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14 results on '"Luan, Jianan"'

1. Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Author

Kentistou, Katherine, Kaisinger, Lena, Stankovic, Stasa, Vaudel, Marc, Mendes de Oliveira, Edson, Messina, Andrea, Walters, Robin, Liu, Xiaoxi, Busch, Alexander, Helgason, Hannes, Thompson, Deborah, Santoni, Federico, Petricek, Konstantin, Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, Daniel, Bratland, Eirik, Lin, Kuang, Gardner, Eugene, Zhao, Yajie, Jia, Raina, Terao, Chikashi, Riggan, Marjorie, Bolla, Manjeet, Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan, Broer, Linda, Campbell, Archie, Chasman, Daniel, Cousminer, Diana, Franceschini, Nora, Franke, Lude, Girotto, Giorgia, He, Chunyan, Järvelin, Marjo-Riitta, Joshi, Peter, Kamatani, Yoichiro, Karlsson, Robert, Luan, Jianan, Lunetta, Kathryn, Mägi, Reedik, Mangino, Massimo, Medland, Sarah, Meisinger, Christa, Noordam, Raymond, Nutile, Teresa, Concas, Maria, Polašek, Ozren, Porcu, Eleonora, Ring, Susan, Sala, Cinzia, Smith, Albert, Tanaka, Toshiko, van der Most, Peter, Vitart, Veronique, Wang, Carol, Willemsen, Gonneke, Zygmunt, Marek, Ahearn, Thomas, Andrulis, Irene, Anton-Culver, Hoda, Antoniou, Antonis, Auer, Paul, Barnes, Catriona, Beckmann, Matthias, Berrington de Gonzalez, Amy, Bogdanova, Natalia, Bojesen, Stig, Brenner, Hermann, Buring, Julie, Canzian, Federico, Chang-Claude, Jenny, Couch, Fergus, Cox, Angela, Crisponi, Laura, Czene, Kamila, Daly, Mary, Demerath, Ellen, Dennis, Joe, Devilee, Peter, De Vivo, Immaculata, Dörk, Thilo, Dunning, Alison, Dwek, Miriam, Eriksson, Johan, Fasching, Peter, Fernandez-Rhodes, Lindsay, Ferreli, Liana, Fletcher, Olivia, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José, González-Neira, Anna, Grallert, Harald, Guénel, Pascal, Haiman, Christopher, Hall, Per, Hamann, Ute, and Hakonarson, Hakon

Subjects
Humans, Female, Menarche, Puberty, Gene Frequency, Animals, Multifactorial Inheritance, Mice, Genome-Wide Association Study, Adolescent, Puberty, Precocious, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, Puberty, Delayed, Child
Abstract

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Published
2024

2. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Author

Keaton, Jacob, Kamali, Zoha, Xie, Tian, Vaez, Ahmad, Williams, Ariel, Goleva, Slavina, Ani, Alireza, Evangelou, Evangelos, Hellwege, Jacklyn, Yengo, Loic, Young, William, Traylor, Matthew, Giri, Ayush, Zheng, Zhili, Zeng, Jian, Chasman, Daniel, Morris, Andrew, Caulfield, Mark, Hwang, Shih-Jen, Kooner, Jaspal, Conen, David, Attia, John, Morrison, Alanna, Loos, Ruth, Kristiansson, Kati, Schmidt, Reinhold, Hicks, Andrew, Pramstaller, Peter, Nelson, Christopher, Samani, Nilesh, Risch, Lorenz, Gyllensten, Ulf, Melander, Olle, Riese, Harriette, Wilson, James, Campbell, Harry, Rich, Stephen, Psaty, Bruce, Lu, Yingchang, Guo, Xiuqing, Rice, Kenneth, Vollenweider, Peter, Sundström, Johan, Langenberg, Claudia, Tobin, Martin, Giedraitis, Vilmantas, Luan, Jianan, Tuomilehto, Jaakko, Kutalik, Zoltan, Ripatti, Samuli, Salomaa, Veikko, Girotto, Giorgia, Trompet, Stella, Jukema, J, van der Harst, Pim, Ridker, Paul, Giulianini, Franco, Vitart, Veronique, Goel, Anuj, Watkins, Hugh, Harris, Sarah, Deary, Ian, van der Most, Peter, Oldehinkel, Albertine, Keavney, Bernard, Hayward, Caroline, Campbell, Archie, Boehnke, Michael, Scott, Laura, Boutin, Thibaud, Mamasoula, Chrysovalanto, Järvelin, Marjo-Riitta, Peters, Annette, Gieger, Christian, Lakatta, Edward, Cucca, Francesco, Hui, Jennie, Knekt, Paul, Enroth, Stefan, De Borst, Martin, Polašek, Ozren, Concas, Maria, Catamo, Eulalia, Cocca, Massimiliano, Li-Gao, Ruifang, Hofer, Edith, Schmidt, Helena, Spedicati, Beatrice, Waldenberger, Melanie, Strachan, David, Laan, Maris, Teumer, Alexander, Dörr, Marcus, Gudnason, Vilmundur, Cook, James, Ruggiero, Daniela, Kolcic, Ivana, Boerwinkle, Eric, Traglia, Michela, and Lehtimäki, Terho

Subjects
Female, Humans, Male, Blood Pressure, Genetic Predisposition to Disease, Genetic Risk Score, Genome-Wide Association Study, Hypertension, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Risk Factors
Abstract

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P

Published
2024

3. Genetic insights into resting heart rate and its role in cardiovascular disease.

Author

van de Vegte, Yordi, Eppinga, Ruben, van der Ende, M, Hagemeijer, Yanick, Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert, Tan, Vanessa, Arking, Dan, Ntalla, Ioanna, Appel, Emil, Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing, Isaacs, Aaron, Wang, Lihua, Luan, Jianan, Hwang, Shih-Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus, Guo, Xiuqing, Lin, Henry, Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond, Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke, Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung, Weiss, Stefan, Sim, Xueling, Li, Hengtong, van der Most, Peter, Nolte, Ilja, Lyytikäinen, Leo-Pekka, Said, M, Witte, Daniel, Iribarren, Carlos, Launer, Lenore, Ring, Susan, de Vries, Paul, Sever, Peter, Linneberg, Allan, Bottinger, Erwin, Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Arnar, David, Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley, Silva, Claudia, Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu, Mohlke, Karen, Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari, Rao, Dabeeru, Cornelis, Marilyn, Faul, Jessica, Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie, and Sinner, Moritz

Subjects
Humans, Cardiovascular Diseases, Risk Factors, Heart Rate, Genetic Predisposition to Disease, Atrial Fibrillation, Mendelian Randomization Analysis, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Published
2023

4. Disentangling the genetics of lean mass.

Author

Karasik, David, Zillikens, M, Hsu, Yi-Hsiang, Aghdassi, Ali, Akesson, Kristina, Amin, Najaf, Barroso, Inês, Bennett, David, Bertram, Lars, Bochud, Murielle, Borecki, Ingrid, Broer, Linda, Buchman, Aron, Byberg, Liisa, Campbell, Harry, Campos-Obando, Natalia, Cauley, Jane, Cawthon, Peggy, Chambers, John, Chen, Zhao, Cho, Nam, Choi, Hyung, Chou, Wen-Chi, Cummings, Steven, de Groot, Lisette, De Jager, Phillip, Demuth, Ilja, Diatchenko, Luda, Econs, Michael, Eiriksdottir, Gudny, Enneman, Anke, Eriksson, Joel, Eriksson, Johan, Estrada, Karol, Evans, Daniel, Feitosa, Mary, Fu, Mao, Gieger, Christian, Grallert, Harald, Gudnason, Vilmundur, Lenore, Launer, Hayward, Caroline, Hofman, Albert, Homuth, Georg, Huffman, Kim, Husted, Lise, Illig, Thomas, Ingelsson, Erik, Ittermann, Till, Jansson, John-Olov, Johnson, Toby, Biffar, Reiner, Jordan, Joanne, Jula, Antti, Karlsson, Magnus, Khaw, Kay-Tee, Kilpeläinen, Tuomas, Klopp, Norman, Kloth, Jacqueline, Koller, Daniel, Kooner, Jaspal, Kraus, William, Kritchevsky, Stephen, Kutalik, Zoltán, Kuulasmaa, Teemu, Kuusisto, Johanna, Laakso, Markku, Lahti, Jari, Langdahl, Bente, Lerch, Markus, Lewis, Joshua, Lill, Christina, Lind, Lars, Lindgren, Cecilia, Liu, Yongmei, Livshits, Gregory, Ljunggren, Östen, Loos, Ruth, Lorentzon, Mattias, Luan, Jianan, Luben, Robert, Malkin, Ida, McGuigan, Fiona, Medina-Gomez, Carolina, Meitinger, Thomas, Melhus, Håkan, Mellström, Dan, Michaëlsson, Karl, Mitchell, Braxton, Morris, Andrew, Mosekilde, Leif, Nethander, Maria, Newman, Anne, OConnell, Jeffery, Oostra, Ben, Orwoll, Eric, Palotie, Aarno, Peacock, Munro, Perola, Markus, and Peters, Annette

Subjects
ADAMTS Proteins, Absorptiometry, Photon, Adipose Tissue, Adolescent, Adult, Aged, Aged, 80 and over, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Composition, Body Fluid Compartments, Electric Impedance, Extracellular Matrix Proteins, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Muscle, Skeletal, Phenotype, Polymorphism, Single Nucleotide, RNA-Binding Proteins, Receptor, Melanocortin, Type 4, Versicans, White People, Young Adult
Abstract

BACKGROUND: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. OBJECTIVES: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. METHODS: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). RESULTS: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as sumo wrestler loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed body builder loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in body builder loci were associated with metabolic protection. CONCLUSIONS: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Published
2019

5. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, Danesh, John, and Spector, Timothy

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Amidohydrolases, Autoimmune Diseases, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D, White People
Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018

6. Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.

Author

Williamson, Alice, Williamson, Alice, Norris, Dougall, Yin, Xianyong, Broadaway, K, Moxley, Anne, Vadlamudi, Swarooparani, Wilson, Emma, Jackson, Anne, Ahuja, Vasudha, Andersen, Mette, Arzumanyan, Zorayr, Bonnycastle, Lori, Bornstein, Stefan, Bretschneider, Maxi, Buchanan, Thomas, Chang, Yi-Cheng, Chuang, Lee-Ming, Chung, Ren-Hua, Clausen, Tine, Damm, Peter, Delgado, Graciela, de Mello, Vanessa, Dupuis, Josée, Dwivedi, Om, Erdos, Michael, Fernandes Silva, Lilian, Frayling, Timothy, Gieger, Christian, Goodarzi, Mark, Guo, Xiuqing, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Hatem, Gad, Herrmann, Sandra, Højlund, Kurt, Horn, Katrin, Hsueh, Willa, Hung, Yi-Jen, Hwu, Chii-Min, Jonsson, Anna, Kårhus, Line, Kleber, Marcus, Kovacs, Peter, Lakka, Timo, Lauzon, Marie, Lee, I-Te, Lindgren, Cecilia, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Luan, Jianan, Aly, Dina, Mathiesen, Elisabeth, Moissl, Angela, Morris, Andrew, Narisu, Narisu, Perakakis, Nikolaos, Peters, Annette, Prasad, Rashmi, Rodionov, Roman, Roll, Kathryn, Rundsten, Carsten, Sarnowski, Chloé, Savonen, Kai, Scholz, Markus, Sharma, Sapna, Stinson, Sara, Suleman, Sufyan, Tan, Jingyi, Taylor, Kent, Uusitupa, Matti, Vistisen, Dorte, Witte, Daniel, Walther, Romy, Wu, Peitao, Xiang, Anny, Zethelius, Björn, Ahlqvist, Emma, Bergman, Richard, Chen, Yii-Der, Collins, Francis, Fall, Tove, Florez, Jose, Fritsche, Andreas, Grallert, Harald, Groop, Leif, Hansen, Torben, Koistinen, Heikki, Komulainen, Pirjo, Laakso, Markku, Lind, Lars, Loeffler, Markus, März, Winfried, Meigs, James, Raffel, Leslie, Rauramaa, Rainer, Schwarz, Peter, Stumvoll, Michael, Sundström, Johan, Williamson, Alice, Williamson, Alice, Norris, Dougall, Yin, Xianyong, Broadaway, K, Moxley, Anne, Vadlamudi, Swarooparani, Wilson, Emma, Jackson, Anne, Ahuja, Vasudha, Andersen, Mette, Arzumanyan, Zorayr, Bonnycastle, Lori, Bornstein, Stefan, Bretschneider, Maxi, Buchanan, Thomas, Chang, Yi-Cheng, Chuang, Lee-Ming, Chung, Ren-Hua, Clausen, Tine, Damm, Peter, Delgado, Graciela, de Mello, Vanessa, Dupuis, Josée, Dwivedi, Om, Erdos, Michael, Fernandes Silva, Lilian, Frayling, Timothy, Gieger, Christian, Goodarzi, Mark, Guo, Xiuqing, Gustafsson, Stefan, Hakaste, Liisa, Hammar, Ulf, Hatem, Gad, Herrmann, Sandra, Højlund, Kurt, Horn, Katrin, Hsueh, Willa, Hung, Yi-Jen, Hwu, Chii-Min, Jonsson, Anna, Kårhus, Line, Kleber, Marcus, Kovacs, Peter, Lakka, Timo, Lauzon, Marie, Lee, I-Te, Lindgren, Cecilia, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Luan, Jianan, Aly, Dina, Mathiesen, Elisabeth, Moissl, Angela, Morris, Andrew, Narisu, Narisu, Perakakis, Nikolaos, Peters, Annette, Prasad, Rashmi, Rodionov, Roman, Roll, Kathryn, Rundsten, Carsten, Sarnowski, Chloé, Savonen, Kai, Scholz, Markus, Sharma, Sapna, Stinson, Sara, Suleman, Sufyan, Tan, Jingyi, Taylor, Kent, Uusitupa, Matti, Vistisen, Dorte, Witte, Daniel, Walther, Romy, Wu, Peitao, Xiang, Anny, Zethelius, Björn, Ahlqvist, Emma, Bergman, Richard, Chen, Yii-Der, Collins, Francis, Fall, Tove, Florez, Jose, Fritsche, Andreas, Grallert, Harald, Groop, Leif, Hansen, Torben, Koistinen, Heikki, Komulainen, Pirjo, Laakso, Markku, Lind, Lars, Loeffler, Markus, März, Winfried, Meigs, James, Raffel, Leslie, Rauramaa, Rainer, Schwarz, Peter, Stumvoll, Michael, and Sundström, Johan

Abstract

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

Published
2023

7. Rare and low-frequency coding variants alter human adult height

Author

Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R., Kjaer, Troels R., Fine, Rebecca S., Lu, Yingchang, Schurmann, Claudia, Highland, Heather M., Reger, Sina, Thorleifsson, Gudmar, Justice, Anne E., Lamparter, David, Stirrups, Kathleen E., Turcot, Valrie, Young, Kristin L., Winkler, Thomas W., Esko, Tnu, Karaderi, Tugce, Locke, Adam E., Masca, Nicholas G. D., Ng, Maggie C. Y., Mudgal, Poorva, Rivas, Manuel A., Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K., Adair, Linda S., Alam, Dewan S., Albrecht, Eva, Allin, Kristine H., Allison, Matthew, Amouyel, Philippe, Appel, Emil V., Arveiler, Dominique, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Banas, Bernhard, Bang, Lia E., Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blher, Matthias, Boeing, Heiner, Boerwinkle, Eric, Bger, Carsten A., Bonnycastle, Lori L., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Burt, Amber A., Butterworth, Adam S., Carey, David J., Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J., Cuellar-Partida, Gabriel, Danesh, John, Davies, Gail, de Bakker, Paul I. W., de Borst, Gert J., de Denus, Simon, de Groot, Mark C. H., de Mutsert, Rene, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., den Hollander, Anneke I., Dennis, Joe G., Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dunning, Alison M., Easton, Douglas F., Ebeling, Tapani, Edwards, Todd L., Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Faul, Jessica D., Feitosa, Mary F., Feng, Shuang, Ferrannini, Ele, Ferrario, Marco M., Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franks, Paul W., Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Giri, Ayush, Girotto, Giorgia, Gordon, Scott D., Gordon-Larsen, Penny, Gorski, Mathias, Grarup, Niels, Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Hayward, Caroline, He, Liang, Heid, Iris M., Heikkil, Kauko, Helgeland, yvind, Hernesniemi, Jussi, Hewitt, Alex W., Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Hovingh, G. Kees, Howson, Joanna M. M., Hoyng, Carel B., Huang, Paul L., Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Hkan, Jarvik, Gail P., Jensen, Gorm B., Jhun, Min A., Jia, Yucheng, Jiang, Xuejuan, Johansson, Stefan, Jrgensen, Marit E., Jrgensen, Torben, Jousilahti, Pekka, Jukema, J. Wouter, Kahali, Bratati, Kahn, Ren S., Khnen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Keeman, Renske, Kiemeney, Lambertus A., Kitajima, Hidetoshi, Kluivers, Kirsten B., Kocher, Thomas, Komulainen, Pirjo, Kontto, Jukka, Kooner, Jaspal S., Kooperberg, Charles, Kovacs, Peter, Kriebel, Jennifer, Kuivaniemi, Helena, Kry, Sbastien, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lakka, Timo A., Lange, Ethan M., Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Larson, Eric B., Lee, I-Te, Lehtimki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindstrm, Jaana, Linneberg, Allan, Liu, Yeheng, Liu, Yongmei, Lophatananon, Artitaya, Luan, Jianan, Lubitz, Steven A., Lyytikinen, Leo-Pekka, Mackey, David A., Madden, Pamela A. F., Manning, Alisa K., Mnnist, Satu, Marenne, Galle, Marten, Jonathan, Martin, Nicholas G., Mazul, Angela L., Meidtner, Karina, Metspalu, Andres, Mitchell, Paul, Mohlke, Karen L., Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew D., Morris, Andrew P., Mller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Nauck, Matthias, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njlstad, Pl R., Nordestgaard, Brge G., Ntalla, Ioanna, OConnel, Jeffrey R., Oksa, Heikki, Loohuis, Loes M. Olde, Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Markus, Perry, James A., Perry, John R. B., Person, Thomas N., Pirie, Ailith, Polasek, Ozren, Posthuma, Danielle, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renstrm, Frida, Ridker, Paul M., Rioux, John D., Robertson, Neil, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sandow, Kevin, Sapkota, Yadav, Sattar, Naveed, Schmidt, Marjanka K., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert Vernon, Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Steinthorsdottir, Valgerdur, Stringham, Heather M., Stumvoll, Michael, Surendran, Praveen, t Hart, Leen M., Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorsteinsdottir, Unnur, Thuesen, Betina H., Tnjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, Andr G., Ulivi, Sheila, van der Laan, Sander W., Van Der Leij, Andries R., van Duijn, Cornelia M., van Schoor, Natasja M., van Setten, Jessica, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Edwards, Digna R. Velez, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vozzi, Diego, Walker, Mark, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Wareham, Nicholas J., Warren, Helen R., Wessel, Jennifer, Willems, Sara M., Wilson, James G., Witte, Daniel R., Woods, Michael O., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Rotter, Jerome I, Boehnke, Michael, Kathiresan, Sekar, McCarthy, Mark I., Willer, Cristen J., Stefansson, Kari, Borecki, Ingrid B., Liu, Dajiang J., North, Kari E., Heard-Costa, Nancy L., Pers, Tune H., Lindgren, Cecilia M., Oxvig, Claus, Kutalik, Zoltn, Rivadeneira, Fernando, Loos, Ruth J. F., Frayling, Timothy M., Hirschhorn, Joel N., Deloukas, Panos, and Lettre, Guillaume

Subjects
Body height -- Genetic aspects, Genetic variation -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.14.8%) and effects of up to 2centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 12centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways., Author(s): Eirini Marouli [1]; Mariaelisa Graff [2]; Carolina Medina-Gomez [3, 4]; Ken Sin Lo [5]; Andrew R. Wood [6]; Troels R. Kjaer [7]; Rebecca S. Fine [8, 9, 10]; Yingchang [...]

Published
2017
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8. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, Momoko, Beaumont, Robin N., Day, Felix R., Warrington, Nicole M., Kooijman, Marjolein N., Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R., Gaulton, Kyle J., Grarup, Niels, Bradfield, Jonathan P., Strachan, David P., Li-Gao, Ruifang, Ahluwalia, Tarunveer S., Kreiner, Eskil, Rueedi, Rico, Lyytikinen, Leo-Pekka, Cousminer, Diana L., Wu, Ying, Thiering, Elisabeth, Wang, Carol A., Have, Christian T., Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K., Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitknen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M., Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A., Zondervan, Krina T., Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M., Bennett, Amanda J., Rahmioglu, Nilufer, Nyholt, Dale R., Ma, Ronald C. W., Tam, Claudia H. T., Tam, Wing Hung, Ganesh, Santhi K., van Rooij, Frank J. A., Jones, Samuel E., Loh, Po-Ru, Ruth, Katherine S., Tuke, Marcus A., Tyrrell, Jessica, Wood, Andrew R., Yaghootkar, Hanieh, Scholtens, Denise M., Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M., Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E., Murcia, Mario, van Beijsterveldt, Catharina E. M., Willemsen, Gonneke, Appel, Emil V. R., Fonvig, Cilius E., Trier, Caecilie, Tiesler, Carla M. T., Standl, Marie, Kutalik, Zoltn, Bons-Guarch, Slvia, Hougaard, David M., Snchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V., de Haan, Hugoline G., Rosendaal, Frits R., Medina-Gomez, Carolina, Ring, Susan M., Hemani, Gibran, McMahon, George, Robertson, Neil R., Groves, Christopher J., Langenberg, Claudia, Luan, Jianan, Scott, Robert A., Zhao, Jing Hua, Mentch, Frank D., MacKenzie, Scott M., Reynolds, Rebecca M., Lowe, William L., Tnjes, Anke, Stumvoll, Michael, Lindi, Virpi, Lakka, Timo A., van Duijn, Cornelia M., Kiess, Wieland, Krner, Antje, Srensen, Thorkild I. A., Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T., Zeggini, Eleftheria, Dedoussis, George V., Teo, Yik-Ying, Saw, Seang-Mei, Melbye, Mads, Campbell, Harry, Wilson, James F., Vrijheid, Martine, de Geus, Eco J. C. N., Boomsma, Dorret I., Kadarmideen, Haja N., Holm, Jens-Christian, Hansen, Torben, Sebert, Sylvain, Hattersley, Andrew T., Beilin, Lawrence J., Newnham, John P., Pennell, Craig E., Heinrich, Joachim, Adair, Linda S., Borja, Judith B., Mohlke, Karen L., Eriksson, Johan G., Widn, Elisabeth, Khnen, Mika, Viikari, Jorma S., Lehtimki, Terho, Vollenweider, Peter, Bnnelykke, Klaus, Bisgaard, Hans, Mook-Kanamori, Dennis O., Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andr G., Pisinger, Charlotta, Pedersen, Oluf, Power, Christine, Hyppnen, Elina, Wareham, Nicholas J., Hakonarson, Hakon, Davies, Eleanor, Walker, Brian R., Jaddoe, Vincent W. V., Jrvelin, Marjo-Riitta, Grant, Struan F. A., Vaag, Allan A., Lawlor, Debbie A., Frayling, Timothy M., Smith, George Davey, Morris, Andrew P., Ong, Ken K., Felix, Janine F., Timpson, Nicholas J., Perry, John R. B., Evans, David M., McCarthy, Mark I., and Freathy, Rachel M.

Subjects
Genome-wide association studies, Birth weight -- Genetic aspects -- Health aspects, Metabolic diseases -- Risk factors -- Genetic aspects, Cardiovascular diseases -- Risk factors -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Momoko Horikoshi [1, 2]; Robin N. Beaumont [3]; Felix R. Day [4]; Nicole M. Warrington [5, 6]; Marjolein N. Kooijman [7, 8, 9]; Juan Fernandez-Tajes [1]; Bjarke Feenstra [10]; [...]

Published
2016
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9. Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Author

Sakornsakolpat, Phuwanat, Prokopenko, Dmitry, Lamontagne, Maxime, Reeve, Nicola F., Guyatt, Anna L., Jackson, Victoria E., Shrine, Nick, Qiao, Dandi, Bartz, Traci M., Kim, Deog Kyeom, Lee, Mi Kyeong, Latourelle, Jeanne C., Li, Xingnan, Morrow, Jarrett D., Obeidat, Ma'en, Wyss, Annah B., Bakke, Per, Barr, R. Graham, Beaty, Terri H., Belinsky, Steven A., Brusselle, Guy G., Crapo, James D., de Jong, Kim, DeMeo, Dawn L., Fingerlin, Tasha E., Gharib, Sina A., Gulsvik, Amund, Hall, Ian P., Hokanson, John E., Kim, Woo Jin, Lomas, David A., London, Stephanie J., Meyers, Deborah A., O'Connor, George T., Rennard, Stephen, I, Schwartz, David A., Sliwinski, Pawel, Sparrow, David, Strachan, David P., Tal-Singer, Ruth, Tesfaigzi, Yohannes, Vestbo, Jorgen, Vonk, Judith M., Yim, Jae-Joon, Zhou, Xiaobo, Bosse, Yohan, Manichaikul, Ani, Lahousse, Lies, Silverman, Edwin K., Boezen, H. Marike, Wain, Louise, V, Tobin, Martin D., Hobbs, Brian D., Cho, Michael H., Batini, Chiara, Zhao, Jing Hua, Wielscher, Matthias, Weiss, Stefan, Kentistou, Katherine A., Cook, James P., Hui, Jennie, Karrasch, Stefan, Imboden, Medea, Harris, Sarah E., Marten, Jonathan, Enroth, Stefan, Kerr, Shona M., Surakka, Ida, Vitart, Veronique, Lehtimaki, Terho, Ewert, Ralf, Gieger, Christian, Homuth, Georg, Joshi, Peter K., Langenberg, Claudia, Lind, Lars, Luan, Jianan, Mahajan, Anubha, Murray, Alison, Porteous, David J., Rawal, Rajesh, Smith, Blair H., Timmers, Paul R. H. J., Raitakari, Olli T., Kahonen, Mika, Polasek, Ozren, Gyllensten, Ulf B., Rudan, Igor, Deary, Ian J., Probst-Hensch, Nicole M., Schulz, Holger, James, Alan L., Wilson, James F., Stubbe, Beate, Zeggini, Eleftheria, Jarvelin, Marjo-Riitta, Wareham, Nick, Hayward, Caroline, Morris, Andrew P., Agusti, Alvar, Anderson, Wayne, Bakerly, Nawar, Bals, Robert, Barnes, Kathleen C., Bleecker, Eugene R., Bowler, Russell, Brightling, Christopher, de Bruijne, Marleen, Castaldi, Peterj, Celli, Bartolome, Coxson, Harvey O., Crystal, Ron, de Jong, Pim, Dirksen, Asger, Dy, Jennifer, Foreman, Marilyn, Garcia-Aymerich, Judith, Gevenois, Pierre, Ghosh, Soumitra, Gietema, Hester, Hansel, Nadia, Hersh, Craig P., Hoffman, Eric, Kalsheker, Noor, Kauczor, Hans-Ulrich, Laitinen, Tarja, Lambrechts, Diether, Litonjua, Augusto A., Loth, Daan W., Lutz, Sharon M., Lynch, David, MacNee, William, McDonald, Merry-Lynn, Newell, John D., Nordestgaard, Borge G., Oh, Yeon-Mok, Pare, Peter D., Pistolesi, Massimo, Postma, Dirkje S., Puhan, Milo, Regan, Elizabeth, Rich, Stephen S., Seo, Joon Beom, Short, Andrea, Stoel, Berend, Sverzellati, Nicola, ter Riet, Gerben, Van Beek, Edwin J. R., Van Ginneken, Bram, Vogelmeier, Claus F., Wanner, Adam, Washko, George, Wauters, Els, Wouters, Emiel F. M., Young, Robert P., Zeigler-Heitbrock, Loems, Sakornsakolpat, Phuwanat, Prokopenko, Dmitry, Lamontagne, Maxime, Reeve, Nicola F., Guyatt, Anna L., Jackson, Victoria E., Shrine, Nick, Qiao, Dandi, Bartz, Traci M., Kim, Deog Kyeom, Lee, Mi Kyeong, Latourelle, Jeanne C., Li, Xingnan, Morrow, Jarrett D., Obeidat, Ma'en, Wyss, Annah B., Bakke, Per, Barr, R. Graham, Beaty, Terri H., Belinsky, Steven A., Brusselle, Guy G., Crapo, James D., de Jong, Kim, DeMeo, Dawn L., Fingerlin, Tasha E., Gharib, Sina A., Gulsvik, Amund, Hall, Ian P., Hokanson, John E., Kim, Woo Jin, Lomas, David A., London, Stephanie J., Meyers, Deborah A., O'Connor, George T., Rennard, Stephen, I, Schwartz, David A., Sliwinski, Pawel, Sparrow, David, Strachan, David P., Tal-Singer, Ruth, Tesfaigzi, Yohannes, Vestbo, Jorgen, Vonk, Judith M., Yim, Jae-Joon, Zhou, Xiaobo, Bosse, Yohan, Manichaikul, Ani, Lahousse, Lies, Silverman, Edwin K., Boezen, H. Marike, Wain, Louise, V, Tobin, Martin D., Hobbs, Brian D., Cho, Michael H., Batini, Chiara, Zhao, Jing Hua, Wielscher, Matthias, Weiss, Stefan, Kentistou, Katherine A., Cook, James P., Hui, Jennie, Karrasch, Stefan, Imboden, Medea, Harris, Sarah E., Marten, Jonathan, Enroth, Stefan, Kerr, Shona M., Surakka, Ida, Vitart, Veronique, Lehtimaki, Terho, Ewert, Ralf, Gieger, Christian, Homuth, Georg, Joshi, Peter K., Langenberg, Claudia, Lind, Lars, Luan, Jianan, Mahajan, Anubha, Murray, Alison, Porteous, David J., Rawal, Rajesh, Smith, Blair H., Timmers, Paul R. H. J., Raitakari, Olli T., Kahonen, Mika, Polasek, Ozren, Gyllensten, Ulf B., Rudan, Igor, Deary, Ian J., Probst-Hensch, Nicole M., Schulz, Holger, James, Alan L., Wilson, James F., Stubbe, Beate, Zeggini, Eleftheria, Jarvelin, Marjo-Riitta, Wareham, Nick, Hayward, Caroline, Morris, Andrew P., Agusti, Alvar, Anderson, Wayne, Bakerly, Nawar, Bals, Robert, Barnes, Kathleen C., Bleecker, Eugene R., Bowler, Russell, Brightling, Christopher, de Bruijne, Marleen, Castaldi, Peterj, Celli, Bartolome, Coxson, Harvey O., Crystal, Ron, de Jong, Pim, Dirksen, Asger, Dy, Jennifer, Foreman, Marilyn, Garcia-Aymerich, Judith, Gevenois, Pierre, Ghosh, Soumitra, Gietema, Hester, Hansel, Nadia, Hersh, Craig P., Hoffman, Eric, Kalsheker, Noor, Kauczor, Hans-Ulrich, Laitinen, Tarja, Lambrechts, Diether, Litonjua, Augusto A., Loth, Daan W., Lutz, Sharon M., Lynch, David, MacNee, William, McDonald, Merry-Lynn, Newell, John D., Nordestgaard, Borge G., Oh, Yeon-Mok, Pare, Peter D., Pistolesi, Massimo, Postma, Dirkje S., Puhan, Milo, Regan, Elizabeth, Rich, Stephen S., Seo, Joon Beom, Short, Andrea, Stoel, Berend, Sverzellati, Nicola, ter Riet, Gerben, Van Beek, Edwin J. R., Van Ginneken, Bram, Vogelmeier, Claus F., Wanner, Adam, Washko, George, Wauters, Els, Wouters, Emiel F. M., Young, Robert P., and Zeigler-Heitbrock, Loems

Abstract

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

Published
2019
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10. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Author

Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valerie, Auer, Paul L., Fine, Rebecca S., Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W., Locke, Adam E., Medina-Gomez, Carolina, Esko, Tonu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie C. Y., Heard-Costa, Nancy L., Feitosa, Mary F., Manning, Alisa K., Willems, Sara M., Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S., Allison, Matthew, Amouyel, Philippe, Arzumanyanm, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blueher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Boeger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Markj, Cesana, Giancarlo, Chambers, John C., Chasman, Daniel, I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audreyy, Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., de Denus, Simon, de Mutsert, Renee, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Di Angelantonio, Emanuele, Doerr, Marcus, Drenos, Fotios, Dube, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Fornage, Myriam, Fox, Caroline S., Franks, Paul W., Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Groves, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kees, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jorgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M., Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kovacs, Peter, Kraemer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, La Nge, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimaeki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, RuifangLi-Gao, Lin, Li-An, Lin, Xu, Lind, Lars, Lindstroem, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian'an, Lyytikainen, Leo-Pekka, MacGregor, Stuart, Magi, Reedik, Mannisto, Satu, Marenne, Gaelle, Marten, Jonathan, Mascal, Nicholas G. D., McCarthy, Mark, I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Mueller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Markus, James, A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Rasheed, Asif, Raulerson, Chelsea K., Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Ridker, Paul M., Rivas, Manuel A., Robertson, Neil R., Robino, Antonietta, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Blair H., Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin M. A., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Toenjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Matti, van Duijn, Cornelia M., Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, N. Icholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Verges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M. Carola, Rivadeneira, Fernando, Borecki, Ingrid B., Pospisilik, J. Andrew, Deloukas, Panos, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome, I, Kutalik, Zoltan, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., O'Connell, Jeffrey R., Raitakari, Olli T., Lange, Leslie A., Uitterlinden, Andr G., Grove, Megan L., Masca, Nicholas G. D., Luan, Jianan, Wareham, Nicholas J., Esko, Tnu, De Bakker, Paul Iw, Caulfield, Mark J., Mller-Nurasyid, Martina, Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valerie, Auer, Paul L., Fine, Rebecca S., Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W., Locke, Adam E., Medina-Gomez, Carolina, Esko, Tonu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie C. Y., Heard-Costa, Nancy L., Feitosa, Mary F., Manning, Alisa K., Willems, Sara M., Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S., Allison, Matthew, Amouyel, Philippe, Arzumanyanm, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blueher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Boeger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Markj, Cesana, Giancarlo, Chambers, John C., Chasman, Daniel, I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audreyy, Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., de Denus, Simon, de Mutsert, Renee, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Di Angelantonio, Emanuele, Doerr, Marcus, Drenos, Fotios, Dube, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Fornage, Myriam, Fox, Caroline S., Franks, Paul W., Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Groves, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kees, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jorgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M., Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kovacs, Peter, Kraemer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, La Nge, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimaeki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, RuifangLi-Gao, Lin, Li-An, Lin, Xu, Lind, Lars, Lindstroem, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian'an, Lyytikainen, Leo-Pekka, MacGregor, Stuart, Magi, Reedik, Mannisto, Satu, Marenne, Gaelle, Marten, Jonathan, Mascal, Nicholas G. D., McCarthy, Mark, I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Mueller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Markus, James, A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Rasheed, Asif, Raulerson, Chelsea K., Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Ridker, Paul M., Rivas, Manuel A., Robertson, Neil R., Robino, Antonietta, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Blair H., Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin M. A., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Toenjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Matti, van Duijn, Cornelia M., Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, N. Icholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Verges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M. Carola, Rivadeneira, Fernando, Borecki, Ingrid B., Pospisilik, J. Andrew, Deloukas, Panos, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome, I, Kutalik, Zoltan, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., O'Connell, Jeffrey R., Raitakari, Olli T., Lange, Leslie A., Uitterlinden, Andr G., Grove, Megan L., Masca, Nicholas G. D., Luan, Jianan, Wareham, Nicholas J., Esko, Tnu, De Bakker, Paul Iw, Caulfield, Mark J., and Mller-Nurasyid, Martina

Abstract

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

Published
2019
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11. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, and Kiel, Douglas P.

Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

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12. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, and Kiel, Douglas P.

Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

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13. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, and Kiel, Douglas P.

Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

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14. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, Kiel, Douglas P., Jiang, Xia, O’Reilly, Paul F., Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J. Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A., Albanes, Demetrius, Lutsey, Pamela L., Yao, Lu, Tang, Weihong, Econs, Michael J., Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I., Michos, Erin D., Boerwinkle, Eric, Weinstein, Stephanie J., Freedman, Neal D., Huang, Wen-Yi, Van Schoor, Natasja M., van der Velde, Nathalie, Groot, Lisette C. P. G. M. de, Enneman, Anke, Cupples, L. Adrienne, Booth, Sarah L., Vasan, Ramachandran S., Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G., Shea, M. Kyla, Houston, Denise K., Kritchevsky, Stephen B., Liu, Yongmei, Lohman, Kurt K., Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E., März, Winfried, de Boer, Ian H., Wood, Alexis C., Rotter, Jerome I., Rich, Stephen S., Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K., Wilson, James F., Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M. Carola, Uitterlinden, Andre G., Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M., Timofeeva, Maria, Dunlop, Malcolm G., Valdes, Ana M., Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T., Mikkilä, Vera, Ikram, M. Arfan, Sattar, Naveed, Jukema, J. Wouter, Wareham, Nicholas J., Langenberg, Claudia, Forouhi, Nita G., Gundersen, Thomas E., Khaw, Kay-Tee, Butterworth, Adam S., Danesh, John, Spector, Timothy, Wang, Thomas J., Hyppönen, Elina, Kraft, Peter, and Kiel, Douglas P.

Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

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