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1. Genetic links between ovarian ageing, cancer risk and de novo mutation rates.

Author

Stankovic, Stasa, Shekari, Saleh, Huang, Qin Qin, Gardner, Eugene J., Ivarsdottir, Erna V., Owens, Nick D. L., Mavaddat, Nasim, Azad, Ajuna, Hawkes, Gareth, Kentistou, Katherine A., Beaumont, Robin N., Day, Felix R., Zhao, Yajie, Jonsson, Hakon, Rafnar, Thorunn, Tragante, Vinicius, Sveinbjornsson, Gardar, Oddsson, Asmundur, Styrkarsdottir, Unnur, and Gudmundsson, Julius

Abstract

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing1. Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility1, with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan—that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk.Analyses focusing on protein-truncating variants from 106,973 women from in the UK Biobank identify variants in genes that reinforce the link between reproductive lifespan in women and cancer risk in both sexes. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Author Correction: Large-scale plasma proteomics comparisons through genetics and disease associations

Author

Eldjarn, Grimur Hjorleifsson, primary, Ferkingstad, Egil, additional, Lund, Sigrun H., additional, Helgason, Hannes, additional, Magnusson, Olafur Th., additional, Gunnarsdottir, Kristbjorg, additional, Olafsdottir, Thorunn A., additional, Halldorsson, Bjarni V., additional, Olason, Pall I., additional, Zink, Florian, additional, Gudjonsson, Sigurjon A., additional, Sveinbjornsson, Gardar, additional, Magnusson, Magnus I., additional, Helgason, Agnar, additional, Oddsson, Asmundur, additional, Halldorsson, Gisli H., additional, Magnusson, Magnus K., additional, Saevarsdottir, Saedis, additional, Eiriksdottir, Thjodbjorg, additional, Masson, Gisli, additional, Stefansson, Hreinn, additional, Jonsdottir, Ingileif, additional, Holm, Hilma, additional, Rafnar, Thorunn, additional, Melsted, Pall, additional, Saemundsdottir, Jona, additional, Norddahl, Gudmundur L., additional, Thorleifsson, Gudmar, additional, Ulfarsson, Magnus O., additional, Gudbjartsson, Daniel F., additional, Thorsteinsdottir, Unnur, additional, Sulem, Patrick, additional, and Stefansson, Kari, additional

Published
2024
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3. Large-scale plasma proteomics comparisons through genetics and disease associations

Author

Eldjarn, Grimur Hjorleifsson, primary, Ferkingstad, Egil, additional, Lund, Sigrun H., additional, Helgason, Hannes, additional, Magnusson, Olafur Th., additional, Gunnarsdottir, Kristbjorg, additional, Olafsdottir, Thorunn A., additional, Halldorsson, Bjarni V., additional, Olason, Pall I., additional, Zink, Florian, additional, Gudjonsson, Sigurjon A., additional, Sveinbjornsson, Gardar, additional, Magnusson, Magnus I., additional, Helgason, Agnar, additional, Oddsson, Asmundur, additional, Halldorsson, Gisli H., additional, Magnusson, Magnus K., additional, Saevarsdottir, Saedis, additional, Eiriksdottir, Thjodbjorg, additional, Masson, Gisli, additional, Stefansson, Hreinn, additional, Jonsdottir, Ingileif, additional, Holm, Hilma, additional, Rafnar, Thorunn, additional, Melsted, Pall, additional, Saemundsdottir, Jona, additional, Norddahl, Gudmundur L., additional, Thorleifsson, Gudmar, additional, Ulfarsson, Magnus O., additional, Gudbjartsson, Daniel F., additional, Thorsteinsdottir, Unnur, additional, Sulem, Patrick, additional, and Stefansson, Kari, additional

Published
2023
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4. Parental influence on human germline de novo mutations in 1,548 trios from Iceland

Author

Jónsson, Hákon, Sulem, Patrick, Kehr, Birte, Kristmundsdottir, Snaedis, Zink, Florian, Hjartarson, Eirikur, Hardarson, Marteinn T., Hjorleifsson, Kristjan E., Eggertsson, Hannes P., Gudjonsson, Sigurjon Axel, Ward, Lucas D., Arnadottir, Gudny A., Helgason, Einar A., Helgason, Hannes, Gylfason, Arnaldur, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Rafnar, Thorunn, Frigge, Mike, Stacey, Simon N., Th. Magnusson, Olafur, Thorsteinsdottir, Unnur, Masson, Gisli, Kong, Augustine, Halldorsson, Bjarni V., Helgason, Agnar, Gudbjartsson, Daniel F., and Stefansson, Kari

Published
2017
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5. The Sequences of 150,119 Genomes in the UK Biobank

Author

Halldorsson, Bjarni V, Eggertsson, Hannes P, Moore, Kristjan H S, Hauswedell, Hannes, Eiriksson, Ogmundur, Ulfarsson, Magnus O, Palsson, Gunnar, Hardarson, Marteinn T, Oddsson, Asmundur, Jensson, Brynjar O, Kristmundsdottir, Snaedis, Sigurpalsdottir, Brynja D, Stefansson, Olafur A, Beyter, Doruk, Holley, Guillaume, Tragante, Vinicius, Gylfason, Arnaldur, Olason, Pall I, Zink, Florian, Asgeirsdottir, Margret, Sverrisson, Sverrir T, Sigurdsson, Brynjar, Gudjonsson, Sigurjon A, Sigurdsson, Gunnar T, Halldorsson, Gisli H, Sveinbjornsson, Gardar, Norland, Kristjan, Styrkarsdottir, Unnur, Magnusdottir, Droplaug N, Snorradottir, Steinunn, Kristinsson, Kari, Sobech, Emilia, Jonsson, Helgi, Geirsson, Arni J, Olafsson, Isleifur, Jonsson, Palmi, Pedersen, Ole Birger, Erikstrup, Christian, Brunak, Søren, Ostrowski, Sisse Rye, Nielsen, Kaspar René, Thorleifsson, Gudmar, Jonsson, Frosti, Melsted, Pall, Jonsdottir, Ingileif, Rafnar, Thorunn, Holm, Hilma, Stefansson, Hreinn, Saemundsdottir, Jona, Gudbjartsson, Daniel F, Magnusson, Olafur T, Masson, Gisli, Thorsteinsdottir, Unnur, Helgason, Agnar, Jonsson, Hakon, Sulem, Patrick, Stefansson, Kari, and Nyegaard, Mette

Subjects
Asia/ethnology, Multidisciplinary, Whole Genome Sequencing, Haplotypes/genetics, Genetic Variation, Ireland/ethnology, Genomics, Polymorphism, Single Nucleotide/genetics, Genome-wide association studies, United Kingdom, Cohort Studies, INDEL Mutation, Africa/ethnology, Databases, Genetic, Exons/genetics, Genetics research, Genome, Human/genetics, Humans, Genetic markers, DNA sequencing, Genetic variation, Conserved Sequence, Biological Specimen Banks, Microsatellite Repeats
Abstract

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

Published
2022
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6. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits

Author

Styrkarsdottir, Unnur, Thorleifsson, Gudmar, Sulem, Patrick, Gudbjartsson, Daniel F., Sigurdsson, Asgeir, Jonasdottir, Aslaug, Jonasdottir, Adalbjorg, Oddsson, Asmundur, Helgason, Agnar, Magnusson, Olafur T., Walters, Bragi G., Frigge, Michael L., Helgadottir, Hafdis T., Johannsdottir, Hrefna, Bergsteinsdottir, Kristin, Ogmundsdottir, Margret H., Center, Jacqueline R., Nguyen, Tuan V., Eisman, John A., Christiansen, Claus, Steingrimsson, Erikur, Jonasson, Jon G., Tryggvadottir, Laufey, Eyjolfsson, Gudmundur I., Theodors, Asgeir, Jonsson, Thorvaldur, Ingvarsson, Thorvaldur, Olafsson, Isleifur, Rafnar, Thorunn, Kong, Augustine, Sigurdsson, Gunnar, Masson, Gisli, Thorsteinsdottir, Unnur, and Stefansson, Kari

Published
2013
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7. FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease

Author

Saevarsdottir, Saedis, primary, Olafsdottir, Thorunn A., additional, Ivarsdottir, Erna V., additional, Halldorsson, Gisli H., additional, Gunnarsdottir, Kristbjorg, additional, Sigurdsson, Asgeir, additional, Johannesson, Ari, additional, Sigurdsson, Jon K., additional, Juliusdottir, Thorhildur, additional, Lund, Sigrun H., additional, Arnthorsson, Asgeir O., additional, Styrmisdottir, Edda L., additional, Gudmundsson, Julius, additional, Grondal, Gerdur M., additional, Steinsson, Kristjan, additional, Alfredsson, Lars, additional, Askling, Johan, additional, Benediktsson, Rafn, additional, Bjarnason, Ragnar, additional, Geirsson, Arni J., additional, Gudbjornsson, Bjorn, additional, Gudjonsson, Hallgrimur, additional, Hjaltason, Haukur, additional, Hreidarsson, Astradur B., additional, Klareskog, Lars, additional, Kockum, Ingrid, additional, Kristjansdottir, Helga, additional, Love, Thorvardur J., additional, Ludviksson, Bjorn R., additional, Olsson, Tomas, additional, Onundarson, Pall T., additional, Orvar, Kjartan B., additional, Padyukov, Leonid, additional, Sigurgeirsson, Bardur, additional, Tragante, Vinicius, additional, Bjarnadottir, Kristbjorg, additional, Rafnar, Thorunn, additional, Masson, Gisli, additional, Sulem, Patrick, additional, Gudbjartsson, Daniel F., additional, Melsted, Pall, additional, Thorleifsson, Gudmar, additional, Norddahl, Gudmundur L., additional, Thorsteinsdottir, Unnur, additional, Jonsdottir, Ingileif, additional, and Stefansson, Kari, additional

Published
2020
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8. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease

Author

Thorgeirsson, Thorgeir E., Geller, Frank, Sulem, Patrick, Rafnar, Thorunn, Wiste, Anna, Magnusson, Kristinn P., Manolescu, Andrei, Thorleifsson, Gudmar, Stefansson, Hreinn, Ingason, Andres, Stacey, Simon N., Bergthorsson, Jon T., Thorlacius, Steinunn, Gudmundsson, Julius, Jonsson, Thorlakur, Jakobsdottir, Margret, Saemundsdottir, Jona, Olafsdottir, Olof, Gudmundsson, Larus J., Bjornsdottir, Gyda, Kristjansson, Kristleifur, Skuladottir, Halla, Isaksson, Helgi J., Gudbjartsson, Tomas, Jones, Gregory T., Mueller, Thomas, Gottsäter, Anders, Flex, Andrea, Aben, Katja K. H., de Vegt, Femmie, Mulders, Peter F. A., Isla, Dolores, Vidal, Maria J., Asin, Laura, Saez, Berta, Murillo, Laura, Blondal, Thorsteinn, Kolbeinsson, Halldor, Stefansson, Jon G., Hansdottir, Ingunn, Runarsdottir, Valgerdur, Pola, Roberto, Lindblad, Bengt, van Rij, Andre M., Dieplinger, Benjamin, Haltmayer, Meinhard, Mayordomo, Jose I., Kiemeney, Lambertus A., Matthiasson, Stefan E., Oskarsson, Hogni, Tyrfingsson, Thorarinn, Gudbjartsson, Daniel F., Gulcher, Jeffrey R., Jonsson, Steinn, Thorsteinsdottir, Unnur, Kong, Augustine, and Stefansson, Kari

Published
2008
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9. FLT3stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease

Author

Saevarsdottir, Saedis, Olafsdottir, Thorunn A., Ivarsdottir, Erna V., Halldorsson, Gisli H., Gunnarsdottir, Kristbjorg, Sigurdsson, Asgeir, Johannesson, Ari, Sigurdsson, Jon K., Juliusdottir, Thorhildur, Lund, Sigrun H., Arnthorsson, Asgeir O., Styrmisdottir, Edda L., Gudmundsson, Julius, Grondal, Gerdur M., Steinsson, Kristjan, Alfredsson, Lars, Askling, Johan, Benediktsson, Rafn, Bjarnason, Ragnar, Geirsson, Arni J., Gudbjornsson, Bjorn, Gudjonsson, Hallgrimur, Hjaltason, Haukur, Hreidarsson, Astradur B., Klareskog, Lars, Kockum, Ingrid, Kristjansdottir, Helga, Love, Thorvardur J., Ludviksson, Bjorn R., Olsson, Tomas, Onundarson, Pall T., Orvar, Kjartan B., Padyukov, Leonid, Sigurgeirsson, Bardur, Tragante, Vinicius, Bjarnadottir, Kristbjorg, Rafnar, Thorunn, Masson, Gisli, Sulem, Patrick, Gudbjartsson, Daniel F., Melsted, Pall, Thorleifsson, Gudmar, Norddahl, Gudmundur L., Thorsteinsdottir, Unnur, Jonsdottir, Ingileif, and Stefansson, Kari

Abstract

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2–7. A low-frequency (1.36%) intronic variant in FLT3(rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P= 2.37 × 10−24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P= 6.46 × 10−4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P= 4.31 × 10−4) and coeliac disease (OR = 1.62, P= 1.20 × 10−4). FLT3encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3are associated with acute myeloid leukaemia8with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P= 5.40 × 10−3). Thus, a predicted loss-of-function germline mutation in FLT3causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.

Published
2020
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