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44 results on '"Holm, Hilma"'

1. Homozygosity for a stop-gain variant in CCDC201causes primary ovarian insufficiency

Author: Oddsson, Asmundur, Steinthorsdottir, Valgerdur, Oskarsson, Gudjon R., Styrkarsdottir, Unnur, Moore, Kristjan H. S., Isberg, Salvor, Halldorsson, Gisli H., Sveinbjornsson, Gardar, Westergaard, David, Nielsen, Henriette Svarre, Fridriksdottir, Run, Jensson, Brynjar O., Arnadottir, Gudny A., Jonsson, Hakon, Sturluson, Arni, Snaebjarnarson, Audunn S., Andreassen, Ole A., Walters, G. Bragi, Nyegaard, Mette, Erikstrup, Christian, Steingrimsdottir, Thora, Lie, Rolv T., Melsted, Pall, Jonsdottir, Ingileif, Halldorsson, Bjarni V., Thorleifsson, Gudmar, Saemundsdottir, Jona, Magnusson, Olafur Th., Banasik, Karina, Sorensen, Erik, Masson, Gisli, Pedersen, Ole Birger, Tryggvadottir, Laufey, Haavik, Jan, Ostrowski, Sisse Rye, Stefansson, Hreinn, Holm, Hilma, Rafnar, Thorunn, Gudbjartsson, Daniel F., Sulem, Patrick, and Stefansson, Kari
Abstract: Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434(A) in CCDC201(p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P= 1.3 × 10−15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P= 3.8 × 10−5). The CCDC201gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause.
Published: 2024
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2. The correlation between CpG methylation and gene expression is driven by sequence variants

Author: Stefansson, Olafur Andri, Sigurpalsdottir, Brynja Dogg, Rognvaldsson, Solvi, Halldorsson, Gisli Hreinn, Juliusson, Kristinn, Sveinbjornsson, Gardar, Gunnarsson, Bjarni, Beyter, Doruk, Jonsson, Hakon, Gudjonsson, Sigurjon Axel, Olafsdottir, Thorunn Asta, Saevarsdottir, Saedis, Magnusson, Magnus Karl, Lund, Sigrun Helga, Tragante, Vinicius, Oddsson, Asmundur, Hardarson, Marteinn Thor, Eggertsson, Hannes Petur, Gudmundsson, Reynir L., Sverrisson, Sverrir, Frigge, Michael L., Zink, Florian, Holm, Hilma, Stefansson, Hreinn, Rafnar, Thorunn, Jonsdottir, Ingileif, Sulem, Patrick, Helgason, Agnar, Gudbjartsson, Daniel F., Halldorsson, Bjarni V., Thorsteinsdottir, Unnur, and Stefansson, Kari
Abstract: Gene promoter and enhancer sequences are bound by transcription factors and are depleted of methylated CpG sites (cytosines preceding guanines in DNA). The absence of methylated CpGs in these sequences typically correlates with increased gene expression, indicating a regulatory role for methylation. We used nanopore sequencing to determine haplotype-specific methylation rates of 15.3 million CpG units in 7,179 whole-blood genomes. We identified 189,178 methylation depleted sequences where three or more proximal CpGs were unmethylated on at least one haplotype. A total of 77,789 methylation depleted sequences (~41%) associated with 80,503 cis-acting sequence variants, which we termed allele-specific methylation quantitative trait loci (ASM-QTLs). RNA sequencing of 896 samples from the same blood draws used to perform nanopore sequencing showed that the ASM-QTL, that is, DNA sequence variability, drives most of the correlation found between gene expression and CpG methylation. ASM-QTLs were enriched 40.2-fold (95% confidence interval 32.2, 49.9) among sequence variants associating with hematological traits, demonstrating that ASM-QTLs are important functional units in the noncoding genome.
Published: 2024
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3. Obesity Variants in the GIPRGene Are not Associated With Risk of Fracture or Bone Mineral Density

Author: Styrkarsdottir, Unnur, Tragante, Vinicius, Stefansdottir, Lilja, Thorleifsson, Gudmar, Oddsson, Asmundur, Sørensen, Erik, Erikstrup, Christian, Schwarz, Peter, Jørgensen, Henrik Løvendahl, Lauritzen, Jes Bruun, Brunak, Søren, Knowlton, Kirk U, Nadauld, Lincoln D, Ullum, Henrik, Pedersen, Ole Birger Vesterager, Ostrowski, Sisse Rye, Holm, Hilma, Gudbjartsson, Daniel F, Sulem, Patrick, and Stefansson, Kari
Published: 2024
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4. Polygenic risk scores associate with blood pressure traits across the lifespan

Author: Øvretveit, Karsten, Ingeström, Emma M L, Spitieris, Michail, Tragante, Vinicius, Wade, Kaitlin H, Thomas, Laurent F, Wolford, Brooke N, Wisløff, Ulrik, Gudbjartsson, Daniel F, Holm, Hilma, Stefansson, Kari, Brumpton, Ben M, and Hveem, Kristian
Abstract: A high genetic risk of elevated blood pressure (BP) is associated with increased BP from early childhood and throughout the lifespan.Inherited predispositions also affect the risk of cardiovascular morbidity and mortality, yet this appears to be modified by the absence or presence of hypertension, indicating that genetic hypertension risk is not deterministic, and that controlling BP can and should be done across the polygenic risk distribution.Given that differences in BP emerge early in life as a function of genetic risk, polygenic risk scores have the potential to reduce the duration of exposure to high BP by identifying high-risk individuals from birth, and thereby attenuate lifelong disease risk.Graphical Abstract
Published: 2024
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5. Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination

Author: Steinthorsdottir, Valgerdur, Halldorsson, Bjarni V., Jonsson, Hakon, Palsson, Gunnar, Oddsson, Asmundur, Westergaard, David, Arnadottir, Gudny A., Stefansdottir, Lilja, Banasik, Karina, Esplin, M. Sean, Hansen, Thomas Folkmann, Brunak, Søren, Nyegaard, Mette, Ostrowski, Sisse Rye, Pedersen, Ole Birger Vesterager, Erikstrup, Christian, Thorleifsson, Gudmar, Nadauld, Lincoln D., Haraldsson, Asgeir, Steingrimsdottir, Thora, Tryggvadottir, Laufey, Jonsdottir, Ingileif, Gudbjartsson, Daniel F., Hoffmann, Eva R., Sulem, Patrick, Holm, Hilma, Nielsen, Henriette Svarre, and Stefansson, Kari
Abstract: Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.
Published: 2024
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6. Variants at the Interleukin 1 Gene Locus and Pericarditis

Author: Thorolfsdottir, Rosa B., Jonsdottir, Andrea B., Sveinbjornsson, Gardar, Aegisdottir, Hildur M., Oddsson, Asmundur, Stefansson, Olafur A., Halldorsson, Gisli H., Saevarsdottir, Saedis, Thorleifsson, Gudmar, Stefansdottir, Lilja, Pedersen, Ole B., Sørensen, Erik, Ghouse, Jonas, Raja, Anna Axelsson, Zheng, Chaoqun, Silajdzija, Elvira, Rand, Søren Albertsen, Erikstrup, Christian, Ullum, Henrik, Mikkelsen, Christina, Banasik, Karina, Brunak, Søren, Ivarsdottir, Erna V., Sigurdsson, Asgeir, Beyter, Doruk, Sturluson, Arni, Einarsson, Hafsteinn, Tragante, Vinicius, Helgason, Hannes, Lund, Sigrun H., Halldorsson, Bjarni V., Sigurpalsdottir, Brynja D., Olafsson, Isleifur, Arnar, David O., Thorgeirsson, Gudmundur, Knowlton, Kirk U., Nadauld, Lincoln D., Gretarsdottir, Solveig, Helgadottir, Anna, Ostrowski, Sisse R., Gudbjartssson, Daniel F., Jonsdottir, Ingileif, Bundgaard, Henning, Holm, Hilma, Sulem, Patrick, and Stefansson, Kari
Abstract: IMPORTANCE: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood. OBJECTIVE: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis. DESIGN, SETTING, AND PARTICIPANTS: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023. EXPOSURE: Genotype. MAIN OUTCOMES AND MEASURES: Pericarditis. RESULTS: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10−16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10−8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein β (encoded by CEBPB). CONCLUSIONS AND RELEVANCE: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1–blocking drugs.
Published: 2024
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7. Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis

Author: Ghouse, Jonas, Sveinbjörnsson, Gardar, Vujkovic, Marijana, Seidelin, Anne-Sofie, Gellert-Kristensen, Helene, Ahlberg, Gustav, Tragante, Vinicius, Rand, Søren A., Brancale, Joseph, Vilarinho, Silvia, Lundegaard, Pia Rengtved, Sørensen, Erik, Erikstrup, Christian, Bruun, Mie Topholm, Jensen, Bitten Aagaard, Brunak, Søren, Banasik, Karina, Ullum, Henrik, Verweij, Niek, Lotta, Luca, Baras, Aris, Mirshahi, Tooraj, Carey, David J., Kaplan, David E., Lynch, Julie, Morgan, Timothy, Schwantes-An, Tae-Hwi, Dochtermann, Daniel R., Pyarajan, Saiju, Tsao, Philip S., Laisk, Triin, Mägi, Reedik, Kozlitina, Julia, Tybjærg-Hansen, Anne, Jones, David, Knowlton, Kirk U., Nadauld, Lincoln, Ferkingstad, Egil, Björnsson, Einar S., Ulfarsson, Magnus O., Sturluson, Árni, Sulem, Patrick, Pedersen, Ole B., Ostrowski, Sisse R., Gudbjartsson, Daniel F., Stefansson, Kari, Olesen, Morten Salling, Chang, Kyong-Mi, Holm, Hilma, Bundgaard, Henning, and Stender, Stefan
Abstract: We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAMassociate with lower ALT, supporting GPAMas a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.
Published: 2024
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8. Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis

Author: Stacey, Simon N., Zink, Florian, Halldorsson, Gisli H., Stefansdottir, Lilja, Gudjonsson, Sigurjon A., Einarsson, Gudmundur, Hjörleifsson, Grimur, Eiriksdottir, Thjodbjorg, Helgadottir, Anna, Björnsdottir, Gyda, Thorgeirsson, Thorgeir E., Olafsdottir, Thorunn A., Jonsdottir, Ingileif, Gretarsdottir, Solveig, Tragante, Vinicius, Magnusson, Magnus K., Jonsson, Hakon, Gudmundsson, Julius, Olafsson, Sigurgeir, Holm, Hilma, Gudbjartsson, Daniel F., Sulem, Patrick, Helgason, Agnar, Thorsteinsdottir, Unnur, Tryggvadottir, Laufey, Rafnar, Thorunn, Melsted, Pall, Ulfarsson, Magnus Ö., Vidarsson, Brynjar, Thorleifsson, Gudmar, and Stefansson, Kari
Abstract: Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164and TCL1A.
Published: 2023
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9. Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target

Author: Roychowdhury, Tanmoy, Klarin, Derek, Levin, Michael G., Spin, Joshua M., Rhee, Yae Hyun, Deng, Alicia, Headley, Colwyn A., Tsao, Noah L., Gellatly, Corry, Zuber, Verena, Shen, Fred, Hornsby, Whitney E., Laursen, Ina Holst, Verma, Shefali S., Locke, Adam E., Einarsson, Gudmundur, Thorleifsson, Gudmar, Graham, Sarah E., Dikilitas, Ozan, Pattee, Jack W., Judy, Renae L., Pauls-Verges, Ferran, Nielsen, Jonas B., Wolford, Brooke N., Brumpton, Ben M., Dilmé, Jaume, Peypoch, Olga, Juscafresa, Laura Calsina, Edwards, Todd L., Li, Dadong, Banasik, Karina, Brunak, Søren, Jacobsen, Rikke L., Garcia-Barrio, Minerva T., Zhang, Jifeng, Rasmussen, Lars M., Lee, Regent, Handa, Ashok, Wanhainen, Anders, Mani, Kevin, Lindholt, Jes S., Obel, Lasse M., Strauss, Ewa, Oszkinis, Grzegorz, Nelson, Christopher P., Saxby, Katie L., van Herwaarden, Joost A., van der Laan, Sander W., van Setten, Jessica, Camacho, Mercedes, Davis, Frank M., Wasikowski, Rachael, Tsoi, Lam C., Gudjonsson, Johann E., Eliason, Jonathan L., Coleman, Dawn M., Henke, Peter K., Ganesh, Santhi K., Chen, Y. Eugene, Guan, Weihua, Pankow, James S., Pankratz, Nathan, Pedersen, Ole B., Erikstrup, Christian, Tang, Weihong, Hveem, Kristian, Gudbjartsson, Daniel, Gretarsdottir, Solveig, Thorsteinsdottir, Unnur, Holm, Hilma, Stefansson, Kari, Ferreira, Manuel A., Baras, Aris, Kullo, Iftikhar J., Ritchie, Marylyn D., Christensen, Alex H., Iversen, Kasper K., Eldrup, Nikolaj, Sillesen, Henrik, Ostrowski, Sisse R., Bundgaard, Henning, Ullum, Henrik, Burgess, Stephen, Gill, Dipender, Gallagher, Katherine, Sabater-Lleal, Maria, Surakka, Ida, Jones, Gregory T., Bown, Matthew J., Tsao, Philip S., Willer, Cristen J., and Damrauer, Scott M.
Abstract: Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9loss of function prevented the development of AAA in a preclinical mouse model.
Published: 2023
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10. Large-scale plasma proteomics comparisons through genetics and disease associations

Author: Eldjarn, Grimur Hjorleifsson, Ferkingstad, Egil, Lund, Sigrun H., Helgason, Hannes, Magnusson, Olafur Th., Gunnarsdottir, Kristbjorg, Olafsdottir, Thorunn A., Halldorsson, Bjarni V., Olason, Pall I., Zink, Florian, Gudjonsson, Sigurjon A., Sveinbjornsson, Gardar, Magnusson, Magnus I., Helgason, Agnar, Oddsson, Asmundur, Halldorsson, Gisli H., Magnusson, Magnus K., Saevarsdottir, Saedis, Eiriksdottir, Thjodbjorg, Masson, Gisli, Stefansson, Hreinn, Jonsdottir, Ingileif, Holm, Hilma, Rafnar, Thorunn, Melsted, Pall, Saemundsdottir, Jona, Norddahl, Gudmundur L., Thorleifsson, Gudmar, Ulfarsson, Magnus O., Gudbjartsson, Daniel F., Thorsteinsdottir, Unnur, Sulem, Patrick, and Stefansson, Kari
Abstract: High-throughput proteomics platforms measuring thousands of proteins in plasma combined with genomic and phenotypic information have the power to bridge the gap between the genome and diseases. Here we performed association studies of Olink Explore 3072 data generated by the UK Biobank Pharma Proteomics Project1on plasma samples from more than 50,000 UK Biobank participants with phenotypic and genotypic data, stratifying on British or Irish, African and South Asian ancestries. We compared the results with those of a SomaScan v4 study on plasma from 36,000 Icelandic people2, for 1,514 of whom Olink data were also available. We found modest correlation between the two platforms. Although cisprotein quantitative trait loci were detected for a similar absolute number of assays on the two platforms (2,101 on Olink versus 2,120 on SomaScan), the proportion of assays with such supporting evidence for assay performance was higher on the Olink platform (72% versus 43%). A considerable number of proteins had genomic associations that differed between the platforms. We provide examples where differences between platforms may influence conclusions drawn from the integration of protein levels with the study of diseases. We demonstrate how leveraging the diverse ancestries of participants in the UK Biobank helps to detect novel associations and refine genomic location. Our results show the value of the information provided by the two most commonly used high-throughput proteomics platforms and demonstrate the differences between them that at times provides useful complementarity.
Published: 2023
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11. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Author: Bjornsdottir, Gyda, Chalmer, Mona A., Stefansdottir, Lilja, Skuladottir, Astros Th., Einarsson, Gudmundur, Andresdottir, Margret, Beyter, Doruk, Ferkingstad, Egil, Gretarsdottir, Solveig, Halldorsson, Bjarni V., Halldorsson, Gisli H., Helgadottir, Anna, Helgason, Hannes, Hjorleifsson Eldjarn, Grimur, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Jonsdottir, Ingileif, Knowlton, Kirk U., Nadauld, Lincoln D., Lund, Sigrun H., Magnusson, Olafur Th., Melsted, Pall, Moore, Kristjan H. S., Oddsson, Asmundur, Olason, Pall I., Sigurdsson, Asgeir, Stefansson, Olafur A., Saemundsdottir, Jona, Sveinbjornsson, Gardar, Tragante, Vinicius, Unnsteinsdottir, Unnur, Walters, G. Bragi, Zink, Florian, Rødevand, Linn, Andreassen, Ole A., Igland, Jannicke, Lie, Rolv T., Haavik, Jan, Banasik, Karina, Brunak, Søren, Didriksen, Maria, T. Bruun, Mie, Erikstrup, Christian, Kogelman, Lisette J. A., Nielsen, Kaspar R., Sørensen, Erik, Pedersen, Ole B., Ullum, Henrik, Masson, Gisli, Thorsteinsdottir, Unnur, Olesen, Jes, Ludvigsson, Petur, Thorarensen, Olafur, Bjornsdottir, Anna, Sigurdardottir, Gudrun R., Sveinsson, Olafur A., Ostrowski, Sisse R., Holm, Hilma, Gudbjartsson, Daniel F., Thorleifsson, Gudmar, Sulem, Patrick, Stefansson, Hreinn, Thorgeirsson, Thorgeir E., Hansen, Thomas F., and Stefansson, Kari
Abstract: Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABOand LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.
Published: 2023
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12. Genome-wide meta-analysis identifies 93 risk loci and enables risk prediction equivalent to monogenic forms of venous thromboembolism

Author: Ghouse, Jonas, Tragante, Vinicius, Ahlberg, Gustav, Rand, Søren A., Jespersen, Jakob B., Leinøe, Eva Birgitte, Vissing, Christoffer Rasmus, Trudsø, Linea, Jonsdottir, Ingileif, Banasik, Karina, Brunak, Søren, Ostrowski, Sisse R., Pedersen, Ole B., Sørensen, Erik, Erikstrup, Christian, Bruun, Mie Topholm, Nielsen, Kaspar Rene, Køber, Lars, Christensen, Alex H., Iversen, Kasper, Jones, David, Knowlton, Kirk U., Nadauld, Lincoln, Halldorsson, Gisli H., Ferkingstad, Egil, Olafsson, Isleifur, Gretarsdottir, Solveig, Onundarson, Pall T., Sulem, Patrick, Thorsteinsdottir, Unnur, Thorgeirsson, Gudmundur, Gudbjartsson, Daniel F., Stefansson, Kari, Holm, Hilma, Olesen, Morten Salling, and Bundgaard, Henning
Abstract: We report a genome-wide association study of venous thromboembolism (VTE) incorporating 81,190 cases and 1,419,671 controls sampled from six cohorts. We identify 93 risk loci, of which 62 are previously unreported. Many of the identified risk loci are at genes encoding proteins with functions converging on the coagulation cascade or platelet function. A VTE polygenic risk score (PRS) enabled effective identification of both high- and low-risk individuals. Individuals within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of the variants G20210A (c.*97 G > A) in F2and p.R534Q in F5. We also document that F2and F5mutation carriers in the bottom 10% of the PRS distribution had a risk similar to that of the general population. We further show that PRS improved individual risk prediction beyond that of genetic and clinical risk factors. We investigated the extent to which venous and arterial thrombosis share clinical risk factors using Mendelian randomization, finding that some risk factors for arterial thrombosis were directionally concordant with VTE risk (for example, body mass index and smoking) whereas others were discordant (for example, systolic blood pressure and triglyceride levels).
Published: 2023
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13. Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles: a Mendelian randomization analysis

Author: Helgadottir, Anna, Thorleifsson, Gudmar, Snaebjarnarson, Audunn, Stefansdottir, Lilja, Sveinbjornsson, Gardar, Tragante, Vinicius, Björnsson, Eyþór, Steinthorsdottir, Valgerdur, Gretarsdottir, Solveig, Helgason, Hannes, Saemundsdottir, Jona, Olafsson, Isleifur, Thune, Jens Jakob, Raja, Anna Axelsson, Ghouse, Jonas, Olesen, Morten Salling, Christensen, Alex, Jacobsen, Rikke Louise, Dowsett, Joseph, Bruun, Mie Topholm, Nielsen, Kaspar, Knowlton, Kirk, Nadauld, Lincoln, Benediktsson, Rafn, Erikstrup, Christian, Pedersen, Ole B, Banasik, Karina, Brunak, Søren, Bundgaard, Henning, Ostrowski, Sisse R, Sulem, Patrick, Arnar, David O, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F, Stefansson, Kari, and Holm, Hilma
Abstract: Graphical Abstract
Published: 2022
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14. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

Author: Aragam, Krishna G., Jiang, Tao, Goel, Anuj, Kanoni, Stavroula, Wolford, Brooke N., Atri, Deepak S., Weeks, Elle M., Wang, Minxian, Hindy, George, Zhou, Wei, Grace, Christopher, Roselli, Carolina, Marston, Nicholas A., Kamanu, Frederick K., Surakka, Ida, Venegas, Loreto Muñoz, Sherliker, Paul, Koyama, Satoshi, Ishigaki, Kazuyoshi, Åsvold, Bjørn O., Brown, Michael R., Brumpton, Ben, de Vries, Paul S., Giannakopoulou, Olga, Giardoglou, Panagiota, Gudbjartsson, Daniel F., Güldener, Ulrich, Haider, Syed M. Ijlal, Helgadottir, Anna, Ibrahim, Maysson, Kastrati, Adnan, Kessler, Thorsten, Kyriakou, Theodosios, Konopka, Tomasz, Li, Ling, Ma, Lijiang, Meitinger, Thomas, Mucha, Sören, Munz, Matthias, Murgia, Federico, Nielsen, Jonas B., Nöthen, Markus M., Pang, Shichao, Reinberger, Tobias, Schnitzler, Gavin, Smedley, Damian, Thorleifsson, Gudmar, von Scheidt, Moritz, Ulirsch, Jacob C., Arnar, David O., Burtt, Noël P., Costanzo, Maria C., Flannick, Jason, Ito, Kaoru, Jang, Dong-Keun, Kamatani, Yoichiro, Khera, Amit V., Komuro, Issei, Kullo, Iftikhar J., Lotta, Luca A., Nelson, Christopher P., Roberts, Robert, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Webb, Thomas R., Baras, Aris, Björkegren, Johan L. M., Boerwinkle, Eric, Dedoussis, George, Holm, Hilma, Hveem, Kristian, Melander, Olle, Morrison, Alanna C., Orho-Melander, Marju, Rallidis, Loukianos S., Ruusalepp, Arno, Sabatine, Marc S., Stefansson, Kari, Zalloua, Pierre, Ellinor, Patrick T., Farrall, Martin, Danesh, John, Ruff, Christian T., Finucane, Hilary K., Hopewell, Jemma C., Clarke, Robert, Gupta, Rajat M., Erdmann, Jeanette, Samani, Nilesh J., Schunkert, Heribert, Watkins, Hugh, Willer, Cristen J., Deloukas, Panos, Kathiresan, Sekar, and Butterworth, Adam S.
Abstract: The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR–Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.
Published: 2022
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15. Multiomics study of nonalcoholic fatty liver disease

Author: Sveinbjornsson, Gardar, Ulfarsson, Magnus O., Thorolfsdottir, Rosa B., Jonsson, Benedikt A., Einarsson, Eythor, Gunnlaugsson, Gylfi, Rognvaldsson, Solvi, Arnar, David O., Baldvinsson, Magnus, Bjarnason, Ragnar G., Eiriksdottir, Thjodbjorg, Erikstrup, Christian, Ferkingstad, Egil, Halldorsson, Gisli H., Helgason, Hannes, Helgadottir, Anna, Hindhede, Lotte, Hjorleifsson, Grimur, Jones, David, Knowlton, Kirk U., Lund, Sigrun H., Melsted, Pall, Norland, Kristjan, Olafsson, Isleifur, Olafsson, Sigurdur, Oskarsson, Gudjon R., Ostrowski, Sisse Rye, Pedersen, Ole Birger, Snaebjarnarson, Auðunn S., Sigurdsson, Emil, Steinthorsdottir, Valgerdur, Schwinn, Michael, Thorgeirsson, Gudmundur, Thorleifsson, Gudmar, Jonsdottir, Ingileif, Bundgaard, Henning, Nadauld, Lincoln, Bjornsson, Einar S., Rulifson, Ingrid C., Rafnar, Thorunn, Norddahl, Gudmundur L., Thorsteinsdottir, Unnur, Sulem, Patrick, Gudbjartsson, Daniel F., Holm, Hilma, and Stefansson, Kari
Abstract: Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.
Published: 2022
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16. 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, 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, and Stefansson, Kari
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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17. The power of genetic diversity in genome-wide association studies of lipids

Author: Graham, Sarah E., Clarke, Shoa L., Wu, Kuan-Han H., Kanoni, Stavroula, Zajac, Greg J. M., Ramdas, Shweta, Surakka, Ida, Ntalla, Ioanna, Vedantam, Sailaja, Winkler, Thomas W., Locke, Adam E., Marouli, Eirini, Hwang, Mi Yeong, Han, Sohee, Narita, Akira, Choudhury, Ananyo, Bentley, Amy R., Ekoru, Kenneth, Verma, Anurag, Trivedi, Bhavi, Martin, Hilary C., Hunt, Karen A., Hui, Qin, Klarin, Derek, Zhu, Xiang, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F., Holm, Hilma, Olafsson, Isleifur, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M., Rasheed, Humaira, Ruotsalainen, Sanni E., Havulinna, Aki S., Veturi, Yogasudha, Feng, QiPing, Rosenthal, Elisabeth A., Lingren, Todd, Pacheco, Jennifer Allen, Pendergrass, Sarah A., Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E., Campbell, Archie, Lin, Kuang, Millwood, Iona Y., Hindy, George, Rasheed, Asif, Faul, Jessica D., Zhao, Wei, Weir, David R., Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Mahajan, Anubha, Brown, Michael R., Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M., Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Willemsen, Gonneke, Wood, Andrew R., Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E., Chai, Jin Fang, Aadahl, Mette, Yao, Jie, Manichaikul, Ani, Warren, Helen R., Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L., Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Sidore, Carlo, Fiorillo, Edoardo, McDaid, Aaron F., Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T., Thuesen, Betina H., Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Daw, E. Warwick, Zmuda, Joseph M., Mitchell, Jonathan S., Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A., Feitosa, Mary F., Wojczynski, Mary K., Preuss, Michael, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W., Engmann, Jorgen, Kember, Rachel L., Slieker, Roderick C., Lo, Ken Sin, Zilhao, Nuno R., Le, Phuong, Kleber, Marcus E., Delgado, Graciela E., Huo, Shaofeng, Ikeda, Daisuke D., Iha, Hiroyuki, Yang, Jian, Liu, Jun, Leonard, Hampton L., Marten, Jonathan, Schmidt, Börge, Arendt, Marina, Smyth, Laura J., Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Ahmed, Meraj, Jackson, Anne U., Yousri, Noha A., Irvin, Marguerite R., Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R. H. J., Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A., Chai, Xiaoran, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N., Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C., Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Hung, Yi-Jen, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A., Gorski, Mathias, Brumat, Marco, Meidtner, Karina, Bielak, Lawrence F., Smith, Jennifer A., Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Xue, Chao, Zhang, Jifeng, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J., Pitkänen, Niina, Cade, Brian E., Lee, Jiwon, van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Zimmermann, Martina E., Lee, Jong Young, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W., Wang, Carol A., Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hildalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O., van Setten, Jessica, Li, Xiaoyin, Schwander, Karen, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D., Reiner, Alexander P., Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Highland, Heather M., Young, Kristin L., Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C., Nadkarni, Girish N., Launer, Lenore J., Li, Huaixing, Nalls, Mike A., Raitakari, Olli T., Ichihara, Sahoko, Wild, Sarah H., Nelson, Christopher P., Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S., Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, Bhatti, Konain Fatima, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H. H., Ikram, M. Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W., Kraaijeveld, Adriaan O., Beulens, Joline W. J., Shu, Xiao-Ou, Rallidis, Loukianos S., Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W., Kähönen, Mika, Pérusse, Louis, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E., Mori, Trevor A., Lieb, Wolfgang, Franke, Andre, Ohlsson, Claes, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M., Stark, Klaus J., Völzke, Henry, Homuth, Georg, Evans, Michele K., Zonderman, Alan B., Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E., Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J., Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Chen, Y. Eugene, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L. R., Kato, Norihiro, Schulze, Matthias B., Girotto, Giorgia, Jung, Bettina, Böger, Carsten A., Joshi, Peter K., Bennett, David A., De Jager, Philip L., Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morris, Caulfield, Mark J., Munroe, Patricia B., Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B., Samani, Nilesh J., Kaprio, Jaakko, Pajukanta, Päivi, Adair, Linda S., Bechayda, Sonny Augustin, de Silva, H. Janaka, Wickremasinghe, Ananda R., Krauss, Ronald M., Wu, Jer-Yuarn, Zheng, Wei, den Hollander, Anneke I., Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G., Lind, Lars, Heng, Chew-Kiat, Nelson, Amanda E., Golightly, Yvonne M., Wilson, James F., Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J., Rao, D. C., Arnett, Donna K., Hunt, Steven C., Walker, Mark, Koistinen, Heikki A., Chandak, Giriraj R., Yajnik, Chittaranjan S., Mercader, Josep M., Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A., Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, E. Shyong, van Dam, Rob M., Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F., McKnight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, McCarthy, Mark I., Palmer, Colin N. A., Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M., Lu, Fan, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Parra, Esteban J., Cruz, Miguel, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, ’t Hart, Leen M., Elders, Petra J. M., Damrauer, Scott M., Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D., Loos, Ruth J. F., Province, Michael A., Psaty, Bruce M., Brandslund, Ivan, Pramstaller, Peter P., Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F. A., Kiemeney, Lambertus A. L. M., de Graaf, Jacqueline, Loeffler, Markus, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W., Linneberg, Allan, Jukema, J. Wouter, Khera, Amit V., Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Cucca, Francesco, Mook-Kanamori, Dennis O., van Dijk, Ko Willems, Watkins, Hugh, Strachan, David P., Grarup, Niels, Sever, Peter, Poulter, Neil, Rotter, Jerome I., Dantoft, Thomas M., Karpe, Fredrik, Neville, Matt J., Timpson, Nicholas J., Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T., Pedersen, Nancy L., Magnusson, Patrik K. E., Boomsma, Dorret I., de Geus, Eco J. C., Cupples, L. Adrienne, van Meurs, Joyce B. J., Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J., Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C., Kooner, Jaspal S., de Vries, Paul S., Morrison, Alanna C., North, Kari E., Daviglus, Martha, Kraft, Peter, Martin, Nicholas G., Whitfield, John B., Abbas, Shahid, Saleheen, Danish, Walters, Robin G., Holmes, Michael V., Black, Corri, Smith, Blair H., Justice, Anne E., Baras, Aris, Buring, Julie E., Ridker, Paul M., Chasman, Daniel I., Kooperberg, Charles, Wei, Wei-Qi, Jarvik, Gail P., Namjou, Bahram, Hayes, M. Geoffrey, Ritchie, Marylyn D., Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Thorsteinsdottir, Unnur, Stefansson, Kari, Ho, Yuk-Lam, Lynch, Julie A., Rader, Daniel J., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Gaziano, John M., Wilson, Peter, Rotimi, Charles N., Hazelhurst, Scott, Ramsay, Michèle, Trembath, Richard C., van Heel, David A., Tamiya, Gen, Yamamoto, Masayuki, Kim, Bong-Jo, Mohlke, Karen L., Frayling, Timothy M., Hirschhorn, Joel N., Kathiresan, Sekar, Boehnke, Michael, Natarajan, Pradeep, Peloso, Gina M., Brown, Christopher D., Morris, Andrew P., Assimes, Themistocles L., Deloukas, Panos, Sun, Yan V., and Willer, Cristen J.
Abstract: Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4–23have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26application of polygenic scores in clinical practice.
Published: 2021
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18. Large-scale integration of the plasma proteome with genetics and disease

Author: Ferkingstad, Egil, Sulem, Patrick, Atlason, Bjarni A., Sveinbjornsson, Gardar, Magnusson, Magnus I., Styrmisdottir, Edda L., Gunnarsdottir, Kristbjorg, Helgason, Agnar, Oddsson, Asmundur, Halldorsson, Bjarni V., Jensson, Brynjar O., Zink, Florian, Halldorsson, Gisli H., Masson, Gisli, Arnadottir, Gudny A., Katrinardottir, Hildigunnur, Juliusson, Kristinn, Magnusson, Magnus K., Magnusson, Olafur Th., Fridriksdottir, Run, Saevarsdottir, Saedis, Gudjonsson, Sigurjon A., Stacey, Simon N., Rognvaldsson, Solvi, Eiriksdottir, Thjodbjorg, Olafsdottir, Thorunn A., Steinthorsdottir, Valgerdur, Tragante, Vinicius, Ulfarsson, Magnus O., Stefansson, Hreinn, Jonsdottir, Ingileif, Holm, Hilma, Rafnar, Thorunn, Melsted, Pall, Saemundsdottir, Jona, Norddahl, Gudmundur L., Lund, Sigrun H., Gudbjartsson, Daniel F., Thorsteinsdottir, Unnur, and Stefansson, Kari
Abstract: The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development.
Published: 2021
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19. Distinction between the effects of parental and fetal genomes on fetal growth

Author: Juliusdottir, Thorhildur, Steinthorsdottir, Valgerdur, Stefansdottir, Lilja, Sveinbjornsson, Gardar, Ivarsdottir, Erna V., Thorolfsdottir, Rosa B., Sigurdsson, Jon K., Tragante, Vinicius, Hjorleifsson, Kristjan E., Helgadottir, Anna, Frigge, Michael L., Thorgeirsson, Gudmundur, Benediktsson, Rafn, Sigurdsson, Emil L., Arnar, David O., Steingrimsdottir, Thora, Jonsdottir, Ingileif, Holm, Hilma, Gudbjartsson, Daniel F., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, and Stefansson, Kari
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.
Published: 2021
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20. Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits

Author: Beyter, Doruk, Ingimundardottir, Helga, Oddsson, Asmundur, Eggertsson, Hannes P., Bjornsson, Eythor, Jonsson, Hakon, Atlason, Bjarni A., Kristmundsdottir, Snaedis, Mehringer, Svenja, Hardarson, Marteinn T., Gudjonsson, Sigurjon A., Magnusdottir, Droplaug N., Jonasdottir, Aslaug, Jonasdottir, Adalbjorg, Kristjansson, Ragnar P., Sverrisson, Sverrir T., Holley, Guillaume, Palsson, Gunnar, Stefansson, Olafur A., Eyjolfsson, Gudmundur, Olafsson, Isleifur, Sigurdardottir, Olof, Torfason, Bjarni, Masson, Gisli, Helgason, Agnar, Thorsteinsdottir, Unnur, Holm, Hilma, Gudbjartsson, Daniel F., Sulem, Patrick, Magnusson, Olafur T., Halldorsson, Bjarni V., and Stefansson, Kari
Abstract: Long-read sequencing (LRS) promises to improve the characterization of structural variants (SVs). We generated LRS data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions). We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association of a rare deletion in PCSK9with lower low-density lipoprotein (LDL) cholesterol levels, compared to the population average. We also discovered an association of a multiallelic SV in ACANwith height; we found 11 alleles that differed in the number of a 57-bp-motif repeat and observed a linear relationship between the number of repeats carried and height. These results show that SVs can be accurately characterized at the population scale using LRS data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.
Published: 2021
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21. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author: Surendran, Praveen, Feofanova, Elena V., Lahrouchi, Najim, Ntalla, Ioanna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi T., Cartwright, James H., Hellwege, Jacklyn N., Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang J., Prins, Bram P., Stewart, Isobel D., Cabrera, Claudia P., Eales, James M., Akbarov, Artur, Auer, Paul L., Bielak, Lawrence F., Bis, Joshua C., Braithwaite, Vickie S., Brody, Jennifer A., Daw, E. Warwick, Warren, Helen R., Drenos, Fotios, Nielsen, Sune Fallgaard, Faul, Jessica D., Fauman, Eric B., Fava, Cristiano, Ferreira, Teresa, Foley, Christopher N., Franceschini, Nora, Gao, He, Giannakopoulou, Olga, Giulianini, Franco, Gudbjartsson, Daniel F., Guo, Xiuqing, Harris, Sarah E., Havulinna, Aki S., Helgadottir, Anna, Huffman, Jennifer E., Hwang, Shih-Jen, Kanoni, Stavroula, Kontto, Jukka, Larson, Martin G., Li-Gao, Ruifang, Lindström, Jaana, Lotta, Luca A., Lu, Yingchang, Luan, Jian’an, Mahajan, Anubha, Malerba, Giovanni, Masca, Nicholas G. D., Mei, Hao, Menni, Cristina, Mook-Kanamori, Dennis O., Mosen-Ansorena, David, Müller-Nurasyid, Martina, Paré, Guillaume, Paul, Dirk S., Perola, Markus, Poveda, Alaitz, Rauramaa, Rainer, Richard, Melissa, Richardson, Tom G., Sepúlveda, Nuno, Sim, Xueling, Smith, Albert V., Smith, Jennifer A., Staley, James R., Stanáková, Alena, Sulem, Patrick, Thériault, Sébastien, Thorsteinsdottir, Unnur, Trompet, Stella, Varga, Tibor V., Velez Edwards, Digna R., Veronesi, Giovanni, Weiss, Stefan, Willems, Sara M., Yao, Jie, Young, Robin, Yu, Bing, Zhang, Weihua, Zhao, Jing-Hua, Zhao, Wei, Zhao, Wei, Evangelou, Evangelos, Aeschbacher, Stefanie, Asllanaj, Eralda, Blankenberg, Stefan, Bonnycastle, Lori L., Bork-Jensen, Jette, Brandslund, Ivan, Braund, Peter S., Burgess, Stephen, Cho, Kelly, Christensen, Cramer, Connell, John, Mutsert, Renée de, Dominiczak, Anna F., Dörr, Marcus, Eiriksdottir, Gudny, Farmaki, Aliki-Eleni, Gaziano, J. Michael, Grarup, Niels, Grove, Megan L., Hallmans, Göran, Hansen, Torben, Have, Christian T., Heiss, Gerardo, Jørgensen, Marit E., Jousilahti, Pekka, Kajantie, Eero, Kamat, Mihir, Käräjämäki, AnneMari, Karpe, Fredrik, Koistinen, Heikki A., Kovesdy, Csaba P., Kuulasmaa, Kari, Laatikainen, Tiina, Lannfelt, Lars, Lee, I-Te, Lee, Wen-Jane, Linneberg, Allan, Martin, Lisa W., Moitry, Marie, Nadkarni, Girish, Neville, Matt J., Palmer, Colin N. A., Papanicolaou, George J., Pedersen, Oluf, Peters, James, Poulter, Neil, Rasheed, Asif, Rasmussen, Katrine L., Rayner, N. William, Mägi, Reedik, Renström, Frida, Rettig, Rainer, Rossouw, Jacques, Schreiner, Pamela J., Sever, Peter S., Sigurdsson, Emil L., Skaaby, Tea, Sun, Yan V., Sundstrom, Johan, Thorgeirsson, Gudmundur, Esko, Tõnu, Trabetti, Elisabetta, Tsao, Philip S., Tuomi, Tiinamaija, Turner, Stephen T., Tzoulaki, Ioanna, Vaartjes, Ilonca, Vergnaud, Anne-Claire, Willer, Cristen J., Wilson, Peter W. F., Witte, Daniel R., Yonova-Doing, Ekaterina, Zhang, He, Aliya, Naheed, Almgren, Peter, Amouyel, Philippe, Asselbergs, Folkert W., Barnes, Michael R., Blakemore, Alexandra I., Boehnke, Michael, Bots, Michiel L., Bottinger, Erwin P., Buring, Julie E., Chambers, John C., Chen, Yii-Der Ida, Chowdhury, Rajiv, Conen, David, Correa, Adolfo, Davey Smith, George, Boer, Rudolf A. de, Deary, Ian J., Dedoussis, George, Deloukas, Panos, Di Angelantonio, Emanuele, Elliott, Paul, Felix, Stephan B., Ferrières, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Franks, Stephen, Frossard, Philippe, Gambaro, Giovanni, Gaunt, Tom R., Groop, Leif, Gudnason, Vilmundur, Harris, Tamara B., Hayward, Caroline, Hennig, Branwen J., Herzig, Karl-Heinz, Ingelsson, Erik, Tuomilehto, Jaakko, Järvelin, Marjo-Riitta, Jukema, J. Wouter, Kardia, Sharon L. R., Kee, Frank, Kooner, Jaspal S., Kooperberg, Charles, Launer, Lenore J., Lind, Lars, Loos, Ruth J. F., Majumder, Abdulla al Shafi., Laakso, Markku, McCarthy, Mark I., Melander, Olle, Mohlke, Karen L., Murray, Alison D., Nordestgaard, Børge Grønne, Orho-Melander, Marju, Packard, Chris J., Padmanabhan, Sandosh, Palmas, Walter, Polasek, Ozren, Porteous, David J., Prentice, Andrew M., Province, Michael A., Relton, Caroline L., Rice, Kenneth, Ridker, Paul M., Rolandsson, Olov, Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sattar, Naveed, Sheu, Wayne H.-H., Smith, Blair H., Soranzo, Nicole, Spector, Timothy D., Starr, John M., Sebert, Sylvain, Taylor, Kent D., Lakka, Timo A., Timpson, Nicholas J., Tobin, Martin D., van der Harst, Pim, van der Meer, Peter, Ramachandran, Vasan S., Verweij, Niek, Virtamo, Jarmo, Völker, Uwe, Weir, David R., Zeggini, Eleftheria, Charchar, Fadi J., Wareham, Nicholas J., Langenberg, Claudia, Tomaszewski, Maciej, Butterworth, Adam S., Caulfield, Mark J., Danesh, John, Edwards, Todd L., Holm, Hilma, Hung, Adriana M., Lindgren, Cecilia M., Liu, Chunyu, Manning, Alisa K., Morris, Andrew P., Morrison, Alanna C., O’Donnell, Christopher J., Psaty, Bruce M., Saleheen, Danish, Stefansson, Kari, Boerwinkle, Eric, Chasman, Daniel I., Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B., and Howson, Joanna M. M.
Abstract: Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency?>?0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency?=?0.01) variant BP associations (P?
Published: 2020
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22. Author Correction: Large-scale plasma proteomics comparisons through genetics and disease associations

Author: Eldjarn, Grimur Hjorleifsson, Ferkingstad, Egil, Lund, Sigrun H., Helgason, Hannes, Magnusson, Olafur Th., Gunnarsdottir, Kristbjorg, Olafsdottir, Thorunn A., Halldorsson, Bjarni V., Olason, Pall I., Zink, Florian, Gudjonsson, Sigurjon A., Sveinbjornsson, Gardar, Magnusson, Magnus I., Helgason, Agnar, Oddsson, Asmundur, Halldorsson, Gisli H., Magnusson, Magnus K., Saevarsdottir, Saedis, Eiriksdottir, Thjodbjorg, Masson, Gisli, Stefansson, Hreinn, Jonsdottir, Ingileif, Holm, Hilma, Rafnar, Thorunn, Melsted, Pall, Saemundsdottir, Jona, Norddahl, Gudmundur L., Thorleifsson, Gudmar, Ulfarsson, Magnus O., Gudbjartsson, Daniel F., Thorsteinsdottir, Unnur, Sulem, Patrick, and Stefansson, Kari
Published: 2024
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23. Phenotypes Associated with HFE p.C282Y Homozygosity, the Main Hereditary Hemochromatosis Genotype, in Four Large Genetic Cohorts

Author: Geirsdottir, Inga S., Lund, Sigrún Helga, Saevarsdottir, Saedis, Vidarsson, Brynjar, Rigas, Andreas Stribolt, Holm, Hilma, Glenthøj, Andreas, Ullum, Henrik, Sulem, Patrick, Gudbjartsson, Daniel, Magnusson, Magnus K., and Stefansson, Kari
Abstract: Introduction
Published: 2023
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24. Author Correction: The power of genetic diversity in genome-wide association studies of lipids

Author: Graham, Sarah E., Clarke, Shoa L., Wu, Kuan-Han H., Kanoni, Stavroula, Zajac, Greg J. M., Ramdas, Shweta, Surakka, Ida, Ntalla, Ioanna, Vedantam, Sailaja, Winkler, Thomas W., Locke, Adam E., Marouli, Eirini, Hwang, Mi Yeong, Han, Sohee, Narita, Akira, Choudhury, Ananyo, Bentley, Amy R., Ekoru, Kenneth, Verma, Anurag, Trivedi, Bhavi, Martin, Hilary C., Hunt, Karen A., Hui, Qin, Klarin, Derek, Zhu, Xiang, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F., Holm, Hilma, Olafsson, Isleifur, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M., Rasheed, Humaira, Ruotsalainen, Sanni E., Havulinna, Aki S., Veturi, Yogasudha, Feng, QiPing, Rosenthal, Elisabeth A., Lingren, Todd, Pacheco, Jennifer Allen, Pendergrass, Sarah A., Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E., Campbell, Archie, Lin, Kuang, Millwood, Iona Y., Hindy, George, Rasheed, Asif, Faul, Jessica D., Zhao, Wei, Weir, David R., Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Mahajan, Anubha, Brown, Michael R., Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M., Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Willemsen, Gonneke, Wood, Andrew R., Ji, Yingji, Gao, Zishan, Haworth, Simon, Mitchell, Ruth E., Chai, Jin Fang, Aadahl, Mette, Yao, Jie, Manichaikul, Ani, Warren, Helen R., Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L., Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Sidore, Carlo, Fiorillo, Edoardo, McDaid, Aaron F., Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T., Thuesen, Betina H., Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Daw, E. Warwick, Zmuda, Joseph M., Mitchell, Jonathan S., Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A., Feitosa, Mary F., Wojczynski, Mary K., Preuss, Michael, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W., Engmann, Jorgen, Kember, Rachel L., Slieker, Roderick C., Lo, Ken Sin, Zilhao, Nuno R., Le, Phuong, Kleber, Marcus E., Delgado, Graciela E., Huo, Shaofeng, Ikeda, Daisuke D., Iha, Hiroyuki, Yang, Jian, Liu, Jun, Leonard, Hampton L., Marten, Jonathan, Schmidt, Börge, Arendt, Marina, Smyth, Laura J., Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Ahmed, Meraj, Jackson, Anne U., Yousri, Noha A., Irvin, Marguerite R., Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R. H. J., Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A., Chai, Xiaoran, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N., Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C., Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Hung, Yi-Jen, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A., Gorski, Mathias, Brumat, Marco, Meidtner, Karina, Bielak, Lawrence F., Smith, Jennifer A., Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Xue, Chao, Zhang, Jifeng, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J., Pitkänen, Niina, Cade, Brian E., Lee, Jiwon, van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Zimmermann, Martina E., Lee, Jong Young, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W., Wang, Carol A., Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hildalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O., van Setten, Jessica, Li, Xiaoyin, Schwander, Karen, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D., Reiner, Alexander P., Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Highland, Heather M., Young, Kristin L., Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C., Nadkarni, Girish N., Launer, Lenore J., Li, Huaixing, Nalls, Mike A., Raitakari, Olli T., Ichihara, Sahoko, Wild, Sarah H., Nelson, Christopher P., Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S., Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, Bhatti, Konain Fatima, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H. H., Ikram, M. Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W., Kraaijeveld, Adriaan O., Beulens, Joline W. J., Shu, Xiao-Ou, Rallidis, Loukianos S., Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W., Kähönen, Mika, Pérusse, Louis, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E., Mori, Trevor A., Lieb, Wolfgang, Franke, Andre, Ohlsson, Claes, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M., Stark, Klaus J., Völzke, Henry, Homuth, Georg, Evans, Michele K., Zonderman, Alan B., Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E., Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J., Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Chen, Y. Eugene, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L. R., Kato, Norihiro, Schulze, Matthias B., Girotto, Giorgia, Jung, Bettina, Böger, Carsten A., Joshi, Peter K., Bennett, David A., De Jager, Philip L., Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morris, Caulfield, Mark J., Munroe, Patricia B., Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B., Samani, Nilesh J., Kaprio, Jaakko, Pajukanta, Päivi, Adair, Linda S., Bechayda, Sonny Augustin, de Silva, H. Janaka, Wickremasinghe, Ananda R., Krauss, Ronald M., Wu, Jer-Yuarn, Zheng, Wei, den Hollander, Anneke I., Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G., Lind, Lars, Heng, Chew-Kiat, Nelson, Amanda E., Golightly, Yvonne M., Wilson, James F., Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J., Rao, D. C., Arnett, Donna K., Hunt, Steven C., Walker, Mark, Koistinen, Heikki A., Chandak, Giriraj R., Yajnik, Chittaranjan S., Mercader, Josep M., Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A., Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, E. Shyong, van Dam, Rob M., Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F., McKnight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, McCarthy, Mark I., Palmer, Colin N. A., Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M., Lu, Fan, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Parra, Esteban J., Cruz, Miguel, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, ’t Hart, Leen M., Elders, Petra J. M., Damrauer, Scott M., Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D., Loos, Ruth J. F., Province, Michael A., Psaty, Bruce M., Brandslund, Ivan, Pramstaller, Peter P., Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F. A., Kiemeney, Lambertus A. L. M., de Graaf, Jacqueline, Loeffler, Markus, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W., Linneberg, Allan, Jukema, J. Wouter, Khera, Amit V., Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Cucca, Francesco, Mook-Kanamori, Dennis O., van Dijk, Ko Willems, Watkins, Hugh, Strachan, David P., Grarup, Niels, Sever, Peter, Poulter, Neil, Rotter, Jerome I., Dantoft, Thomas M., Karpe, Fredrik, Neville, Matt J., Timpson, Nicholas J., Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T., Pedersen, Nancy L., Magnusson, Patrik K. E., Boomsma, Dorret I., de Geus, Eco J. C., Cupples, L. Adrienne, van Meurs, Joyce B. J., Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J., Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C., Kooner, Jaspal S., de Vries, Paul S., Morrison, Alanna C., North, Kari E., Daviglus, Martha, Kraft, Peter, Martin, Nicholas G., Whitfield, John B., Abbas, Shahid, Saleheen, Danish, Walters, Robin G., Holmes, Michael V., Black, Corri, Smith, Blair H., Justice, Anne E., Baras, Aris, Buring, Julie E., Ridker, Paul M., Chasman, Daniel I., Kooperberg, Charles, Wei, Wei-Qi, Jarvik, Gail P., Namjou, Bahram, Hayes, M. Geoffrey, Ritchie, Marylyn D., Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Thorsteinsdottir, Unnur, Stefansson, Kari, Ho, Yuk-Lam, Lynch, Julie A., Rader, Daniel J., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Gaziano, John M., Wilson, Peter, Rotimi, Charles N., Hazelhurst, Scott, Ramsay, Michèle, Trembath, Richard C., van Heel, David A., Tamiya, Gen, Yamamoto, Masayuki, Kim, Bong-Jo, Mohlke, Karen L., Frayling, Timothy M., Hirschhorn, Joel N., Kathiresan, Sekar, Boehnke, Michael, Natarajan, Pradeep, Peloso, Gina M., Brown, Christopher D., Morris, Andrew P., Assimes, Themistocles L., Deloukas, Panos, Sun, Yan V., and Willer, Cristen J.
Published: 2023
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25. Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels

Author: Tin, Adrienne, Marten, Jonathan, Halperin Kuhns, Victoria L., Li, Yong, Wuttke, Matthias, Kirsten, Holger, Sieber, Karsten B., Qiu, Chengxiang, Gorski, Mathias, Yu, Zhi, Giri, Ayush, Sveinbjornsson, Gardar, Li, Man, Chu, Audrey Y., Hoppmann, Anselm, O’Connor, Luke J., Prins, Bram, Nutile, Teresa, Noce, Damia, Akiyama, Masato, Cocca, Massimiliano, Ghasemi, Sahar, van der Most, Peter J., Horn, Katrin, Xu, Yizhe, Fuchsberger, Christian, Sedaghat, Sanaz, Afaq, Saima, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boerwinkle, Eric, Bottinger, Erwin P., Boutin, Thibaud S., Brumat, Marco, Burkhardt, Ralph, Campana, Eric, Campbell, Archie, Campbell, Harry, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Ciullo, Marina, Concas, Maria Pina, Coresh, Josef, Corre, Tanguy, Cusi, Daniele, Felicita, Sala Cinzia, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko P. J., Delgado, Graciela, Demirkan, Ayşe, Devuyst, Olivier, Dittrich, Katalin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Evans, Michele K., Gansevoort, Ron T., Gasparini, Paolo, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Gögele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hayward, Caroline, Hicks, Andrew A., Hofer, Edith, Holm, Hilma, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Ikram, M. Arfan, Lewis, Raychel M., Ingelsson, Erik, Jakobsdottir, Johanna, Jonsdottir, Ingileif, Jonsson, Helgi, Joshi, Peter K., Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Kerr, Shona M., Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Krämer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, La Bianca, Martina, Lange, Leslie A., Lehne, Benjamin, Lehtimäki, Terho, Liu, Jun, Loeffler, Markus, Loos, Ruth J. F., Lyytikäinen, Leo-Pekka, Magi, Reedik, Mahajan, Anubha, Martin, Nicholas G., März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Meisinger, Christa, Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, O’Donnell, Christopher J., Wilson, Otis D., Gaziano, J. Michael, Mishra, Pashupati P., Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Müller-Nurasyid, Martina, Nadkarni, Girish N., Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., Noordam, Raymond, O’Connell, Jeffrey R., Olafsson, Isleifur, Padmanabhan, Sandosh, Penninx, Brenda W. J. H., Perls, Thomas, Peters, Annette, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Preuss, Michael H., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rizzi, Federica, Robino, Antonietta, Rudan, Igor, Krajcoviechova, Alena, Cifkova, Renata, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Salvi, Erika, Schmidt, Helena, Schmidt, Reinhold, Shaffer, Christian M., Smith, Albert V., Smith, Blair H., Spracklen, Cassandra N., Strauch, Konstantin, Stumvoll, Michael, Sulem, Patrick, Tajuddin, Salman M., Teren, Andrej, Thiery, Joachim, Thio, Chris H. L., Thorsteinsdottir, Unnur, Toniolo, Daniela, Tönjes, Anke, Tremblay, Johanne, Uitterlinden, André G., Vaccargiu, Simona, van der Harst, Pim, van Duijn, Cornelia M., Verweij, Niek, Völker, Uwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Whitfield, John B., Wild, Sarah H., Wilson, James F., Yang, Qiong, Zhang, Weihua, Zonderman, Alan B., Bochud, Murielle, Wilson, James G., Pendergrass, Sarah A., Ho, Kevin, Parsa, Afshin, Pramstaller, Peter P., Psaty, Bruce M., Böger, Carsten A., Snieder, Harold, Butterworth, Adam S., Okada, Yukinori, Edwards, Todd L., Stefansson, Kari, Susztak, Katalin, Scholz, Markus, Heid, Iris M., Hung, Adriana M., Teumer, Alexander, Pattaro, Cristian, Woodward, Owen M., Vitart, Veronique, and Köttgen, Anna
Abstract: Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1Aand HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
Published: 2019
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26. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6

Author: Prins, Bram, Mead, Timothy, Brody, Jennifer, Sveinbjornsson, Gardar, Ntalla, Ioanna, Bihlmeyer, Nathan, van den Berg, Marten, Bork-Jensen, Jette, Cappellani, Stefania, Van Duijvenboden, Stefan, Klena, Nikolai, Gabriel, George, Liu, Xiaoqin, Gulec, Cagri, Grarup, Niels, Haessler, Jeffrey, Hall, Leanne, Iorio, Annamaria, Isaacs, Aaron, Li-Gao, Ruifang, Lin, Honghuang, Liu, Ching-Ti, Lyytikäinen, Leo-Pekka, Marten, Jonathan, Mei, Hao, Müller-Nurasyid, Martina, Orini, Michele, Padmanabhan, Sandosh, Radmanesh, Farid, Ramirez, Julia, Robino, Antonietta, Schwartz, Molly, van Setten, Jessica, Smith, Albert, Verweij, Niek, Warren, Helen, Weiss, Stefan, Alonso, Alvaro, Arnar, David, Bots, Michiel, de Boer, Rudolf, Dominiczak, Anna, Eijgelsheim, Mark, Ellinor, Patrick, Guo, Xiuqing, Felix, Stephan, Harris, Tamara, Hayward, Caroline, Heckbert, Susan, Huang, Paul, Jukema, J., Kähönen, Mika, Kors, Jan, Lambiase, Pier, Launer, Lenore, Li, Man, Linneberg, Allan, Nelson, Christopher, Pedersen, Oluf, Perez, Marco, Peters, Annette, Polasek, Ozren, Psaty, Bruce, Raitakari, Olli, Rice, Kenneth, Rotter, Jerome, Sinner, Moritz, Soliman, Elsayed, Spector, Tim, Strauch, Konstantin, Thorsteinsdottir, Unnur, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Vaartjes, Ilonca, van der Meer, Peter, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wilson, James, Xie, Zhijun, Asselbergs, Folkert, Dörr, Marcus, van Duijn, Cornelia, Gasparini, Paolo, Gudbjartsson, Daniel, Gudnason, Vilmundur, Hansen, Torben, Kääb, Stefan, Kanters, Jørgen, Kooperberg, Charles, Lehtimäki, Terho, Lin, Henry, Lubitz, Steven, Mook-Kanamori, Dennis, Conti, Francesco, Newton-Cheh, Christopher, Rosand, Jonathan, Rudan, Igor, Samani, Nilesh, Sinagra, Gianfranco, Smith, Blair, Holm, Hilma, Stricker, Bruno, Ulivi, Sheila, Sotoodehnia, Nona, Apte, Suneel, van der Harst, Pim, Stefansson, Kari, Munroe, Patricia, Arking, Dan, Lo, Cecilia, and Jamshidi, Yalda
Abstract: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6in connexin 43 gap junction expression, which is essential for myocardial conduction. Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
Published: 2018
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27. Insights into imprinting from parent-of-origin phased methylomes and transcriptomes

Author: Zink, Florian, Magnusdottir, Droplaug N., Magnusson, Olafur T., Walker, Nicolas J., Morris, Tiffany J., Sigurdsson, Asgeir, Halldorsson, Gisli H., Gudjonsson, Sigurjon A., Melsted, Pall, Ingimundardottir, Helga, Kristmundsdottir, Snædis, Alexandersson, Kristjan F., Helgadottir, Anna, Gudmundsson, Julius, Rafnar, Thorunn, Jonsdottir, Ingileif, Holm, Hilma, Eyjolfsson, Gudmundur Ingi, Sigurdardottir, Olof, Olafsson, Isleifur, Masson, Gisli, Gudbjartsson, Daniel F., Thorsteinsdottir, Unnur, Halldorsson, Bjarni V., Stacey, Simon N., and Stefansson, Kari
Abstract: Imprinting is the preferential expression of one parental allele over the other. It is controlled primarily through differential methylation of cytosine at CpG dinucleotides. Here we combine 285 methylomes and 11,617 transcriptomes from peripheral blood samples with parent-of-origin phased haplotypes, to produce a new map of imprinted methylation and gene expression patterns across the human genome. We demonstrate how imprinted methylation is a continuous rather than a binary characteristic. We describe at high resolution the parent-of-origin methylation pattern at the 15q11.2 Prader–Willi/Angelman syndrome locus, with nearly confluent stochastic paternal methylation punctuated by ‘spikes’ of maternal methylation. We find examples of polymorphic imprinted methylation unrelated (at VTRNA2-1 and PARD6G) or related (at CHRNE) to nearby SNP genotypes. We observe RNA isoform-specific imprinted expression patterns suggestive of a methylation-sensitive transcriptional elongation block. Finally, we gain new insights into parent-of-origin-specific effects on phenotypes at the DLK1/MEG3 and GNAS loci.
Published: 2018
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28. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology

Author: Nielsen, Jonas B., Thorolfsdottir, Rosa B., Fritsche, Lars G., Zhou, Wei, Skov, Morten W., Graham, Sarah E., Herron, Todd J., McCarthy, Shane, Schmidt, Ellen M., Sveinbjornsson, Gardar, Surakka, Ida, Mathis, Michael R., Yamazaki, Masatoshi, Crawford, Ryan D., Gabrielsen, Maiken E., Skogholt, Anne Heidi, Holmen, Oddgeir L., Lin, Maoxuan, Wolford, Brooke N., Dey, Rounak, Dalen, Håvard, Sulem, Patrick, Chung, Jonathan H., Backman, Joshua D., Arnar, David O., Thorsteinsdottir, Unnur, Baras, Aris, O’Dushlaine, Colm, Holst, Anders G., Wen, Xiaoquan, Hornsby, Whitney, Dewey, Frederick E., Boehnke, Michael, Kheterpal, Sachin, Mukherjee, Bhramar, Lee, Seunggeun, Kang, Hyun M., Holm, Hilma, Kitzman, Jacob, Shavit, Jordan A., Jalife, José, Brummett, Chad M., Teslovich, Tanya M., Carey, David J., Gudbjartsson, Daniel F., Stefansson, Kari, Abecasis, Gonçalo R., Hveem, Kristian, and Willer, Cristen J.
Abstract: To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)1, or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an ‘atrial cardiomyopathy’2, either during fetal heart development or as a response to stress in the adult heart.
Published: 2018
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29. Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability

Author: Ivarsdottir, Erna V, Steinthorsdottir, Valgerdur, Daneshpour, Maryam S, Thorleifsson, Gudmar, Sulem, Patrick, Holm, Hilma, Sigurdsson, Snaevar, Hreidarsson, Astradur B, Sigurdsson, Gunnar, Bjarnason, Ragnar, Thorsson, Arni V, Benediktsson, Rafn, Eyjolfsson, Gudmundur, Sigurdardottir, Olof, Olafsson, Isleifur, Zeinali, Sirous, Azizi, Fereidoun, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F, and Stefansson, Kari
Abstract: Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10−10), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7.5% per allele, P = 4.9 × 10−11and 7.3% per allele, P = 7.5 × 10−18, respectively). Variants that increase mean and between-subject variance in fasting glucose levels tend to increase T2D risk, whereas those that increase the mean but reduce variance do not (r2= 0.61). The variants that increase between-subject variance increase fasting glucose heritability estimates. Intuitively, our results show that increasing the mean and variance of glucose levels is more likely to cause pathologically high glucose levels than increase in the mean offset by a decrease in variance.
Published: 2017
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30. Identification of sequence variants influencing immunoglobulin levels

Author: Jonsson, Stefan, Sveinbjornsson, Gardar, de Lapuente Portilla, Aitzkoa Lopez, Swaminathan, Bhairavi, Plomp, Rosina, Dekkers, Gillian, Ajore, Ram, Ali, Mina, Bentlage, Arthur E H, Elmér, Evelina, Eyjolfsson, Gudmundur I, Gudjonsson, Sigurjon A, Gullberg, Urban, Gylfason, Arnaldur, Halldorsson, Bjarni V, Hansson, Markus, Holm, Hilma, Johansson, Åsa, Johnsson, Ellinor, Jonasdottir, Aslaug, Ludviksson, Bjorn R, Oddsson, Asmundur, Olafsson, Isleifur, Olafsson, Sigurgeir, Sigurdardottir, Olof, Sigurdsson, Asgeir, Stefansdottir, Lilja, Masson, Gisli, Sulem, Patrick, Wuhrer, Manfred, Wihlborg, Anna-Karin, Thorleifsson, Gudmar, Gudbjartsson, Daniel F, Thorsteinsdottir, Unnur, Vidarsson, Gestur, Jonsdottir, Ingileif, Nilsson, Björn, and Stefansson, Kari
Abstract: Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10−55, β = −0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10−8, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
Published: 2017
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31. Diversity in non-repetitive human sequences not found in the reference genome

Author: Kehr, Birte, Helgadottir, Anna, Melsted, Pall, Jonsson, Hakon, Helgason, Hannes, Jonasdottir, Adalbjörg, Jonasdottir, Aslaug, Sigurdsson, Asgeir, Gylfason, Arnaldur, Halldorsson, Gisli H, Kristmundsdottir, Snaedis, Thorgeirsson, Gudmundur, Olafsson, Isleifur, Holm, Hilma, Thorsteinsdottir, Unnur, Sulem, Patrick, Helgason, Agnar, Gudbjartsson, Daniel F, Halldorsson, Bjarni V, and Stefansson, Kari
Abstract: Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR) sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (r2> 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally, we report an association (P = 3.8 × 10−8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the importance of including variation of all complexity levels when searching for variants that associate with disease.
Published: 2017
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32. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author: Kanoni, Stavroula, Graham, Sarah E., Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L., Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W., Locke, Adam E., Marouli, Eirini, Zajac, Greg J. M., Wu, Kuan-Han H., Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T., Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F., Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M., Rasheed, Humaira, Havulinna, Aki S., Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A., Lingren, Todd, Feng, QiPing, Kullo, Iftikhar J., Narita, Akira, Takayama, Jun, Martin, Hilary C., Hunt, Karen A., Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E., Campbell, Archie, Lin, Kuang, Millwood, Iona Y., Rasheed, Asif, Hindy, George, Faul, Jessica D., Zhao, Wei, Weir, David R., Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R., Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M., Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Wood, Andrew R., Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A., Mitchell, Ruth E., Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A., Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R., Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L., Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Floris, McDaid, Aaron F., Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T., Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Ruotsalainen, Sanni E., Daw, EWarwick, Zmuda, Joseph M., Mitchell, Jonathan S., Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A., Vazquez-Moreno, Miguel, Feitosa, Mary F., Wojczynski, Mary K., Wang, Zhe, Preuss, Michael H., Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W., Engmann, Jorgen, Tsao, Noah L., Verma, Anurag, Slieker, Roderick C., Lo, Ken Sin, Zilhao, Nuno R., Le, Phuong, Kleber, Marcus E., Delgado, Graciela E., Huo, Shaofeng, Ikeda, Daisuke D., Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L., Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J., Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Nongmaithem, Suraj S., Bayyana, Swati, Stringham, Heather M., Irvin, Marguerite R., Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R. H. J., Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A., Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N., Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C., Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A., Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F., Smith, Jennifer A., Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J., Pitkänen, Niina, Cade, Brian E., van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R., Doumatey, Ayo P., Adeyemo, Adebowale A., Lee, Jong Young, Petersen, Eva R. B., Nielsen, Aneta A., Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W., Wang, Carol A., Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O., van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D., Reiner, Alexander P., Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C., Launer, Lenore J., Li, Huaixing, Nalls, Mike A., Raitakari, Olli T., Ichihara, Sahoko, Wild, Sarah H., Nelson, Christopher P., Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S., Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H. H., Ikram, M. Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W., Kraaijeveld, Adriaan O., Beulens, Joline W. J., Shu, Xiao-Ou, Rallidis, Loukianos S., Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W., Kähönen, Mika, Pérusse, Louis, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E., Mori, Trevor A., Lieb, Wolfgang, Franke, Andre, Ohlsson, Claes, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M., Stark, Klaus J., Zimmermann, Martina E., Völzke, Henry, Homuth, Georg, Evans, Michele K., Zonderman, Alan B., Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E., Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J., Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L. R., Peyser, Patricia A., Kato, Norihiro, Schulze, Matthias B., Girotto, Giorgia, Böger, Carsten A., Jung, Bettina, Joshi, Peter K., Bennett, David A., De Jager, Philip L., Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morris, Caulfield, Mark J., Munroe, Patricia B., Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B., Samani, Nilesh J., Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A., Adair, Linda S., Bechayda, Sonny Augustin, de Silva, H. Janaka, Wickremasinghe, Ananda R., Krauss, Ronald M., Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G., Lind, Lars, Heng, Chew-Kiat, Nelson, Amanda E., Golightly, Yvonne M., Wilson, James F., Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J., Rao, D. C., Arnett, Donna K., Hunt, Steven C., Walker, Mark, Koistinen, Heikki A., Chandak, Giriraj R., Mercader, Josep M., Costanzo, Maria C., Jang, Dongkeun, Burtt, Noël P., Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, EShyong, van Dam, Rob M., Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F., McKnight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, McCarthy, Mark I., Palmer, Colin N. A., Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M., Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M.‘t, Elders, Petra J. M., Damrauer, Scott M., Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D., Loos, Ruth J. F., Province, Michael A., Parra, Esteban J., Cruz, Miguel, Psaty, Bruce M., Brandslund, Ivan, Pramstaller, Peter P., Rotimi, Charles N., Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F. A., Kiemeney, Lambertus A. L. M., de Graaf, Jacqueline, Loeffler, Markus, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W., Linneberg, Allan, Jukema, J. Wouter, Khera, Amit V., Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O., van Dijk, Ko Willems, Watkins, Hugh, Strachan, David P., Grarup, Niels, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I., Dantoft, Thomas M., Karpe, Fredrik, Neville, Matt J., Timpson, Nicholas J., Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T., Pedersen, Nancy L., Magnusson, Patrik K. E., Boomsma, Dorret I., Willemsen, Allegonda H. M., Cupples, LAdrienne, van Meurs, Joyce B. J., Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J., Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C., Kooner, Jaspal S., de Vries, Paul S., Morrison, Alanna C., Hazelhurst, Scott, Ramsay, Michèle, North, Kari E., Daviglus, Martha, Kraft, Peter, Martin, Nicholas G., Whitfield, John B., Abbas, Shahid, Saleheen, Danish, Walters, Robin G., Holmes, Michael V., Black, Corri, Smith, Blair H., Baras, Aris, Justice, Anne E., Buring, Julie E., Ridker, Paul M., Chasman, Daniel I., Kooperberg, Charles, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A., Trembath, Richard C., Wei, Wei-Qi, Jarvik, Gail P., Namjou, Bahram, Hayes, M. Geoffrey, Ritchie, Marylyn D., Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, YEugene, Ho, Yuk-Lam, Lynch, Julie A., Rader, Daniel J., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Gaziano, John M., Wilson, Peter W. F., Frayling, Timothy M., Hirschhorn, Joel N., Kathiresan, Sekar, Mohlke, Karen L., Sun, Yan V., Morris, Andrew P., Boehnke, Michael, Brown, Christopher D., Natarajan, Pradeep, Deloukas, Panos, Willer, Cristen J., Assimes, Themistocles L., and Peloso, Gina M.
Abstract: Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N= 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Published: 2022
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33. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

Author: Helgadottir, Anna, Gretarsdottir, Solveig, Thorleifsson, Gudmar, Hjartarson, Eirikur, Sigurdsson, Asgeir, Magnusdottir, Audur, Jonasdottir, Aslaug, Kristjansson, Helgi, Sulem, Patrick, Oddsson, Asmundur, Sveinbjornsson, Gardar, Steinthorsdottir, Valgerdur, Rafnar, Thorunn, Masson, Gisli, Jonsdottir, Ingileif, Olafsson, Isleifur, Eyjolfsson, Gudmundur I, Sigurdardottir, Olof, Daneshpour, Maryam S, Khalili, Davood, Azizi, Fereidoun, Swinkels, Dorine W, Kiemeney, Lambertus, Quyyumi, Arshed A, Levey, Allan I, Patel, Riyaz S, Hayek, Salim S, Gudmundsdottir, Ingibjorg J, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F, Holm, Hilma, and Stefansson, Kari
Abstract: Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10−28), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10−8), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk.
Published: 2016
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34. Weighting sequence variants based on their annotation increases power of whole-genome association studies

Author: Sveinbjornsson, Gardar, Albrechtsen, Anders, Zink, Florian, Gudjonsson, Sigurjón A, Oddson, Asmundur, Másson, Gísli, Holm, Hilma, Kong, Augustine, Thorsteinsdottir, Unnur, Sulem, Patrick, Gudbjartsson, Daniel F, and Stefansson, Kari
Abstract: The consensus approach to genome-wide association studies (GWAS) has been to assign equal prior probability of association to all sequence variants tested. However, some sequence variants, such as loss-of-function and missense variants, are more likely than others to affect protein function and are therefore more likely to be causative. Using data from whole-genome sequencing of 2,636 Icelanders and the association results for 96 quantitative and 123 binary phenotypes, we estimated the enrichment of association signals by sequence annotation. We propose a weighted Bonferroni adjustment that controls for the family-wise error rate (FWER), using as weights the enrichment of sequence annotations among association signals. We show that this weighted adjustment increases the power to detect association over the standard Bonferroni correction. We use the enrichment of associations by sequence annotation we have estimated in Iceland to derive significance thresholds for other populations with different numbers and combinations of sequence variants.
Published: 2016
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35. Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study.

Author: Preuss, Michael, König, Inke R., Thompson, John R., Erdmann, Jeanette, Absher, Devin, Assimes, Themistocles L., Blankenberg, Stefan, Boerwinkle, Eric, Li Chen, Cupples, L. Adrienne, Hall, Alistair S., Halperin, Eran, Hengstenberg, Christian, Holm, Hilma, Laaksonen, Reijo, Mingyao Li, März, Winfried, McPherson, Ruth, Musunuru, Kiran, and Nelson, Christopher P.
Subjects: CORONARY disease, MYOCARDIAL infarction, HUMAN genetic variation, CONSORTIA, GENOMICS, GENOMES
Abstract: The article focuses on a study which examined the design of the Coronary ARtery Disease Genome-wide Replication And Meta-analysis (CARDIOGRAM) consortium. Study authors claimed that the CARDIoGRAM consortium was established in an effort to search novel susceptibility for coronary artery disease (CAD) and myocardial infarction (MI). They concluded that CARDIoGRAM may contribute to understanding the role of common genetic variation on risk for CAD and MI.
Published: 2010
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36. Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease

Author: Dichgans, Martin, Malik, Rainer, König, Inke R., Rosand, Jonathan, Clarke, Robert, Gretarsdottir, Solveig, Thorleifsson, Gudmar, Mitchell, Braxton D., Assimes, Themistocles L., Levi, Christopher, O´Donnell, Christopher J., Fornage, Myriam, Thorsteinsdottir, Unnur, Psaty, Bruce M., Hengstenberg, Christian, Seshadri, Sudha, Erdmann, Jeanette, Bis, Joshua C., Peters, Annette, Boncoraglio, Giorgio B., März, Winfried, Meschia, James F., Kathiresan, Sekar, Ikram, M. Arfan, McPherson, Ruth, Stefansson, Kari, Sudlow, Cathie, Reilly, Muredach P., Thompson, John R., Sharma, Pankaj, Hopewell, Jemma C., Chambers, John C., Watkins, Hugh, Rothwell, Peter M., Roberts, Robert, Markus, Hugh S., Samani, Nilesh J., Farrall, Martin, Schunkert, Heribert, Gschwendtner, Andreas, Bevan, Steve, Chen, Yu-Ching, DeStefano, Anita L., Parati, Eugenio A., Quertermous, Tom, Ziegler, Andreas, Boerwinkle, Eric, Holm, Hilma, Fischer, Marcus, Kessler, Thorsten, Willenborg, Christina, Laaksonen, Reijo, Voight, Benjamin F., Stewart, Alexandre F.R., Rader, Daniel J., Hall, Alistair S., and Kooner, Jaspal S.
Abstract: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.
Published: 2014
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37. Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis CARDIoGRAM Study

Author: Preuss, Michael, König, Inke R., Thompson, John R., Erdmann, Jeanette, Absher, Devin, Assimes, Themistocles L., Blankenberg, Stefan, Boerwinkle, Eric, Chen, Li, Cupples, L. Adrienne, Hall, Alistair S., Halperin, Eran, Hengstenberg, Christian, Holm, Hilma, Laaksonen, Reijo, Li, Mingyao, März, Winfried, McPherson, Ruth, Musunuru, Kiran, Nelson, Christopher P., Susan Burnett, Mary, Epstein, Stephen E., O'Donnell, Christopher J., Quertermous, Thomas, Rader, Daniel J., Roberts, Robert, Schillert, Arne, Stefansson, Kari, Stewart, Alexandre F.R., Thorleifsson, Gudmar, Voight, Benjamin F., Wells, George A., Ziegler, Andreas, Kathiresan, Sekar, Reilly, Muredach P., Samani, Nilesh J., and Schunkert, Heribert
Abstract: Recent genome-wide association studies GWAS of myocardial infarction MI and other forms of coronary artery disease CAD have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis CARDIoGRAM consortium was formed.
Published: 2010
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38. Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Author: Gorski, Mathias, Rasheed, Humaira, Teumer, Alexander, Thomas, Laurent F., Graham, Sarah E., Sveinbjornsson, Gardar, Winkler, Thomas W., Günther, Felix, Stark, Klaus J., Chai, Jin-Fang, Tayo, Bamidele O., Wuttke, Matthias, Li, Yong, Tin, Adrienne, Ahluwalia, Tarunveer S., Ärnlöv, Johan, Åsvold, Bjørn Olav, Bakker, Stephan J.L., Banas, Bernhard, Bansal, Nisha, Biggs, Mary L., Biino, Ginevra, Böhnke, Michael, Boerwinkle, Eric, Bottinger, Erwin P., Brenner, Hermann, Brumpton, Ben, Carroll, Robert J., Chaker, Layal, Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Chu, Audrey Y., Ciullo, Marina, Cocca, Massimiliano, Cook, James P., Coresh, Josef, Cusi, Daniele, de Borst, Martin H., Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Evans, Michele K., Feitosa, Mary F., Franke, Andre, Freitag-Wolf, Sandra, Fuchsberger, Christian, Gampawar, Piyush, Gansevoort, Ron T., Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Gieger, Christian, Gudbjartsson, Daniel F., Hallan, Stein, Hamet, Pavel, Hishida, Asahi, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Holm, Hilma, Hoppmann, Anselm, Horn, Katrin, Hutri-Kähönen, Nina, Hveem, Kristian, Hwang, Shih-Jen, Ikram, M. Arfan, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Karabegović, Irma, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Krämer, Bernhard K., Kühnel, Brigitte, Kuusisto, Johanna, Laakso, Markku, Lange, Leslie A., Lehtimäki, Terho, Li, Man, Lieb, Wolfgang, Lind, Lars, Lindgren, Cecilia M., Loos, Ruth J.F., Lukas, Mary Ann, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Matias-Garcia, Pamela R., Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P., Mononen, Nina, Morris, Andrew P., Mychaleckyj, Josyf C., Nadkarni, Girish N., Naito, Mariko, Nakatochi, Masahiro, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., Nutile, Teresa, O’Donoghue, Michelle L., O'Connell, Jeffrey, Olafsson, Isleifur, Orho-Melander, Marju, Parsa, Afshin, Pendergrass, Sarah A., Penninx, Brenda W.J. H., Pirastu, Mario, Preuss, Michael H., Psaty, Bruce M., Raffield, Laura M., Raitakari, Olli T., Rheinberger, Myriam, Rice, Kenneth M., Rizzi, Federica, Rosenkranz, Alexander R., Rossing, Peter, Rotter, Jerome I., Ruggiero, Daniela, Ryan, Kathleen A., Sabanayagam, Charumathi, Salvi, Erika, Schmidt, Helena, Schmidt, Reinhold, Scholz, Markus, Schöttker, Ben, Schulz, Christina-Alexandra, Sedaghat, Sanaz, Shaffer, Christian M., Sieber, Karsten B., Sim, Xueling, Sims, Mario, Snieder, Harold, Stanzick, Kira J., Thorsteinsdottir, Unnur, Stocker, Hannah, Strauch, Konstantin, Stringham, Heather M., Sulem, Patrick, Szymczak, Silke, Taylor, Kent D., Thio, Chris H.L., Tremblay, Johanne, Vaccargiu, Simona, van der Harst, Pim, van der Most, Peter J., Verweij, Niek, Völker, Uwe, Wakai, Kenji, Waldenberger, Melanie, Wallentin, Lars, Wallner, Stefan, Wang, Judy, Waterworth, Dawn M., White, Harvey D., Willer, Cristen J., Wong, Tien-Yin, Woodward, Mark, Yang, Qiong, Yerges-Armstrong, Laura M., Zimmermann, Martina, Zonderman, Alan B., Bergler, Tobias, Stefansson, Kari, Böger, Carsten A., Pattaro, Cristian, Köttgen, Anna, Kronenberg, Florian, and Heid, Iris M.
Abstract: Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silicoevidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
Published: 2022
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39. Abstract 13222: Genetic Variants Close to NKX2-5and MYH6Are Associated With AV Nodal Reentry Tachycardia in First Genome-Wide Association Study

Author: Andreasen, Laura, Ahlberg, Gustav, Lundegaard, Pia Rengtved, Ægisdottir, Hildur, Hartmann, Jacob Peter, Paludan-Mueller, Christian, Hadji-Turdeghal, Katra, Ghouse, Jonas, Pehrson, Steen, Jensen, Henrik, Riahi, Sam, Hansen, Jim, Sandgaard, Niels, Haunso, stig, Kanters, Jorgen, Ellervik, Christina, Bundgaard, Henning, Ullum, Henrik, Holm, Hilma, Arnar, David, Svendsen, Jesper Hastrup, and Olesen, Morten
Abstract: Introduction:AV nodal re-entry tachycardia (AVNRT) is the most common type of paroxysmal supraventricular tachycardia. At present, the underlying etiology of AVNRT is unclear.Hypothesis:In a genome-wide association study (GWAS), we aimed to identify common genetic variants associated with AVNRT.Methods:We performed a GWAS meta-analysis of Danish patients diagnosed with AVNRT verified by invasive electrophysiological study. An Icelandic population of AVNRT patients was used for replication. We performed conditional analysis by adjusting our analysis for atrial fibrillation (AF) genetics and transcriptome-wide analyses (TWAS) to assess associations between gene expression and AVNRT. Electrophysiological consequences were investigated in CRISPR-Cas9 modified zebrafish.Results:A total of 1,515 AVNRT patients and 38,428 controls were available for meta-analysis. Two genetic loci associated with AVNRT; at chromosome 5q35.1, close to the NKX2-5gene (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.38-1.58, P = 2.6 х 10-13), and at 14q11.2 in the MYH6gene (OR 1.26, 95% CI 1.18-1.34, P = 2.3 х 10-8). We found similar effect sizes and direction of effect for both loci in the Icelandic AVNRT cohort. Using conditional analyses, we found that these loci were associated with AVNRT independent of AF. Analyses of loss of Nkx2-5 zebrafish showed no difference with regards to electrocardiographic parameters and transmission electron microscopy of atrial tissue compared with wildtype.Conclusion:This is, to our knowledge, the first GWAS on AVNRT. We identified two genetic loci that associated with AVNRT.
Published: 2021
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40. Publisher Correction: Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author: Surendran, Praveen, Feofanova, Elena V., Lahrouchi, Najim, Ntalla, Ioanna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi T., Cartwright, James H., Hellwege, Jacklyn N., Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang J., Prins, Bram P., Stewart, Isobel D., Cabrera, Claudia P., Eales, James M., Akbarov, Artur, Auer, Paul L., Bielak, Lawrence F., Bis, Joshua C., Braithwaite, Vickie S., Brody, Jennifer A., Daw, E. Warwick, Warren, Helen R., Drenos, Fotios, Nielsen, Sune Fallgaard, Faul, Jessica D., Fauman, Eric B., Fava, Cristiano, Ferreira, Teresa, Foley, Christopher N., Franceschini, Nora, Gao, He, Giannakopoulou, Olga, Giulianini, Franco, Gudbjartsson, Daniel F., Guo, Xiuqing, Harris, Sarah E., Havulinna, Aki S., Helgadottir, Anna, Huffman, Jennifer E., Hwang, Shih-Jen, Kanoni, Stavroula, Kontto, Jukka, Larson, Martin G., Li-Gao, Ruifang, Lindström, Jaana, Lotta, Luca A., Lu, Yingchang, Luan, Jian’an, Mahajan, Anubha, Malerba, Giovanni, Masca, Nicholas G. D., Mei, Hao, Menni, Cristina, Mook-Kanamori, Dennis O., Mosen-Ansorena, David, Müller-Nurasyid, Martina, Paré, Guillaume, Paul, Dirk S., Perola, Markus, Poveda, Alaitz, Rauramaa, Rainer, Richard, Melissa, Richardson, Tom G., Sepúlveda, Nuno, Sim, Xueling, Smith, Albert V., Smith, Jennifer A., Staley, James R., Stanáková, Alena, Sulem, Patrick, Thériault, Sébastien, Thorsteinsdottir, Unnur, Trompet, Stella, Varga, Tibor V., Velez Edwards, Digna R., Veronesi, Giovanni, Weiss, Stefan, Willems, Sara M., Yao, Jie, Young, Robin, Yu, Bing, Zhang, Weihua, Zhao, Jing-Hua, Zhao, Wei, Zhao, Wei, Evangelou, Evangelos, Aeschbacher, Stefanie, Asllanaj, Eralda, Blankenberg, Stefan, Bonnycastle, Lori L., Bork-Jensen, Jette, Brandslund, Ivan, Braund, Peter S., Burgess, Stephen, Cho, Kelly, Christensen, Cramer, Connell, John, Mutsert, Renée de, Dominiczak, Anna F., Dörr, Marcus, Eiriksdottir, Gudny, Farmaki, Aliki-Eleni, Gaziano, J. Michael, Grarup, Niels, Grove, Megan L., Hallmans, Göran, Hansen, Torben, Have, Christian T., Heiss, Gerardo, Jørgensen, Marit E., Jousilahti, Pekka, Kajantie, Eero, Kamat, Mihir, Käräjämäki, AnneMari, Karpe, Fredrik, Koistinen, Heikki A., Kovesdy, Csaba P., Kuulasmaa, Kari, Laatikainen, Tiina, Lannfelt, Lars, Lee, I-Te, Lee, Wen-Jane, Linneberg, Allan, Martin, Lisa W., Moitry, Marie, Nadkarni, Girish, Neville, Matt J., Palmer, Colin N. A., Papanicolaou, George J., Pedersen, Oluf, Peters, James, Poulter, Neil, Rasheed, Asif, Rasmussen, Katrine L., Rayner, N. William, Mägi, Reedik, Renström, Frida, Rettig, Rainer, Rossouw, Jacques, Schreiner, Pamela J., Sever, Peter S., Sigurdsson, Emil L., Skaaby, Tea, Sun, Yan V., Sundstrom, Johan, Thorgeirsson, Gudmundur, Esko, Tõnu, Trabetti, Elisabetta, Tsao, Philip S., Tuomi, Tiinamaija, Turner, Stephen T., Tzoulaki, Ioanna, Vaartjes, Ilonca, Vergnaud, Anne-Claire, Willer, Cristen J., Wilson, Peter W. F., Witte, Daniel R., Yonova-Doing, Ekaterina, Zhang, He, Aliya, Naheed, Almgren, Peter, Amouyel, Philippe, Asselbergs, Folkert W., Barnes, Michael R., Blakemore, Alexandra I., Boehnke, Michael, Bots, Michiel L., Bottinger, Erwin P., Buring, Julie E., Chambers, John C., Chen, Yii-Der Ida, Chowdhury, Rajiv, Conen, David, Correa, Adolfo, Davey Smith, George, Boer, Rudolf A. de, Deary, Ian J., Dedoussis, George, Deloukas, Panos, Di Angelantonio, Emanuele, Elliott, Paul, Felix, Stephan B., Ferrières, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Franks, Stephen, Frossard, Philippe, Gambaro, Giovanni, Gaunt, Tom R., Groop, Leif, Gudnason, Vilmundur, Harris, Tamara B., Hayward, Caroline, Hennig, Branwen J., Herzig, Karl-Heinz, Ingelsson, Erik, Tuomilehto, Jaakko, Järvelin, Marjo-Riitta, Jukema, J. Wouter, Kardia, Sharon L. R., Kee, Frank, Kooner, Jaspal S., Kooperberg, Charles, Launer, Lenore J., Lind, Lars, Loos, Ruth J. F., Majumder, Abdulla al Shafi., Laakso, Markku, McCarthy, Mark I., Melander, Olle, Mohlke, Karen L., Murray, Alison D., Nordestgaard, Børge Grønne, Orho-Melander, Marju, Packard, Chris J., Padmanabhan, Sandosh, Palmas, Walter, Polasek, Ozren, Porteous, David J., Prentice, Andrew M., Province, Michael A., Relton, Caroline L., Rice, Kenneth, Ridker, Paul M., Rolandsson, Olov, Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sattar, Naveed, Sheu, Wayne H.-H., Smith, Blair H., Soranzo, Nicole, Spector, Timothy D., Starr, John M., Sebert, Sylvain, Taylor, Kent D., Lakka, Timo A., Timpson, Nicholas J., Tobin, Martin D., van der Harst, Pim, van der Meer, Peter, Ramachandran, Vasan S., Verweij, Niek, Virtamo, Jarmo, Völker, Uwe, Weir, David R., Zeggini, Eleftheria, Charchar, Fadi J., Wareham, Nicholas J., Langenberg, Claudia, Tomaszewski, Maciej, Butterworth, Adam S., Caulfield, Mark J., Danesh, John, Edwards, Todd L., Holm, Hilma, Hung, Adriana M., Lindgren, Cecilia M., Liu, Chunyu, Manning, Alisa K., Morris, Andrew P., Morrison, Alanna C., O’Donnell, Christopher J., Psaty, Bruce M., Saleheen, Danish, Stefansson, Kari, Boerwinkle, Eric, Chasman, Daniel I., Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B., and Howson, Joanna M. M.
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00832-z.
Published: 2021
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41. Abstract 15391: Genome-Wide Association Study of Over One Million Participants Identifies 49 Novel Loci Associated With Coronary Artery Disease

Author: Aragam, Krishna G, Jiang, Tao, Kanoni, Stavroula, Anuj, Goel, Wolford, Brooke, Surakka, Ida, Grace, Christopher, Thorleifsson, Gudmar, Nelson, Christopher, Roselli, Carolina, Hindy, George, Wang, Wallace, Munoz Venegas, Maria Loreto, Hopewell, Jemma C, Ruff, Christian, Sabatine, Marc S, Watkins, Hugh C, Danesh, John, Ellinor, Patrick T, Holm, Hilma, Clarke, Robert J, Schunkert, Heribert, Farrall, Martin, Erdmann, Jeanette, Stefansson, Kari, Thorsteinsdottir, Unnur, Willer, Cristen, Samani, Nilesh J, Deloukas, Panos, Kathiresan, Sekar, and Butterworth, Adam
Abstract: Genome-wide association studies (GWAS) have identified 164 common genetic loci associated with coronary artery disease (CAD), providing important biological and clinical insights, but the global burden of CAD remains high. Additional genetic discovery may further our understanding of CAD and related conditions and improve approaches to disease management. We performed GWAS and meta-analysis of CAD in 1,165,680 individuals across cohort studies, biobanks, and clinical trials (EPIC-CVD, HUNT, deCODE, GerMIFS, UK Biobank, Partners Biobank, Greek CAD, PEGASUS-TIMI 54, SAVOR-TIMI 53, ENGAGE-TIMI 48), as well as CARDIoGRAMplusC4D. Study-specific GWAS were performed by logistic regression or generalized mixed models. Conditional and joint analyses were used to identify independent genetic signals. We developed a genome-wide polygenic risk score (PRS) and tested it in the Malmo Diet and Cancer Study (MDCS; N= 22,872, N_CAD = 3,307; median follow-up 21 years). Analyses included 181,522 CAD cases and 984,158 controls. We identified 241 independent genetic variants associated with CAD at genome-wide significance (P < 5x10-8); 75 variants were not previously identified, representing 49 novel genomic regions. For the first time, genetic variation at HMG-CoA reductase, the target of statin therapy, reached genome-wide significance (HMGCR; p=1.31x10-8), validating the biological insights gained for CAD from such unbiased scans of the genome. Novel loci included regulators of: an anti-apoptotic protein (MCL1, p=1.0x10-14) and transmembrane tyrosine kinase (FER; p=1.1x10-9) linked to acute myeloid leukemia; fibrillin-2 (FBN2, p=9.7x10-10) and myosin heavy chain 11 (MYH11, p=2.5x10-9) associated with Marfan syndrome and thoracic aortic aneurysm; and an activin receptor (ACVR2A, p=1.5x10-8) involved in preeclampsia. Ingenuity analyses highlighted pathways mediating hepatic fibrosis. A genome-wide PRS predicted incident CAD in MDCS (HR=1.45 per-SD increase in PRS; p=1.1x10-100; C-stat=0.61). We identified 49 novel loci associated with CAD, bringing the total number of CAD-associated loci to 213. Our findings highlight non-traditional CAD risk factors with possible shared pathways, and provide a robust tool for genetic risk prediction.
Published: 2019
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42. Variants in NKX2-5and FLNCCause Dilated Cardiomyopathy and Sudden Cardiac Death

Author: Sveinbjornsson, Gardar, Olafsdottir, Eva F., Thorolfsdottir, Rosa B., Davidsson, Olafur B., Helgadottir, Anna, Jonasdottir, Adalbjorg, Jonasdottir, Aslaug, Bjornsson, Eythor, Jensson, Brynjar O., Arnadottir, Gudny A., Kristinsdottir, Hallfridur, Stephensen, Sigurdur S., Oskarsson, Gylfi, Gudbjartsson, Tomas, Sigurdsson, Emil L., Andersen, Karl, Danielsen, Ragnar, Arnar, David O., Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Sulem, Patrick, Thorgeirsson, Gudmundur, Gudbjartsson, Daniel F., Holm, Hilma, and Stefansson, Kari
Abstract: Supplemental Digital Content is available in the text.
Published: 2018
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43. Genetic Correction of PSA Values Using Sequence Variants Associated with PSA Levels

Author: Gudmundsson, Julius, Besenbacher, Soren, Sulem, Patrick, Gudbjartsson, Daniel F., Olafsson, Isleifur, Arinbjarnarson, Sturla, Agnarsson, Bjarni A., Benediktsdottir, Kristrun R., Isaksson, Helgi J., Kostic, Jelena P., Gudjonsson, Sigurjon A., Stacey, Simon N., Gylfason, Arnaldur, Sigurdsson, Asgeir, Holm, Hilma, Bjornsdottir, Unnur S., Eyjolfsson, Gudmundur I., Navarrete, Sebastian, Fuertes, Fernando, Garcia-Prats, Maria D., Polo, Eduardo, Checherita, Ionel A., Jinga, Mariana, Badea, Paula, Aben, Katja K., Schalken, Jack A., van Oort, Inge M., Sweep, Fred C., Helfand, Brian T., Davis, Michael, Donovan, Jenny L., Hamdy, Freddie C., Kristjansson, Kristleifur, Gulcher, Jeffrey R., Masson, Gisli, Kong, Augustine, Catalona, William J., Mayordomo, Jose I., Geirsson, Gudmundur, Einarsson, Gudmundur V., Barkardottir, Rosa B., Jonsson, Eirikur, Jinga, Viorel, Mates, Dana, Kiemeney, Lambertus A., Neal, David E., Thorsteinsdottir, Unnur, Rafnar, Thorunn, and Stefansson, Kari
Published: 2010
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44. Predicting atrial fibrillation

Author: Arnar, David O, Holm, Hilma, and Gudbjartsson, Daniel F
Published: 2009
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