence-absence data have shown changes with latitude and average species size, but little is known about the underlying processes. To elucidate these processes we use metabolic, neutral and descriptive statistical models to analyse how richness responds to maximum species length, fish abundance, temperature, primary production, depth, latitude and longitude, while accounting for differences in species catchability, sampling effort and mesh size. Data: Results from 53,382 bottom trawl hauls representing 50 fish assemblages. Location: The northern Atlantic from Nova Scotia to Guinea. Time period: 1977–2013. Methods: A descriptive generalized additive model was used to identify functional relationships between species richness and potential drivers, after which nonlinear estimation techniques were used to parameterize: (a) a ‘best’ fitting model of species richness built on the functional relationships, (b) an environmental model based on latitude, longitude and depth, and mechanistic models based on (c) metabolic and (d) neutral theory. Results: In the ‘best’ model the number of species observed is a lognormal function of maximum species length. It increases significantly with temperature, primary production, sampling effort, and abundance, and declines with depth and, for small species, with the mesh size in the trawl. The ‘best’ model explains close to 90% of the deviance and the neutral, metabolic and environmental models 89%. In all four models, maximum species length and either temperature or latitude account for more than half of the deviance explained. Main conclusions: The two mechanistic models explain the patterns in demersal fish species richness in the northern Atlantic almost equally well. A better understanding of the underlying drivers is likely to require development of dynamic mechanistic models of richness and size evolution, fit not only to extant distributions, but also to historical environmental conditions and to past speciation and extinction rates, Sí

Published
2020

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

Author

Hildigunnur Katrinardottir, Daniel F. Gudbjartsson, Vinicius Tragante, Jona Saemundsdottir, Aslaug Jonasdottir, Anna Helgadottir, Brynjar O. Jensson, Stefania Benonisdottir, Isleifur Olafsson, Pall T. Onundarson, Jon K. Sigurdsson, Olafur B. Davidsson, Thorunn Rafnar, Stefan Jonsson, Unnur Thorsteinsdottir, Bjarni Gunnarsson, Gisli H. Halldorsson, Reynir L. Gudmundsson, Lilja Stefansdottir, Adalbjorg Jonasdottir, Egil Ferkingstad, Amy L. Lee, Gudmar Thorleifsson, Gudjon R. Oskarsson, Erna V. Ivarsdottir, Anna M. Kristinsdottir, Magnus K. Magnusson, Asmundur Oddsson, Patrick Sulem, Gudmundur L. Norddahl, Kari Stefansson, Florian Zink, Ragnar P. Kristjansson, Gardar Sveinbjornsson, Hilma Holm, Folkert W. Asselbergs, Gudny A. Arnadottir, Gisli Masson, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
medicine.medical_specialty, Blóðrannsóknir, Regulator, Iceland, Medicine (miscellaneous), Locus (genetics), Pedigree chart, Biology, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Hemoglobins, 0302 clinical medicine, Loss of Function Mutation, Internal medicine, Databases, Genetic, Genetics research, medicine, Missense mutation, Humans, Erythropoiesis, Iron Regulatory Protein 1, Hemoglobin, Genome-wide, lcsh:QH301-705.5, ACO1, 030304 developmental biology, Genetic association, 0303 health sciences, Gen, Rare variants, United Kingdom, Endocrinology, lcsh:Biology (General), Gain of Function Mutation, General Agricultural and Biological Sciences, Erfðarannsóknir, 030217 neurology & neurosurgery, Homeostasis, Biomarkers, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser = −1.61 SD, CI95 = [−1.98, −1.35]; EffectLys334Ter = 0.63 SD, CI95 = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10−14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration., We thank the individuals who participated in this study and whose contributions made this work possible. We also thank our valued colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK Biobank Resource under application number 24711. F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre.

Published
2020

45. Front Cover

Author

Henrik Gislason, Jeremy Collie, Brian R. MacKenzie, Anders Nielsen, Maria de Fatima Borges, Teresa Bottari, Corina Chaves, Andrey V. Dolgov, Jakov Dulčić, Daniel Duplisea, Heino O. Fock, Didier Gascuel, Luís Gil de Sola, Jan Geert Hiddink, Remment Hofstede, Igor Isajlović, Jónas Páll Jonasson, Ole Jørgensen, Kristján Kristinsson, Gudrun Marteinsdottir, Hicham Masski, Sanja Matić‐Skoko, Mark R. Payne, Melita Peharda, Jakup Reinert, Jón Sólmundsson, Cristina Silva, Lilja Stefansdottir, Francisco Velasco, and Nedo Vrgoč

Subjects
Global and Planetary Change, Ecology, Ecology, Evolution, Behavior and Systematics
Published
2020

46. Genome-wide association identifies seven loci for pelvic organ prolapse in Iceland and the UK Biobank

Author

Gudmar Thorleifsson, Unnur Styrkarsdottir, Asgeir Sigurdsson, Daniel F. Gudbjartsson, Vinicius Tragante, Olafur A. Stefansson, Asmundur Oddsson, Kari Stefansson, Hilma Holm, Helga Medek, I. Jonsdottir, Michael L. Frigge, Orri Ingthorsson, Gisli H. Halldorsson, Hannes P. Eggertsson, Lilja Stefansdottir, Valgerdur Steinthorsdottir, Sigrun H. Lund, Julius Gudmundsson, Thorunn Rafnar, Unnur Thorsteinsdottir, Páll Melsted, Valur Gudmundsson, Jon K. Sigurdsson, Thorhildur Ólafsdóttir, Patrick Sulem, Kristín Jónsdóttir, Bjarni V. Halldorsson, Karl Olafsson, Ragnar P. Kristjansson, Folkert W. Asselbergs, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræðideild (HR), Department of Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Tæknisvið (HR), School of Technology (RU), Háskóli Íslands, University of Iceland, Háskólinn í Reykjavík, and Reykjavik University

Subjects
0301 basic medicine, genetic structures, Iceland, Uterus, Endometriosis, Medicine (miscellaneous), Genome-wide association study, Comorbidity, Genome-wide association studies, Body Mass Index, 0302 clinical medicine, Gene Frequency, Risk Factors, Uterine Prolapse, Wnt4 Protein, lcsh:QH301-705.5, Extracellular Matrix Proteins, Genome-wide association, 030219 obstetrics & reproductive medicine, 3. Good health, Phenotype, medicine.anatomical_structure, Leiomyoma, Female, Erfðarannsóknir, General Agricultural and Biological Sciences, psychological phenomena and processes, Reproductive signs and symptoms, medicine.medical_specialty, Connective tissue, Pathophysiology, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Risk Assessment, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Gynecology, Leg, urogenital system, business.industry, Grindargliðnun, medicine.disease, United Kingdom, Pelvic organ prolapse, body regions, Minor allele frequency, 030104 developmental biology, Genes, lcsh:Biology (General), Genetic Loci, Connective tissue metabolism, Case-Control Studies, Etiology, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P 5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP., This research has been conducted using the UK Biobank Resource under Application Number 24898 and 24711. We thank the individuals who participated in the study and whose contribution made this work possible. Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre.

Published
2020

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

Author

Dilbar Najmutdinova, Firuza Nishanova, Tatyana Hegay, John P. Kemp, Anna Helgadottir, Lucilla Poston, Saedis Saevarsdottir, Ralph McGinnis, Lilja Stefansdottir, Yr Frisbaek, Hrefna Johannsdottir, Olafur A. Stefansson, Thorunn A. Olafsdottir, Markus Perola, Scott Shooter, Frank Geller, Mads Melbye, Reynir Tómas Geirsson, Lill Trogstad, Thorhildur Juliusdottir, Kari Stefansson, Jonas Bybjerg-Grauholm, Eleonora Staines-Urias, Nodira Zakhidova, Daniel F. Gudbjartsson, Vinicius Tragante, João Fadista, Galina Berezina, Damilya Salimbayeva, Zosia Miedzybrodska, Katja Kivinen, James J. Walker, Kari Klungsøyr, Anna F. Dominiczak, Maria Carolina Borges, Fiona Broughton Pipkin, Nigel Simpson, Quaker E. Harmon, Per Magnus, Ashley Moffett, Tamara Aripova, Gordon Prescott, Sigrun Hjartardottir, Noor Kalsheker, Karina Meden Sørensen, Nicholas Williams, Hannele Laivuori, David M. Hougaard, Gulnara Svyatova, Debbie A Lawlor, Stephanie M. Engel, Gudmar Thorleifsson, Wai K. Lee, Paula J. Scaife, Christopher S. Franklin, Bjarke Feenstra, Irina Colgiu, Ann-Charlotte Iversen, Abdumadjit Kasimov, Jon K. Sigurdsson, Liv Cecilie Vestrheim Thomsen, Unnur Thorsteinsdottir, Line Skotte, Linda Morgan, Juan P Casas, Michael L. Frigge, Vivien A. Dolby, Frank Dudbridge, Valgerdur Steinthorsdottir, Suzannah Bumpstead, Kirsi M Auro, Ingileif Jonsdottir, Tiina Jääskeläinen, Heather A. Boyd, Solveig Gretarsdottir, Pregnancy and Genes, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki University Hospital Area, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, HUS Children and Adolescents, Lastentautien yksikkö, Clinicum, Children's Hospital, STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Tampere University, Department of Gynaecology and Obstetrics, Clinical Medicine, University of Helsinki, Research Programs Unit, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, HUS Gynecology and Obstetrics, University of Helsinki, HUS Children and Adolescents, University of Helsinki, STEMM - Stem Cells and Metabolism Research Program, Steinthorsdottir, Valgerdur [0000-0003-1846-6274], McGinnis, Ralph [0000-0003-4540-9857], Williams, Nicholas O [0000-0003-3989-9167], Berezina, Galina [0000-0002-5442-4461], Bybjerg-Grauholm, Jonas [0000-0003-1705-4008], Dudbridge, Frank [0000-0002-8817-8908], Franklin, Christopher S [0000-0003-3893-0759], Geller, Frank [0000-0002-9238-3269], Gudbjartsson, Daniel F [0000-0002-5222-9857], Hougaard, David Michael [0000-0001-5928-3517], Helgadottir, Anna [0000-0002-1806-2467], Jääskeläinen, Tiina [0000-0002-1202-0936], Jonsdottir, Ingileif [0000-0001-8339-150X], Kemp, John P [0000-0002-9105-2249], Kivinen, Katja [0000-0002-1135-7625], Melbye, Mads [0000-0001-8264-6785], Moffett, Ashley [0000-0002-8388-9073], Pipkin, Fiona Broughton [0000-0002-6209-5987], Prescott, Gordon [0000-0002-9156-2361], Saevarsdottir, Saedis [0000-0001-9392-6184], Skotte, Line [0000-0002-7398-1271], Stefansson, Olafur A [0000-0002-9663-3018], Simpson, Nigel AB [0000-0002-0758-7583], Dominiczak, Anna F [0000-0003-4913-3608], Walker, James J [0000-0002-8922-083X], Iversen, Ann-Charlotte [0000-0001-7726-7684], Feenstra, Bjarke [0000-0003-1478-649X], Lawlor, Deborah A [0000-0002-6793-2262], Boyd, Heather Allison [0000-0001-6849-9985], Laivuori, Hannele [0000-0003-3212-7826], Svyatova, Gulnara [0000-0001-5092-3143], Stefansson, Kari [0000-0003-1676-864X], Morgan, Linda [0000-0002-2995-4081], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Gestational hypertension, Multifactorial Inheritance, Reproductive disorders, A990, Datasets as Topic, General Physics and Astronomy, Blood Pressure, Genome-wide association study, VARIANTS, Genome-wide association studies, 0302 clinical medicine, Pre-Eclampsia, 3123 Gynaecology and paediatrics, Medicine, Prospective Studies, 030212 general & internal medicine, reproductive and urinary physiology, 2. Zero hunger, RISK, Multidisciplinary, biology, Obstetrics, Middle Aged, MEDICAL BIRTH REGISTRY, female genital diseases and pregnancy complications, 3. Good health, Europe, PREGNANCY, CARDIOVASCULAR-DISEASE, Hypertension, embryonic structures, Asia, Central, Female, Adult, medicine.medical_specialty, Fibroblast Growth Factor 5, Science, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Article, General Biochemistry, Genetics and Molecular Biology, Preeclampsia, 03 medical and health sciences, Fibroblast growth factor-5, Genetic predisposition, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, FETAL, METAANALYSIS, Adaptor Proteins, Signal Transducing, Aged, Pregnancy, business.industry, Case-control study, Hypertension, Pregnancy-Induced, General Chemistry, medicine.disease, MDS1 and EVI1 Complex Locus Protein, BODY-MASS INDEX, 030104 developmental biology, Genetic Loci, Case-Control Studies, COHORT PROFILE, biology.gene, business, Body mass index, Genome-Wide Association Study
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., Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020

48. Author Correction: Germline variants at SOHLH2 influence multiple myeloma risk

Author

Martin Kaiser, Maroulio Pertesi, Richard S. Houlston, Laura Duran-Lozano, Markus Hansson, Gisli H. Halldorsson, Anders Waage, Ulf-Henrik Mellqvist, Molly Went, Kari Stefansson, G. Bragi Walters, Annette Juul-Vangsted, Unnur Thorsteinsdottir, Björn Nilsson, Aitzkoa Lopez de Lapuente Portilla, Abhishek Niroula, Gudmar Thorleifsson, Niels Abildgaard, Ram Ajore, Ingemar Turesson, Lilja Stefansdottir, Niels Frost Andersen, Caterina Cafaro, Thorunn Rafnar, Pall I. Olason, Malte Thodberg, and Niels Weinhold

Subjects
Oncology, medicine.medical_specialty, business.industry, Published Erratum, MEDLINE, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hematology, medicine.disease, Germline, Internal medicine, medicine, business, Multiple myeloma, RC254-282
Published
2021

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

Author

Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott 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C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics

Subjects
0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract

Publisher's version (útgefin grein)., 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 (FROH) for >1.4 million individuals, we show that FROH 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: FROH 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 FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Published
2019

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

Author

Simon N. Stacey, Reynir Tómas Geirsson, Asgeir Thoroddsen, Gardar Sveinbjornsson, Gudny A. Arnadottir, Gisli Masson, Unnur Styrkarsdottir, Bjarni V. Halldorsson, Andres Ingason, Gudmar Thorleifsson, Anna Salvarsdottir, Patrick Sulem, Ragnheidur Arnadottir, Daniel F. Gudbjartsson, Vinicius Tragante, Jon G. Jonasson, Elisabet A. Helgadottir, Unnur Thorsteinsdottir, Karl Olafsson, Olafur B. Davidsson, Katrin Kristjansdottir, Michael L. Frigge, Ragnar P. Kristjansson, Thorunn Rafnar, Folkert W. Asselbergs, Valgerdur Steinthorsdottir, Florian Zink, Bjarni Gunnarsson, Gisli H. Halldorsson, Valur Gudmundsson, Lilja Stefansdottir, Jon K. Sigurdsson, Julius Gudmundsson, Olafur A. Stefansson, Orri Ingthorsson, Asmundur Oddsson, Kari Stefansson, Læknadeild (HÍ), Faculty of Medicine (UI), School of Science and Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Tækni- og verkfræðideild (HR), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskólinn í Reykjavík, Reykjavik University, Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, General Physics and Astronomy, Genome-wide association study, Identifies 2, Bioinformatics, Breast cancer, Brjóstakrabbamein, Genamengi, Beinþéttni, European Continental Ancestry Group/genetics, lcsh:Science, Non-U.S. Gov't, education.field_of_study, Multidisciplinary, Uterine leiomyoma, Leiomyoma, Research Support, Non-U.S. Gov't, Eitlar, musculoskeletal system, Leiomyoma/genetics, female genital diseases and pregnancy complications, 3. Good health, surgical procedures, operative, Uterine Neoplasms, Steinefni, Female, Science, Population, Endometriosis, Biology, Research Support, White People, Article, General Biochemistry, Genetics and Molecular Biology, Sequence variants, 03 medical and health sciences, Krabbameinsrannsóknir, medicine, Bone mineral density, Journal Article, Humans, Uterine Neoplasms/genetics, Hvítblæði, education, neoplasms, Genetic association, Krabbamein, Genome association, Risk loci, Telomere length, Case-control study, Cancer, General Chemistry, Epithelial ovarian cancer, medicine.disease, body regions, 030104 developmental biology, Eggjastokkar, Case-Control Studies, lcsh:Q, Chronic lymphocytic leukemia, Susceptibility loci, Endometriosis/genetics, Genome-Wide Association Study, Meta-Analysis
Abstract

We thank the individuals who participated in the study and whose contribution made this work possible. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the cancer patients. T.R., B.G., P.S., B.V.H., G.T, and K.S. designed the study and interpreted the results. A.S, A.T., E.A.H., K.K., O.I., V.G., R.T.G., R.A., J.G.J., and K.O. carried out the subject ascertainment, recruitment, and collection of clinical data. U.S., V.S., S.N.S., J.G., G.A.A., A.O., F.Z., G.H., R.P.K., O.B.D., G.M., V.T., F.W.A., and U.T. collected, processed, and analyzed the genotype and phenotype data. O.A.S. performed the functional annotations. A.I., M.L.F., L.S., J.K.S., G.S., D.F.G., B.G., and B.V.H., performed the statistical and bioinformatics analyses. T.R., B.G., O.A.S, G.T., and K.S., drafted the manuscript. All authors contributed to the final version of the paper., 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., This research has been conducted using the UK Biobank Resource under Application Number ‘24711’.

Published
2018

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