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1. DanMAC5: a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals

Author

Banasik, Karina, Møller, Peter L., Techlo, Tanya R., Holm, Peter C., Walters, G. Bragi, Ingason, Andrés, Rosengren, Anders, Rohde, Palle D., Kogelman, Lisette J. A., Westergaard, David, Siggaard, Troels, Chmura, Piotr J., Chalmer, Mona A., Magnússon, Ólafur Þ., Þórisson, Guðmundur Á., Stefánsson, Hreinn, Guðbjartsson, Daníel F., Stefánsson, Kári, Olesen, Jes, Winther, Simon, Bøttcher, Morten, Brunak, Søren, Werge, Thomas, Nyegaard, Mette, and Hansen, Thomas F.

Published
2023
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2. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

3. Biallelic variants in POPDC2 cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy

Author

Genetica Groep Van Tintelen, Cancer, Child Health, Circulatory Health, Nicastro, Michele, Vermeer, Alexa M C, Postema, Pieter G, Tadros, Rafik, Bowling, Forrest Z, Aegisdottir, Hildur M, Tragante, Vinicius, Mach, Lukas, Postma, Alex V, Lodder, Elisabeth M, van Duijvenboden, Karel, Zwart, Rob, Beekman, Leander, Wu, Lingshuang, van der Zwaag, Paul A, Alders, Mariëlle, Allouba, Mona, Aguib, Yasmine, Santomel, J Luis, de Una, David, Monserrat, Lorenzo, Miranda, Antonio M A, Kanemaru, Kazumasa, Cranley, James, van Zeggeren, Ingeborg E, Aronica, Eleonora M A, Ripolone, Michela, Zanotti, Simona, Sveinbjornsson, Gardar, Ivarsdottir, Erna V, Hólm, Hilma, Guðbjartsson, Daníel F, Skúladóttir, Ástrós Th, Stefánsson, Kári, Nadauld, Lincoln, Knowlton, Kirk U, Ostrowski, Sisse Rye, Sørensen, Erik, Vesterager Pedersen, Ole Birger, Ghouse, Jonas, Rand, Søren, Bundgaard, Henning, Ullum, Henrik, Erikstrup, Christian, Aagaard, Bitten, Bruun, Mie Topholm, Christiansen, Mette, Jensen, Henrik K, Carere, Deanna Alexis, Cummings, Christopher T, Fishler, Kristen, Tøring, Pernille Mathiesen, Brusgaard, Klaus, Juul, Trine Maxel, Saaby, Lotte, Winkel, Bo Gregers, Mogensen, Jens, Fortunato, Francesco, Comi, Giacomo Pietro, Ronchi, Dario, van Tintelen, J Peter, Noseda, Michela, Airola, Michael V, Christiaans, Imke, Wilde, Arthur A M, Wilders, Ronald, Clur, Sally-Ann, Verkerk, Arie O, Bezzina, Connie R, Lahrouchi, Najim, Genetica Groep Van Tintelen, Cancer, Child Health, Circulatory Health, Nicastro, Michele, Vermeer, Alexa M C, Postema, Pieter G, Tadros, Rafik, Bowling, Forrest Z, Aegisdottir, Hildur M, Tragante, Vinicius, Mach, Lukas, Postma, Alex V, Lodder, Elisabeth M, van Duijvenboden, Karel, Zwart, Rob, Beekman, Leander, Wu, Lingshuang, van der Zwaag, Paul A, Alders, Mariëlle, Allouba, Mona, Aguib, Yasmine, Santomel, J Luis, de Una, David, Monserrat, Lorenzo, Miranda, Antonio M A, Kanemaru, Kazumasa, Cranley, James, van Zeggeren, Ingeborg E, Aronica, Eleonora M A, Ripolone, Michela, Zanotti, Simona, Sveinbjornsson, Gardar, Ivarsdottir, Erna V, Hólm, Hilma, Guðbjartsson, Daníel F, Skúladóttir, Ástrós Th, Stefánsson, Kári, Nadauld, Lincoln, Knowlton, Kirk U, Ostrowski, Sisse Rye, Sørensen, Erik, Vesterager Pedersen, Ole Birger, Ghouse, Jonas, Rand, Søren, Bundgaard, Henning, Ullum, Henrik, Erikstrup, Christian, Aagaard, Bitten, Bruun, Mie Topholm, Christiansen, Mette, Jensen, Henrik K, Carere, Deanna Alexis, Cummings, Christopher T, Fishler, Kristen, Tøring, Pernille Mathiesen, Brusgaard, Klaus, Juul, Trine Maxel, Saaby, Lotte, Winkel, Bo Gregers, Mogensen, Jens, Fortunato, Francesco, Comi, Giacomo Pietro, Ronchi, Dario, van Tintelen, J Peter, Noseda, Michela, Airola, Michael V, Christiaans, Imke, Wilde, Arthur A M, Wilders, Ronald, Clur, Sally-Ann, Verkerk, Arie O, Bezzina, Connie R, and Lahrouchi, Najim

Published
2024

4. Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor

Author

Winsvold, Bendik S., Harder, Aster V. E., Ran, Caroline, Chalmer, Mona A., Dalmasso, Maria Carolina, Ferkingstad, Egil, Tripathi, Kumar Parijat, Bacchelli, Elena, Børte, Sigrid, Fourier, Carmen, Petersen, Anja S., Vijfhuizen, Lisanne S., Magnusson, Sigurdur H., O'Connor, Emer, Bjornsdottir, Gyda, Häppölä, Paavo, Wang, Yen Feng, Callesen, Ida, Kelderman, Tim, Gallardo, Victor J., de Boer, Irene, Olofsgård, Felicia Jennysdotter, Heinze, Katja, Lund, Nunu, Thomas, Laurent F., Hsu, Chia Lin, Pirinen, Matti, Hautakangas, Heidi, Ribasés, Marta, Guerzoni, Simona, Sivakumar, Prasanth, Yip, Janice, Heinze, Axel, Küçükali, Fahri, Ostrowski, Sisse R., Pedersen, Ole B., Kristoffersen, Espen S., Martinsen, Amy E., Artigas, María S., Lagrata, Susie, Cainazzo, Maria Michela, Adebimpe, Joycee, Quinn, Olivia, Göbel, Carl, Cirkel, Anna, Volk, Alexander E., Heilmann-Heimbach, Stefanie, Skogholt, Anne Heidi, Gabrielsen, Maiken E., Wilbrink, Leopoldine A., Danno, Daisuke, Mehta, Dwij, Guðbjartsson, Daníel F., Rosendaal, Frits R., Willems van Dijk, Ko, Fronczek, Rolf, Wagner, Michael, Scherer, Martin, Göbel, Hartmut, Sleegers, Kristel, Sveinsson, Olafur A., Pani, Luca, Zoli, Michele, Ramos-Quiroga, Josep A., Dardiotis, Efthimios, Steinberg, Anna, Riedel-Heller, Steffi, Sjöstrand, Christina, Thorgeirsson, Thorgeir E., Stefansson, Hreinn, Southgate, Laura, Trembath, Richard C., Vandrovcova, Jana, Noordam, Raymond, Paemeleire, Koen, Stefansson, Kari, Fann, Cathy Shen Jang, Waldenlind, Elisabet, Tronvik, Erling, Jensen, Rigmor H., Chen, Shih Pin, Houlden, Henry, Terwindt, Gisela M., Kubisch, Christian, Maestrini, Elena, Vikelis, Michail, Pozo-Rosich, Patricia, Belin, Andrea C., Matharu, Manjit, van den Maagdenberg, Arn M. J. M., Hansen, Thomas F., Ramirez, Alfredo, Zwart, John-Anker, Winsvold, Bendik S., Harder, Aster V. E., Ran, Caroline, Chalmer, Mona A., Dalmasso, Maria Carolina, Ferkingstad, Egil, Tripathi, Kumar Parijat, Bacchelli, Elena, Børte, Sigrid, Fourier, Carmen, Petersen, Anja S., Vijfhuizen, Lisanne S., Magnusson, Sigurdur H., O'Connor, Emer, Bjornsdottir, Gyda, Häppölä, Paavo, Wang, Yen Feng, Callesen, Ida, Kelderman, Tim, Gallardo, Victor J., de Boer, Irene, Olofsgård, Felicia Jennysdotter, Heinze, Katja, Lund, Nunu, Thomas, Laurent F., Hsu, Chia Lin, Pirinen, Matti, Hautakangas, Heidi, Ribasés, Marta, Guerzoni, Simona, Sivakumar, Prasanth, Yip, Janice, Heinze, Axel, Küçükali, Fahri, Ostrowski, Sisse R., Pedersen, Ole B., Kristoffersen, Espen S., Martinsen, Amy E., Artigas, María S., Lagrata, Susie, Cainazzo, Maria Michela, Adebimpe, Joycee, Quinn, Olivia, Göbel, Carl, Cirkel, Anna, Volk, Alexander E., Heilmann-Heimbach, Stefanie, Skogholt, Anne Heidi, Gabrielsen, Maiken E., Wilbrink, Leopoldine A., Danno, Daisuke, Mehta, Dwij, Guðbjartsson, Daníel F., Rosendaal, Frits R., Willems van Dijk, Ko, Fronczek, Rolf, Wagner, Michael, Scherer, Martin, Göbel, Hartmut, Sleegers, Kristel, Sveinsson, Olafur A., Pani, Luca, Zoli, Michele, Ramos-Quiroga, Josep A., Dardiotis, Efthimios, Steinberg, Anna, Riedel-Heller, Steffi, Sjöstrand, Christina, Thorgeirsson, Thorgeir E., Stefansson, Hreinn, Southgate, Laura, Trembath, Richard C., Vandrovcova, Jana, Noordam, Raymond, Paemeleire, Koen, Stefansson, Kari, Fann, Cathy Shen Jang, Waldenlind, Elisabet, Tronvik, Erling, Jensen, Rigmor H., Chen, Shih Pin, Houlden, Henry, Terwindt, Gisela M., Kubisch, Christian, Maestrini, Elena, Vikelis, Michail, Pozo-Rosich, Patricia, Belin, Andrea C., Matharu, Manjit, van den Maagdenberg, Arn M. J. M., Hansen, Thomas F., Ramirez, Alfredo, and Zwart, John-Anker

Abstract

Objective The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL, Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023.

Published
2023

5. DanMAC5:a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals

Author

Banasik, Karina, Møller, Peter L., Techlo, Tanya R., Holm, Peter C., Walters, G. Bragi, Ingason, Andrés, Rosengren, Anders, Rohde, Palle D., Kogelman, Lisette J.A., Westergaard, David, Siggaard, Troels, Chmura, Piotr J., Chalmer, Mona A., Magnússon, Ólafur, Þórisson, Guðmundur, Stefánsson, Hreinn, Guðbjartsson, Daníel F., Stefánsson, Kári, Olesen, Jes, Winther, Simon, Bøttcher, Morten, Brunak, Søren, Werge, Thomas, Nyegaard, Mette, Hansen, Thomas F., Banasik, Karina, Møller, Peter L., Techlo, Tanya R., Holm, Peter C., Walters, G. Bragi, Ingason, Andrés, Rosengren, Anders, Rohde, Palle D., Kogelman, Lisette J.A., Westergaard, David, Siggaard, Troels, Chmura, Piotr J., Chalmer, Mona A., Magnússon, Ólafur, Þórisson, Guðmundur, Stefánsson, Hreinn, Guðbjartsson, Daníel F., Stefánsson, Kári, Olesen, Jes, Winther, Simon, Bøttcher, Morten, Brunak, Søren, Werge, Thomas, Nyegaard, Mette, and Hansen, Thomas F.

Abstract

Objectives Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https:// ident ifiers. org/ ega. datas et: EGAD0 00010 09756) and in a dedicated browser, DanMAC5 (available at www. danma c5. dk). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation. Data description Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high-quality summary level dataset of sequence variants., Objectives: Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https://identifiers.org/ega.dataset:EGAD00001009756) and in a dedicated browser, DanMAC5 (available at www.danmac5.dk). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation. Data description: Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high-quality summary level dataset of sequence variants.

Published
2023

6. Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland

Author

Björnsson, Eythór, primary, Thorgeirsson, Guðmundur, additional, Helgadóttir, Anna, additional, Thorleifsson, Guðmar, additional, Sveinbjörnsson, Garðar, additional, Kristmundsdóttir, Snaedís, additional, Jónsson, Hákon, additional, Jónasdóttir, Aðalbjörg, additional, Jónasdóttir, Áslaug, additional, Sigurðsson, Ásgeir, additional, Guðnason, Thórarinn, additional, Ólafsson, Ísleifur, additional, Sigurðsson, Emil L., additional, Sigurðardóttir, Ólöf, additional, Viðarsson, Brynjar, additional, Baldvinsson, Magnús, additional, Bjarnason, Ragnar, additional, Danielsen, Ragnar, additional, Matthíasson, Stefán E., additional, Thórarinsson, Björn L., additional, Grétarsdóttir, Sólveig, additional, Steinthórsdóttir, Valgerður, additional, Halldórsson, Bjarni V., additional, Andersen, Karl, additional, Arnar, Davíð O., additional, Jónsdóttir, Ingileif, additional, Guðbjartsson, Daníel F., additional, Hólm, Hilma, additional, Thorsteinsdóttir, Unnur, additional, Sulem, Patrick, additional, and Stefánsson, Kári, additional

Published
2021
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7. Association of Genetically Predicted Lipid Levels With the Extent of Coronary Atherosclerosis in Icelandic Adults

Author

Björnsson, Eythór, primary, Thorleifsson, Guðmar, additional, Helgadóttir, Anna, additional, Guðnason, Thórarinn, additional, Guðbjartsson, Tómas, additional, Andersen, Karl, additional, Grétarsdóttir, Sólveig, additional, Ólafsson, Ísleifur, additional, Tragante, Vinicius, additional, Ólafsson, Ólafur Hreiðar, additional, Jónsdóttir, Birna, additional, Eyjólfsson, Guðmundur I., additional, Sigurðardóttir, Ólöf, additional, Thorgeirsson, Guðmundur, additional, Guðbjartsson, Daníel F., additional, Thorsteinsdóttir, Unnur, additional, Hólm, Hilma, additional, and Stefánsson, Kári, additional

Published
2020
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8. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

Author

Deelen, Joris, Beekman, Marian, Uh, Hae-Won, Broer, Linda, Ayers, Kristin L, Tan, Qihua, Kamatani, Yoichiro, Bennet, Anna M, Tamm, Riin, Trompet, Stella, Guðbjartsson, Daníel F, Flachsbart, Friederike, Rose, Giuseppina, Viktorin, Alexander, Fischer, Krista, Nygaard, Marianne, Cordell, Heather J, Crocco, Paolina, van den Akker, Erik B, Böhringer, Stefan, Helmer, Quinta, Nelson, Christopher P, Saunders, Gary I, Alver, Maris, Andersen-Ranberg, Karen, Breen, Marie E, van der Breggen, Ruud, Caliebe, Amke, Capri, Miriam, Cevenini, Elisa, Collerton, Joanna C, Dato, Serena, Davies, Karen, Ford, Ian, Gampe, Jutta, Garagnani, Paolo, de Geus, Eco J C, Harrow, Jennifer, van Heemst, Diana, Heijmans, Bastiaan T, Heinsen, Femke-Anouska, Hottenga, Jouke-Jan, Hofman, Albert, Jeune, Bernard, Jonsson, Palmi V, Lathrop, Mark, Lechner, Doris, Martin-Ruiz, Carmen, Mcnerlan, Susan E, Mihailov, Evelin, Montesanto, Alberto, Mooijaart, Simon P, Murphy, Anne, Nohr, Ellen A, Paternoster, Lavinia, Postmus, Iris, Rivadeneira, Fernando, Ross, Owen A, Salvioli, Stefano, Sattar, Naveed, Schreiber, Stefan, Stefánsson, Hreinn, Stott, David J, Tiemeier, Henning, Uitterlinden, André G, Westendorp, Rudi G J, Willemsen, Gonneke, Samani, Nilesh J, Galan, Pilar, Sørensen, Thorkild I A, Boomsma, Dorret I, Jukema, J Wouter, Rea, Irene Maeve, Passarino, Giuseppe, de Craen, Anton J M, Christensen, Kaare, Nebel, Almut, Stefánsson, Kári, Metspalu, Andres, Magnusson, Patrik, Blanché, Hélène, Christiansen, Lene, Kirkwood, Thomas B L, van Duijn, Cornelia M, Franceschi, Claudio, Houwing-Duistermaat, Jeanine J, Slagboom, P Eline, Deelen, Joris, Beekman, Marian, Uh, Hae-Won, Broer, Linda, Ayers, Kristin L, Tan, Qihua, Kamatani, Yoichiro, Bennet, Anna M, Tamm, Riin, Trompet, Stella, Guðbjartsson, Daníel F, Flachsbart, Friederike, Rose, Giuseppina, Viktorin, Alexander, Fischer, Krista, Nygaard, Marianne, Cordell, Heather J, Crocco, Paolina, van den Akker, Erik B, Böhringer, Stefan, Helmer, Quinta, Nelson, Christopher P, Saunders, Gary I, Alver, Maris, Andersen-Ranberg, Karen, Breen, Marie E, van der Breggen, Ruud, Caliebe, Amke, Capri, Miriam, Cevenini, Elisa, Collerton, Joanna C, Dato, Serena, Davies, Karen, Ford, Ian, Gampe, Jutta, Garagnani, Paolo, de Geus, Eco J C, Harrow, Jennifer, van Heemst, Diana, Heijmans, Bastiaan T, Heinsen, Femke-Anouska, Hottenga, Jouke-Jan, Hofman, Albert, Jeune, Bernard, Jonsson, Palmi V, Lathrop, Mark, Lechner, Doris, Martin-Ruiz, Carmen, Mcnerlan, Susan E, Mihailov, Evelin, Montesanto, Alberto, Mooijaart, Simon P, Murphy, Anne, Nohr, Ellen A, Paternoster, Lavinia, Postmus, Iris, Rivadeneira, Fernando, Ross, Owen A, Salvioli, Stefano, Sattar, Naveed, Schreiber, Stefan, Stefánsson, Hreinn, Stott, David J, Tiemeier, Henning, Uitterlinden, André G, Westendorp, Rudi G J, Willemsen, Gonneke, Samani, Nilesh J, Galan, Pilar, Sørensen, Thorkild I A, Boomsma, Dorret I, Jukema, J Wouter, Rea, Irene Maeve, Passarino, Giuseppe, de Craen, Anton J M, Christensen, Kaare, Nebel, Almut, Stefánsson, Kári, Metspalu, Andres, Magnusson, Patrik, Blanché, Hélène, Christiansen, Lene, Kirkwood, Thomas B L, van Duijn, Cornelia M, Franceschi, Claudio, Houwing-Duistermaat, Jeanine J, and Slagboom, P Eline

Abstract

The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Published
2014

9. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

Author

Deelen, Joris, primary, Beekman, Marian, additional, Uh, Hae-Won, additional, Broer, Linda, additional, Ayers, Kristin L., additional, Tan, Qihua, additional, Kamatani, Yoichiro, additional, Bennet, Anna M., additional, Tamm, Riin, additional, Trompet, Stella, additional, Guðbjartsson, Daníel F., additional, Flachsbart, Friederike, additional, Rose, Giuseppina, additional, Viktorin, Alexander, additional, Fischer, Krista, additional, Nygaard, Marianne, additional, Cordell, Heather J., additional, Crocco, Paolina, additional, van den Akker, Erik B., additional, Böhringer, Stefan, additional, Helmer, Quinta, additional, Nelson, Christopher P., additional, Saunders, Gary I., additional, Alver, Maris, additional, Andersen-Ranberg, Karen, additional, Breen, Marie E., additional, van der Breggen, Ruud, additional, Caliebe, Amke, additional, Capri, Miriam, additional, Cevenini, Elisa, additional, Collerton, Joanna C., additional, Dato, Serena, additional, Davies, Karen, additional, Ford, Ian, additional, Gampe, Jutta, additional, Garagnani, Paolo, additional, de Geus, Eco J.C., additional, Harrow, Jennifer, additional, van Heemst, Diana, additional, Heijmans, Bastiaan T., additional, Heinsen, Femke-Anouska, additional, Hottenga, Jouke-Jan, additional, Hofman, Albert, additional, Jeune, Bernard, additional, Jonsson, Palmi V., additional, Lathrop, Mark, additional, Lechner, Doris, additional, Martin-Ruiz, Carmen, additional, Mcnerlan, Susan E., additional, Mihailov, Evelin, additional, Montesanto, Alberto, additional, Mooijaart, Simon P., additional, Murphy, Anne, additional, Nohr, Ellen A., additional, Paternoster, Lavinia, additional, Postmus, Iris, additional, Rivadeneira, Fernando, additional, Ross, Owen A., additional, Salvioli, Stefano, additional, Sattar, Naveed, additional, Schreiber, Stefan, additional, Stefánsson, Hreinn, additional, Stott, David J., additional, Tiemeier, Henning, additional, Uitterlinden, André G., additional, Westendorp, Rudi G.J., additional, Willemsen, Gonneke, additional, Samani, Nilesh J., additional, Galan, Pilar, additional, Sørensen, Thorkild I.A., additional, Boomsma, Dorret I., additional, Jukema, J. Wouter, additional, Rea, Irene Maeve, additional, Passarino, Giuseppe, additional, de Craen, Anton J.M., additional, Christensen, Kaare, additional, Nebel, Almut, additional, Stefánsson, Kári, additional, Metspalu, Andres, additional, Magnusson, Patrik, additional, Blanché, Hélène, additional, Christiansen, Lene, additional, Kirkwood, Thomas B.L., additional, van Duijn, Cornelia M., additional, Franceschi, Claudio, additional, Houwing-Duistermaat, Jeanine J., additional, and Slagboom, P. Eline, additional

Published
2014
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11. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K., Wilk, Jemma B., Morley, Michael P., Chaffin, Mark D., Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G., Ärnlöv, Johan, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Brandimarto, Jeffrey, Brown, Michael R., Buckbinder, Leonard, Carey, David J., Chasman, Daniel I., Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P., Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Dunn, Michael E., Engström, Gunnar, Esko, Tõnu, Felix, Stephan B., Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hyde, Craig L., Ingelsson, Erik, Jukema, J. Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian’an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B., März, Winfried, Melander, Olle, Mordi, Ify R., Morgan, Thomas, Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Niessner, Alexander, Niiranen, Teemu, O’Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N. A., Parry, Helen M., Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P. R., Rotter, Jerome I., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stender, Steen, Stott, David J., Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D., Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G., Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Waterworth, Dawn, Weeke, Peter E., Weiss, Raul, Wiggins, Kerri L., Xing, Heming, Yerges-Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J., McMurray, John J. V., Yang, Jian, Visscher, Peter M., Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A., Sattar, Naveed, Holmes, Michael V., Cappola, Thomas P., Asselbergs, Folkert W., Hingorani, Aroon D., Kuchenbaecker, Karoline, Ellinor, Patrick T., Lang, Chim C., Stefansson, Kari, Smith, J. Gustav, Vasan, Ramachandran S., Swerdlow, Daniel I., Lumbers, R. Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M., Habegger, Lukas, Hahn, Young, Hawes, Alicia, Van Hout, Cristopher, Jones, Marcus B., Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K., McCarthy, Shane, Mitnaul, Lyndon J., O’Dushlaine, Colm, Overton, John D., Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G., Schleicher, Thomas D., Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C., Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H., Widom, Louis, Wolf, Sarah E., Yadav, Ashish, and Ye, Bin

Subjects
2. Zero hunger, 631/443/592/2727, 631/208/205/2138, 692/699/75/230, 45/43, article, 692/308/174, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

12. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hedman, Åsa K., Helgadottir, Anna, Hillege, Hans, Hyde, Craig L., Jacob, Jaison, Jukema, J. Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay‐Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B., Marston, Nicholas A., März, Winfried, McMurray, John J.V., Melander, Olle, Melloni, Giorgio, Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Newton‐Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N.A., Paré, Guillaume, Perola, Markus, Perreault, Louis‐Philippe Lemieux, Portilla‐Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P.R., Roselli, Carolina, Rotter, Jerome I., Ruff, Christian T., Sabatine, Marc S., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stefansson, Kari, Stender, Steen, Stott, David J., Sveinbjörnsson, Garðar, Tammesoo, Mari‐Liis, Tardif, Jean‐Claude, Taylor, Kent D., Teder‐Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp‐Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G., Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M., Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Weeke, Peter E., Weiss, Raul, White, Harvey D., Wiggins, Kerri L., Xing, Heming, Yang, Jian, Yang, Yifan, Yerges‐Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B., Holm, Hilma, Sattar, Naveed, Lubitz, Steven A., Lanfear, David E., Shah, Svati, Dunn, Michael E., Wells, Quinn S., Asselbergs, Folkert W., Hingorani, Aroon D., Dubé, Marie‐Pierre, Samani, Nilesh J., Lang, Chim C., Cappola, Thomas P., Ellinor, Patrick T., Vasan, Ramachandran S., and Smith, J. Gustav

Subjects
Study Design, Cardiomyopathy, FOS: Biological sciences, Study Designs, Genetics, Heart failure, Biomarkers, 3. Good health, Association studies
Abstract

Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063, Funder: Swedish National Health Service, Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077, Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173, Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748, Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927, Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050, Funder: British Heart Foundation Cardiovascular Biomedicine, Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317, Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

13. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I, Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V, Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G, Asselin, Geraldine, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R, Brunner-La Rocca, Hans-Peter, Carey, David J, Chaffin, Mark D, Chasman, Daniel I, Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H, Chutkow, William, Cleland, John GF, Cook, James P, De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B, Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hedman, Åsa K, Helgadottir, Anna, Hillege, Hans, Hyde, Craig L, Jacob, Jaison, Jukema, J Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B, Marston, Nicholas A, März, Winfried, McMurray, John JV, Melander, Olle, Melloni, Giorgio, Mordi, Ify R, Morley, Michael P, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Newton-Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Paré, Guillaume, Perola, Markus, Perreault, Louis-Philippe Lemieux, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Roselli, Carolina, Rotter, Jerome I, Ruff, Christian T, Sabatine, Marc S, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stefansson, Kari, Stender, Steen, Stott, David J, Sveinbjörnsson, Garðar, Tammesoo, Mari-Liis, Tardif, Jean-Claude, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G, Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Weeke, Peter E, Weiss, Raul, White, Harvey D, Wiggins, Kerri L, Xing, Heming, Yang, Jian, Yang, Yifan, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B, Holm, Hilma, Sattar, Naveed, Lubitz, Steven A, Lanfear, David E, Shah, Svati, Dunn, Michael E, Wells, Quinn S, Asselbergs, Folkert W, Hingorani, Aroon D, Dubé, Marie-Pierre, Samani, Nilesh J, Lang, Chim C, Cappola, Thomas P, Ellinor, Patrick T, Vasan, Ramachandran S, and Smith, J Gustav

Subjects
Aged, 80 and over, Heart Failure, Male, Cardiomyopathy, Genomics, Middle Aged, 16. Peace & justice, Prognosis, 3. Good health, FOS: Biological sciences, Genetics, Humans, Female, Biomarkers, Association studies, Aged, Genome-Wide Association Study
Abstract

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

14. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin N A, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon P R, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John J V, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

15. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, Cyclin-Dependent Kinase Inhibitor p21, Heart Failure, Microfilament Proteins, Muscle Proteins, Coronary Artery Disease, Mendelian Randomization Analysis, Ventricular Function, Left, 3. Good health, Risk Factors, Case-Control Studies, Atrial Fibrillation, Humans, Apoptosis Regulatory Proteins, Cardiomyopathies, Carrier Proteins, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

17. Biallelic variants in POPDC2 cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy.

Author

Nicastro M, Vermeer AMC, Postema PG, Tadros R, Bowling FZ, Aegisdottir HM, Tragante V, Mach L, Postma AV, Lodder EM, van Duijvenboden K, Zwart R, Beekman L, Wu L, van der Zwaag PA, Alders M, Allouba M, Aguib Y, Santomel JL, de Una D, Monserrat L, Miranda AMA, Kanemaru K, Cranley J, van Zeggeren IE, Aronica EMA, Ripolone M, Zanotti S, Sveinbjornsson G, Ivarsdottir EV, Hólm H, Guðbjartsson DF, Skúladóttir ÁT, Stefánsson K, Nadauld L, Knowlton KU, Ostrowski SR, Sørensen E, Vesterager Pedersen OB, Ghouse J, Rand S, Bundgaard H, Ullum H, Erikstrup C, Aagaard B, Bruun MT, Christiansen M, Jensen HK, Carere DA, Cummings CT, Fishler K, Tøring PM, Brusgaard K, Juul TM, Saaby L, Winkel BG, Mogensen J, Fortunato F, Comi GP, Ronchi D, van Tintelen JP, Noseda M, Airola MV, Christiaans I, Wilde AAM, Wilders R, Clur SA, Verkerk AO, Bezzina CR, and Lahrouchi N

Abstract

POPDC2 encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia and morpholino knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. Using homology modelling we show that the identified POPDC2 variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies we demonstrated that, while co-expression of wild-type POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 variants found in the patients failed to increase TREK-1 current density. While patient muscle biopsy did not show clear myopathic disease, it showed significant reduction of the expression of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in any of the two proteins. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and 2 was most prevalent in AV node, AV node pacemaker and AV bundle cells. Sinoatrial node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse. Together, these results concur with predisposition to AV node disease in humans with loss-of-function variants in POPDC1 and POPDC2 and presence of sinus node disease in POPDC2, but not in POPDC1 related disease in human. Using population-level genetic data of more than 1 million individuals we showed that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for POPDC2 as the cause of a novel Mendelian autosomal recessive cardiac syndrome, consistent with previous work showing that mice and zebrafish deficient in functional POPDC2 display sinus and AV node dysfunction.

Published
2024
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18. Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

Author

Winsvold BS, Harder AVE, Ran C, Chalmer MA, Dalmasso MC, Ferkingstad E, Tripathi KP, Bacchelli E, Børte S, Fourier C, Petersen AS, Vijfhuizen LS, Magnusson SH, O'Connor E, Bjornsdottir G, Häppölä P, Wang YF, Callesen I, Kelderman T, Gallardo VJ, de Boer I, Olofsgård FJ, Heinze K, Lund N, Thomas LF, Hsu CL, Pirinen M, Hautakangas H, Ribasés M, Guerzoni S, Sivakumar P, Yip J, Heinze A, Küçükali F, Ostrowski SR, Pedersen OB, Kristoffersen ES, Martinsen AE, Artigas MS, Lagrata S, Cainazzo MM, Adebimpe J, Quinn O, Göbel C, Cirkel A, Volk AE, Heilmann-Heimbach S, Skogholt AH, Gabrielsen ME, Wilbrink LA, Danno D, Mehta D, Guðbjartsson DF, Rosendaal FR, Willems van Dijk K, Fronczek R, Wagner M, Scherer M, Göbel H, Sleegers K, Sveinsson OA, Pani L, Zoli M, Ramos-Quiroga JA, Dardiotis E, Steinberg A, Riedel-Heller S, Sjöstrand C, Thorgeirsson TE, Stefansson H, Southgate L, Trembath RC, Vandrovcova J, Noordam R, Paemeleire K, Stefansson K, Fann CS, Waldenlind E, Tronvik E, Jensen RH, Chen SP, Houlden H, Terwindt GM, Kubisch C, Maestrini E, Vikelis M, Pozo-Rosich P, Belin AC, Matharu M, van den Maagdenberg AMJM, Hansen TF, Ramirez A, and Zwart JA

Subjects
Male, Humans, Female, Risk Factors, Genome-Wide Association Study, Smoking adverse effects, Smoking genetics, Polymorphism, Single Nucleotide genetics, Genetic Predisposition to Disease genetics, Cluster Headache epidemiology, Cluster Headache genetics, Migraine Disorders
Abstract

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights., Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses., Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine., Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2023
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19. The genomics of heart failure: design and rationale of the HERMES consortium.

Author

Lumbers RT, Shah S, Lin H, Czuba T, Henry A, Swerdlow DI, Mälarstig A, Andersson C, Verweij N, Holmes MV, Ärnlöv J, Svensson P, Hemingway H, Sallah N, Almgren P, Aragam KG, Asselin G, Backman JD, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunner-La Rocca HP, Carey DJ, Chaffin MD, Chasman DI, Chazara O, Chen X, Chen X, Chung JH, Chutkow W, Cleland JGF, Cook JP, de Denus S, Dehghan A, Delgado GE, Denaxas S, Doney AS, Dörr M, Dudley SC, Engström G, Esko T, Fatemifar G, Felix SB, Finan C, Ford I, Fougerousse F, Fouodjio R, Ghanbari M, Ghasemi S, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gui H, Gutmann R, Haggerty CM, van der Harst P, Hedman ÅK, Helgadottir A, Hillege H, Hyde CL, Jacob J, Jukema JW, Kamanu F, Kardys I, Kavousi M, Khaw KT, Kleber ME, Køber L, Koekemoer A, Kraus B, Kuchenbaecker K, Langenberg C, Lind L, Lindgren CM, London B, Lotta LA, Lovering RC, Luan J, Magnusson P, Mahajan A, Mann D, Margulies KB, Marston NA, März W, McMurray JJV, Melander O, Melloni G, Mordi IR, Morley MP, Morris AD, Morris AP, Morrison AC, Nagle MW, Nelson CP, Newton-Cheh C, Niessner A, Niiranen T, Nowak C, O'Donoghue ML, Owens AT, Palmer CNA, Paré G, Perola M, Perreault LL, Portilla-Fernandez E, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Roselli C, Rotter JI, Ruff CT, Sabatine MS, Salo P, Salomaa V, van Setten J, Shalaby AA, Smelser DT, Smith NL, Stefansson K, Stender S, Stott DJ, Sveinbjörnsson G, Tammesoo ML, Tardif JC, Taylor KD, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Trompet S, Tuckwell D, Tyl B, Uitterlinden AG, Vaura F, Veluchamy A, Visscher PM, Völker U, Voors AA, Wang X, Wareham NJ, Weeke PE, Weiss R, White HD, Wiggins KL, Xing H, Yang J, Yang Y, Yerges-Armstrong LM, Yu B, Zannad F, Zhao F, Wilk JB, Holm H, Sattar N, Lubitz SA, Lanfear DE, Shah S, Dunn ME, Wells QS, Asselbergs FW, Hingorani AD, Dubé MP, Samani NJ, Lang CC, Cappola TP, Ellinor PT, Vasan RS, and Smith JG

Subjects
Aged, Aged, 80 and over, Female, Genomics, Humans, Male, Middle Aged, Prognosis, Genome-Wide Association Study, Heart Failure genetics
Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure., Methods and Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 -8 under an additive genetic model., Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Published
2021
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20. A sequence variant associating with educational attainment also affects childhood cognition.

Author

Gunnarsson B, Jónsdóttir GA, Björnsdóttir G, Konte B, Sulem P, Kristmundsdóttir S, Kehr B, Gústafsson Ó, Helgason H, Iordache PD, Ólafsson S, Frigge ML, Þorleifsson G, Arnarsdóttir S, Stefánsdóttir B, Giegling I, Djurovic S, Sundet KS, Espeseth T, Melle I, Hartmann AM, Thorsteinsdottir U, Kong A, Guðbjartsson DF, Ettinger U, Andreassen OA, Dan Rujescu, Halldórsson JG, Stefánsson H, Halldórsson BV, and Stefánsson K

Subjects
Academic Success, Adolescent, Adult, Child, Chromosomes, Human, Pair 2 genetics, Databases, Genetic, Educational Status, Female, Genetic Markers, Humans, Iceland, Male, Multifactorial Inheritance, Nuclear Proteins genetics, Cognition, Dyslexia genetics, Intelligence genetics, Polymorphism, Single Nucleotide
Abstract

Only a few common variants in the sequence of the genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores of educational attainment predict specific aspects of childhood cognition, as measured with IQ. Recently, three sequence variants were shown to associate with educational attainment, a confluence phenotype of genetic and environmental factors contributing to academic success. We show that one of these variants associating with educational attainment, rs4851266-T, also associates with Verbal IQ in dyslexic children (P = 4.3 × 10 -4 , β = 0.16 s.d.). The effect of 0.16 s.d. corresponds to 1.4 IQ points for heterozygotes and 2.8 IQ points for homozygotes. We verified this association in independent samples consisting of adults (P = 8.3 × 10 -5 , β = 0.12 s.d., combined P = 2.2 x 10 -7 , β = 0.14 s.d.). Childhood cognition is unlikely to be affected by education attained later in life, and the variant explains a greater fraction of the variance in verbal IQ than in educational attainment (0.7% vs 0.12%,. P = 1.0 × 10 -5 )., Competing Interests: B.G., G.A.J., G.B., P.S., S.K., B.Ke., O.G., H.H., P.I., S.O., M.F., G.Þ., S.A., B.S., U.Th., A.K., D.F.G., H.S., B.V.H. and K.S. are employees of deCODE Genetics/Amgen.

Published
2016
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