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1. Integration of rare expression outlier-associated variants improves polygenic risk prediction

Author

Smail, Craig, Ferraro, Nicole M., Hui, Qin, Durrant, Matthew G., Aguirre, Matthew, Tanigawa, Yosuke, Keever-Keigher, Marissa R., Rao, Abhiram S., Justesen, Johanne M., Li, Xin, Gloudemans, Michael J., Assimes, Themistocles L., Kooperberg, Charles, Reiner, Alexander P., Huang, Jie, O'Donnell, Christopher J., Sun, Yan V., Rivas, Manuel A., and Montgomery, Stephen B.

Published
2022
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2. A functional genomic framework to elucidate novel causal non-alcoholic fatty liver disease genes

Author

Saliba-Gustafsson, Peter, primary, Justesen, Johanne M., additional, Ranta, Amanda, additional, Sharma, Disha, additional, Bielczyk-Maczynska, Ewa, additional, Li, Jiehan, additional, Najmi, Laeya A., additional, Apodaka, Maider, additional, Aspichueta, Patricia, additional, Björck, Hanna M., additional, Eriksson, Per, additional, Franco-Cereceda, Anders, additional, Gloudemans, Mike, additional, Mujica, Endrina, additional, Hoed, Marcel den, additional, Assimes, Themistocles L., additional, Quertermous, Thomas, additional, Carcamo-Orive, Ivan, additional, Park, Chong Y., additional, and Knowles, Joshua W., additional

Published
2024
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3. 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, Valérie, 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, Tõnu, 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, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Mark J., Cesana, Giancarlo, Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Di Angelantonio, Emanuele, Dörr, Marcus, Drenos, Fotios, Dubé, 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, Grove, 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, Jørgensen, 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, Krämer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian’an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas G. D., McCarthy, Mark I., Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, O’Connell, Jeffrey R., Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Markus, Perry, James A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T., 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., Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André 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, Nicholas 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, Yerges-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, Zoltán, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., and Lindgren, Cecilia M.

Published
2019
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6. Abstract P3005: Cannabinoid Receptor 1 Antagonist Genistein Attenuates Marijuana-Induced Vascular Inflammation

Author

Chandy, Mark, primary, Wei, Tzu-tang T, additional, Nishiga, Masataka, additional, Zhang, Angela, additional, Kumar, Kaavya K, additional, Thomas, Dilip, additional, Manhas, Amit, additional, Rhee, Siyeon, additional, Justesen, Johanne M, additional, Chen, Ian Y, additional, Wo, Hung-Ta, additional, Yang, Johnson Y, additional, Khanamiri, Saereh, additional, Seidl, Frederick, additional, Burns, Noah, additional, Liu, Chun, additional, Sayed, Nazish, additional, Shie, Jiun-Jie, additional, Yeh, Chih Fan, additional, YANG, Kai-chien, additional, Lau, Edward, additional, Lynch, Kara, additional, Rivas, Manuel, additional, Kobilka, Brian, additional, and Wu, Joseph C, additional

Published
2022
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7. Interactions of physical activity, muscular fitness, adiposity, and genetic risk for NAFLD

Author

Schnurr, Theresia M., primary, Katz, Sophia Figueroa, additional, Justesen, Johanne M., additional, O’Sullivan, Jack W., additional, Saliba‐Gustafsson, Peter, additional, Assimes, Themistocles L., additional, Carcamo‐Orive, Ivan, additional, Ahmed, Aijaz, additional, Ashley, Euan A., additional, Hansen, Torben, additional, and Knowles, Joshua W., additional

Published
2022
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10. Genetic risk score of 46 type 2 diabetes risk variants associates with changes in plasma glucose and estimates of pancreatic β-cell function over 5 years of follow-up

Author

Andersson, Ehm A., Allin, Kristine H., Sandholt, Camilla H., Borglykke, Anders, Lau, Cathrine J., Ribel-Madsen, Rasmus, Sparso, Thomas, Justesen, Johanne M., Harder, Marie N., Jorgensen, Marit E., Jorgensen, Torben, Hansen, Torben, and Pedersen, Oluf

Subjects
Pancreatic beta cells -- Physiological aspects, Glucose metabolism -- Physiological aspects, Type 2 diabetes -- Risk factors -- Genetic aspects, Health
Abstract

More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test whether a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and whether the effects were modulated by changes in BMI and lifestyle. The Inter99 study population was genotyped for 46 variants, and a genetic risk score was constructed. During a median follow-up of 11 years, 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n = 3,727). The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 (95% CI 1.03-1.08) per risk allele. While the population in general had improved glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min, and 120-min plasma glucose values and a relative decrease in measures of β-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI. In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and β-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose., Type 2 diabetes is a complex metabolic disorder where both environment and genetic disposition act in concert to cause the disease. Over the last few years, genome-wide association studies and [...]

Published
2013
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11. Fast Lasso method for large-scale and ultrahigh-dimensional Cox model with applications to UK Biobank.

Author

Li, Ruilin, Chang, Christopher, Justesen, Johanne M, Tanigawa, Yosuke, Qian, Junyang, Hastie, Trevor, Rivas, Manuel A, and Tibshirani, Robert

Abstract

We develop a scalable and highly efficient algorithm to fit a Cox proportional hazard model by maximizing the $L^1$-regularized (Lasso) partial likelihood function, based on the Batch Screening Iterative Lasso (BASIL) method developed in Qian and others (2019). Our algorithm is particularly suitable for large-scale and high-dimensional data that do not fit in the memory. The output of our algorithm is the full Lasso path, the parameter estimates at all predefined regularization parameters, as well as their validation accuracy measured using the concordance index (C-index) or the validation deviance. To demonstrate the effectiveness of our algorithm, we analyze a large genotype-survival time dataset across 306 disease outcomes from the UK Biobank (Sudlow and others, 2015). We provide a publicly available implementation of the proposed approach for genetics data on top of the PLINK2 package and name it snpnet-Cox. [ABSTRACT FROM AUTHOR]

Published
2022
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14. Solute Carrier Family 2 Member 1 Is Involved in the Development of Nonalcoholic Fatty Liver Disease

Author

Vazquez-Chantada, Mercedes, Gonzalez-Lahera, Aintzane, Martinez-Arranz, Ibon, Garcia-Monzon, Carmelo, Regueiro, Manuela M., Garcia-Rodriguez, Juan L., Schlangen, Karin A., Mendibil, Iñaki, Rodriguez-Ezpeleta, Naiara, Lozano, Juan J., Banasik, Karina, Justesen, Johanne M., Joergensen, Torben, Witte, Daniel R., Lauritzen, Torsten, Hansen, Torben, Pedersen, Oluf, Veyrie, Nicolas, Clement, Karine, Tordjman, Joan, Tran, Albert, Le Marchand-Brustel, Yannik, Buque, Xabier, Aspichueta, Patricia, Echevarria-Uraga, Jose J., Martin-Duce, Antonio, Caballeria, Joan, Gual, Philippe, Castro, Azucena, Mato, Jose M., Martinez-Chantar, Maria L., and Aransay, Ana M.

Published
2013
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18. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 1; peer review: 1 approved, 1 approved with reservations]

Author

Jackson, Victoria E., Latourelle, Jeanne C., Wain, Louise V., Smith, Albert V., Grove, Megan L., Bartz, Traci M., Obeidat, Ma’En, Province, Michael A., Gao, Wei, Qaiser, Beenish, Porteous, David J., Cassano, Patricia A., Ahluwalia, Tarunveer S., Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E., Manichaikul, Ani, Pottinger, Tess D., Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M., Brody, Jennifer A., Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M., Linneberg, Allan, Lange, Leslie A., Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E., Brusselle, Guy G., Hansen, Torben, Uitterlinden, André G., Ikram, M. Arfan, Dupuis, Josée, Epidemiology, Erasmus School of Economics, Department of Finance, Internal Medicine, and Radiology & Nuclear Medicine

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018

19. The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load

Author

Pisinger Charlotta, Lauritzen Torsten, Sandbæk Annelli, Andersson Åsa, Sandholt Camilla H, Krarup Nikolaj T, Justesen Johanne M, Banasik Karina, Hornbak Malene, Witte Daniel R, Sørensen Thorkild IA, Pedersen Oluf, and Hansen Torben

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid β-oxidation. Chronic exposure to fatty acids due to an impaired β-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D. Methods The variants were genotyped using KASPar® PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (nACADS = 4,324; nACADM = 4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (nACADS = 8,313; nACADM = 8,344). Results In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (β) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (β = 2.9% (0.5%;5.2%), P = 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, P = 0.21). rs11161510 of ACADM did not associate with any indices of glucose-stimulated insulin release or with T2D. Conclusions In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired β-oxidation of fatty acids.

Published
2011
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20. is involved in the development of nonalcoholic fatty liver disease

Author

Vazquez-Chantada, Mercedes, Gonzalez-Lahera, Aintzane, Martinez-Arranz, Ibon, Garcia-Monzon, Carmelo, Regueiro, Manuela M., Garcia-Rodriguez, Juan L., Schlangen, Karin A., Mendibil, Iñaki, Rodriguez-Ezpeleta, Naiara, Lozano, Juan J., Banasik, Karina, Justesen, Johanne M., Joergensen, Torben, Witte, Daniel R., Lauritzen, Torsten, Hansen, Torben, Pedersen, Oluf, Veyrie, Nicolas, Clement, Karine, Tordjman, Joan, Tran, Albert, Le Marchand-Brustel, Yannik, Buque, Xabier, Aspichueta, Patricia, Echevarria-Uraga, Jose J., Martin-Duce, Antonio, Caballeria, Joan, Gual, Philippe, Castro, Azucena, Mato, Jose M., Martinez-Chantar, Maria L., and Aransay, Ana M.

Published
2013
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21. Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during five years

Author

Justesen, Johanne M, Andersson, Ehm A, Allin, Kristine H, Sandholt, Camilla H, Jørgensen, Torben, Linneberg, Allan, Jørgensen, Marit E, Hansen, Torben, Pedersen, Oluf, and Grarup, Niels

Abstract

Blood concentrations of triglycerides are influenced by genetic factors, as well as a number of environmental factors including adiposity and glucose homeostasis. The aim to investigate the association between a weighted serum triglyceride genetic risk score (wGRS) and changes in fasting serum triglyceride level over five years and to test whether the effect of the wGRS was modified by 5-year changes of adiposity, insulin resistance and lifestyle factors. A total of 3,474 non-diabetic individuals from the Danish Inter99 cohort participated in both the baseline and 5-year follow-up physical examinations and had information on the wGRS comprising 39 genetic variants. In a linear regression model adjusted for age, sex and baseline serum triglyceride, the wGRS was associated with increased serum triglyceride levels over 5 years (per allele effect=1.3% (1.0;1.6); P=1.0*10(-17)). This triglyceride increasing effect of the wGRS interacted with changes in insulin resistance (Pint=1.5*10(-6)). This interaction suggested that the effect of the wGRS was stronger in individuals who became more insulin resistant over five years. In conclusion, our findings suggest that increased genetic risk load is associated with a larger increase in fasting serum triglyceride levels in non-diabetic individuals during five years of follow-up. This effect of the wGRS is accentuated by increasing insulin resistance.

Published
2016

22. Meta-analysis of exome array data identifies six novel genetic loci for lung function

Author

Jackson, Victoria E, primary, Latourelle, Jeanne C, additional, Wain, Louise V, additional, Smith, Albert V., additional, Grove, Megan L., additional, Bartz, Traci M, additional, Obeidat, Maen, additional, Province, Michael A, additional, Gao, Wei, additional, Qaiser, Beenish, additional, Porteous, David J, additional, Cassano, Patricia A, additional, Ahluwalia, Tarunveer S., additional, Grarup, Niels, additional, Li, Jin, additional, Altmaier, Elisabeth, additional, Marten, Jonathan, additional, Harris, Sarah E, additional, Manichaikul, Ani, additional, Pottinger, Tess D, additional, Li-Gao, Ruifang, additional, Lind-Thomsen, Allan, additional, Mahajan, Anubha, additional, Lahousse, Lies, additional, Imboden, Medea, additional, Teumer, Alexander, additional, Prins, Bram, additional, Lyytikäinen, Leo-Pekka, additional, Eiriksdottir, Gudny, additional, Franceschini, Nora, additional, Sitlani, Colleen M, additional, Brody, Jennifer A, additional, Bossé, Yohan, additional, Timens, Wim, additional, Kraja, Aldi, additional, Loukola, Anu, additional, Tang, Wenbo, additional, Liu, Yongmei, additional, Bork-Jensen, Jette, additional, Justesen, Johanne M., additional, Linneberg, Allan, additional, Lange, Leslie A., additional, Rawal, Rajesh, additional, Karrasch, Stefan, additional, Huffman, Jennifer E, additional, Smith, Blair H, additional, Davies, Gail, additional, Burkart, Kristin M, additional, Mychaleckyj, Josyf C, additional, Bonten, Tobias N., additional, Enroth, Stefan, additional, Lind, Lars, additional, Brusselle, Guy G, additional, Kumar, Ashish, additional, Stubbe, Beate, additional, Kähönen, Mika, additional, Wyss, Annah B., additional, Psaty, Bruce M, additional, Heckbert, Susan R, additional, Hao, Ke, additional, Rantanen, Taina, additional, Kritchevsky, Stephen B, additional, Lohman, Kurt, additional, Skaaby, Tea, additional, Pisinger, Charlotta, additional, Hansen, Torben, additional, Schulz, Holger, additional, Polasek, Ozren, additional, Campbell, Archie, additional, Starr, John M, additional, Rich, Stephen S, additional, Mook-Kanamori, Dennis O., additional, Johansson, Åsa, additional, Ingelsson, Erik, additional, Uitterlinden, André G, additional, Weiss, Stefan, additional, Raitakari, Olli T., additional, Gudnason, Vilmundur, additional, North, Kari E., additional, Gharib, Sina A, additional, Sin, Don D, additional, Taylor, Kent D, additional, O’Connor, George T, additional, Kaprio, Jaakko, additional, Harris, Tamara B, additional, Pedersen, Oluf, additional, Vestergaard, Henrik, additional, Wilson, James G., additional, Strauch, Konstantin, additional, Hayward, Caroline, additional, Kerr, Shona, additional, Deary, Ian J, additional, Barr, R Graham, additional, de Mutsert, Renée, additional, Gyllensten, Ulf, additional, Morris, Andrew P, additional, Ikram, M. Arfan, additional, Probst-Hensch, Nicole M, additional, Gläser, Sven, additional, Zeggini, Eleftheria, additional, Lehtimäki, Terho, additional, Strachan, David P, additional, Dupuis, Josee, additional, Morrison, Alanna C., additional, Hall, Ian P, additional, Tobin, Martin D, additional, and London, Stephanie J, additional

Published
2017
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24. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author

Justesen, Johanne M, Verweij, Niek, Stram, Daniel O, Asselbergs, Folkert W, Chambers, John C, Ueshima, Hirotsugu, Elliott, Paul, Deloukas, Panos, Chong, Yap-Seng, Kooner, Jaspal S, Dorajoo, Rajkumar, Franke, Lude, Akiyama, Koichi, Liewald, David C M, Tai, E Shyong, Campanella, Gianluca, van der Harst, Pim, Abbott, James, Esko, Tõnu, Lee, Jong-Young, Wijmenga, Cisca, Takeuchi, Fumihiko, Ohnaka, Keizo, Spiering, Wilko, Ye, Xingwang, Kleber, Marcus E, Linneberg, Allan, Nakatochi, Masahiro, and Soong, Richie

Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Published
2015
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26. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes

Author

Steinthorsdottir, Valgerdur, primary, Thorleifsson, Gudmar, additional, Sulem, Patrick, additional, Helgason, Hannes, additional, Grarup, Niels, additional, Sigurdsson, Asgeir, additional, Helgadottir, Hafdis T, additional, Johannsdottir, Hrefna, additional, Magnusson, Olafur T, additional, Gudjonsson, Sigurjon A, additional, Justesen, Johanne M, additional, Harder, Marie N, additional, Jørgensen, Marit E, additional, Christensen, Cramer, additional, Brandslund, Ivan, additional, Sandbæk, Annelli, additional, Lauritzen, Torsten, additional, Vestergaard, Henrik, additional, Linneberg, Allan, additional, Jørgensen, Torben, additional, Hansen, Torben, additional, Daneshpour, Maryam S, additional, Fallah, Mohammad-Sadegh, additional, Hreidarsson, Astradur B, additional, Sigurdsson, Gunnar, additional, Azizi, Fereidoun, additional, Benediktsson, Rafn, additional, Masson, Gisli, additional, Helgason, Agnar, additional, Kong, Augustine, additional, Gudbjartsson, Daniel F, additional, Pedersen, Oluf, additional, Thorsteinsdottir, Unnur, additional, and Stefansson, Kari, additional

Published
2014
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27. Exome-wide association study of plasma lipids in >300,000 individuals

Author

Liu, Dajiang J, Peloso, Gina M, Yu, Haojie, Butterworth, Adam S, Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, Di Angelantonio, Emanuele, Arveiler, Dominique, Assimes, Themistocles L, Auer, Paul L, Baber, Usman, Ballantyne, Christie M, Bang, Lia E, Benn, Marianne, Bis, Joshua C, Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P, Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Chen, Y Eugene, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Connell, John M, Cucca, Francesco, Cupples, L Adrienne, Damrauer, Scott M, Davies, Gail, Deary, Ian J, Dedoussis, George, Denny, Joshua C, Dominiczak, Anna, Dubé, Marie-Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Farmaki, Aliki-Eleni, Feitosa, Mary F, Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W, Frayling, Timothy M, Frikke-Schmidt, Ruth, Fritsche, Lars G, Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K, Gao, Wei, Garcia, Melissa E, Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O, Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B, Hayward, Caroline, Hirschhorn, Joel N, Holmen, Oddgeir L, Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U, Jakobsdottir, Johanna, Jarvelin, Marjo-Riitta, Jensen, Gorm B, Jørgensen, Marit E, Jukema, J Wouter, Justesen, Johanne M, Kamstrup, Pia R, Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V, Klarin, Derek, Koistinen, Heikki A, Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J, Lauritzen, Torsten, Liewald, David C M, Lin, Li An, Linneberg, Allan, Loos, Ruth J F, Lu, Yingchang, Lu, Xiangfeng, Mägi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K, Mäntyselkä, Pekka, Marouli, Eirini, Masca, Nicholas G D, Maschio, Andrea, Meigs, James B, Melander, Olle, Metspalu, Andres, Morris, Andrew P, Morrison, Alanna C, Mulas, Antonella, Müller-Nurasyid, Martina, Munroe, Patricia B, Neville, Matt J, Nielsen, Jonas B, Nielsen, Sune F, Nordestgaard, Børge G, Ordovas, Jose M, Mehran, Roxana, O'Donnell, Christoper J, Orho-Melander, Marju, Molony, Cliona M, Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin N A, Pasko, Dorota, Patel, Aniruddh P, Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M, Rader, Daniel J, Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Renström, Frida, Rich, Stephen S, Ridker, Paul M, Rioux, John D, Robertson, Neil R, Roden, Dan M, Rotter, Jerome I, Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M, Scott, Robert A, Sever, Peter, Sevilla, Raquel S, Shaffer, Christian M, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, Smith, Albert V, Smith, Blair H, Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Starr, John M, Stirrups, Kathleen E, Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M, Surendran, Praveen, Tada, Hayato, Tall, Alan R, Tang, Hua, Tardif, Jean-Claude, Taylor, Kent D, Trompet, Stella, Tsao, Philip S, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, van Zuydam, Natalie R, Varbo, Anette, Varga, Tibor V, Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J, Warren, Helen R, Weeke, Peter E, Weinstock, Joshua, Wessel, Jennifer, Wilson, James G, Wilson, Peter W F, Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S, Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna M M, Danesh, John, McCarthy, Mark I, Cowan, Chad A, Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J, and Kathiresan, Sekar

Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

Published
2017
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28. Solute carrier family 2 member 1is involved in the development of nonalcoholic fatty liver disease

Author

Vazquez-Chantada, Mercedes, primary, Gonzalez-Lahera, Aintzane, additional, Martinez-Arranz, Ibon, additional, Garcia-Monzon, Carmelo, additional, Regueiro, Manuela M., additional, Garcia-Rodriguez, Juan L., additional, Schlangen, Karin A., additional, Mendibil, Iñaki, additional, Rodriguez-Ezpeleta, Naiara, additional, Lozano, Juan J., additional, Banasik, Karina, additional, Justesen, Johanne M., additional, Joergensen, Torben, additional, Witte, Daniel R., additional, Lauritzen, Torsten, additional, Hansen, Torben, additional, Pedersen, Oluf, additional, Veyrie, Nicolas, additional, Clement, Karine, additional, Tordjman, Joan, additional, Tran, Albert, additional, Le Marchand-Brustel, Yannik, additional, Buque, Xabier, additional, Aspichueta, Patricia, additional, Echevarria-Uraga, Jose J., additional, Martin-Duce, Antonio, additional, Caballeria, Joan, additional, Gual, Philippe, additional, Castro, Azucena, additional, Mato, Jose M., additional, Martinez-Chantar, Maria L., additional, and Aransay, Ana M., additional

Published
2012
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29. Implications of Central Obesity-Related Variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on Quantitative Metabolic Traits in Adult Danes

Author

Bille, Dorthe S., primary, Banasik, Karina, additional, Justesen, Johanne M., additional, Sandholt, Camilla H., additional, Sandbæk, Annelli, additional, Lauritzen, Torsten, additional, Jørgensen, Torben, additional, Witte, Daniel R., additional, Holm, Jens-Christian, additional, Hansen, Torben, additional, and Pedersen, Oluf, additional

Published
2011
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30. Bioinformatics-Driven Identification and Examination of Candidate Genes for Non-Alcoholic Fatty Liver Disease

Author

Banasik, Karina, primary, Justesen, Johanne M., additional, Hornbak, Malene, additional, Krarup, Nikolaj T., additional, Gjesing, Anette P., additional, Sandholt, Camilla H., additional, Jensen, Thomas S., additional, Grarup, Niels, additional, Andersson, Åsa, additional, Jørgensen, Torben, additional, Witte, Daniel R., additional, Sandbæk, Annelli, additional, Lauritzen, Torsten, additional, Thorens, Bernard, additional, Brunak, Søren, additional, Sørensen, Thorkild I. A., additional, Pedersen, Oluf, additional, and Hansen, Torben, additional

Published
2011
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31. The minor C-allele of rs2014355 in ACADSis associated with reduced insulin release following an oral glucose load

Author

Hornbak, Malene, primary, Banasik, Karina, additional, Justesen, Johanne M, additional, Krarup, Nikolaj T, additional, Sandholt, Camilla H, additional, Andersson, Åsa, additional, Sandbæk, Annelli, additional, Lauritzen, Torsten, additional, Pisinger, Charlotta, additional, Witte, Daniel R, additional, Sørensen, Thorkild IA, additional, Pedersen, Oluf, additional, and Hansen, Torben, additional

Published
2011
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32. Exome-wide association study of plasma lipids in >300,000 individuals

Author

Liu, Dajiang J., Peloso, Gina M., Yu, Haojie, Butterworth, Adam S., Wang, Xiao, Mahajan, Anubha, Saleheen, Danish, Emdin, Connor, Alam, Dewan, Alves, Alexessander Couto, Amouyel, Philippe, di Angelantonio, Emanuele, Arveiler, Dominique, Assimes, Themistocles L., Auer, Paul L., Baber, Usman, Ballantyne, Christie M., Bang, Lia E., Benn, Marianne, Bis, Joshua C., Boehnke, Michael, Boerwinkle, Eric, Bork-Jensen, Jette, Bottinger, Erwin P., Brandslund, Ivan, Brown, Morris, Busonero, Fabio, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I., Chen, Y. Eugene, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Connell, John M, Cucca, Francesco, Cupples, L. Adrienne, Damrauer, Scott M., Davies, Gail, Deary, Ian J, Dedoussis, George, Denny, Joshua C., Dominiczak, Anna, Dubé, Marie-Pierre, Ebeling, Tapani, Eiriksdottir, Gudny, Esko, Tõnu, Farmaki, Aliki-Eleni, Feitosa, Mary F, Ferrario, Marco, Ferrieres, Jean, Ford, Ian, Fornage, Myriam, Franks, Paul W., Frayling, Timothy M., Frikke-Schmidt, Ruth, Fritsche, Lars, Frossard, Philippe, Fuster, Valentin, Ganesh, Santhi K., Gao, Wei, Garcia, Melissa E., Gieger, Christian, Giulianini, Franco, Goodarzi, Mark O., Grallert, Harald, Grarup, Niels, Groop, Leif, Grove, Megan L., Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hirschhorn, Joel N., Holmen, Oddgeir L., Huffman, Jennifer, Huo, Yong, Hveem, Kristian, Jabeen, Sehrish, Jackson, Anne U, Jakobsdottir, Johanna, Jarvelin, Marjo-Riitta, Jensen, Gorm B, Jørgensen, Marit E., Jukema, J. Wouter, Justesen, Johanne M., Kamstrup, Pia R., Kanoni, Stavroula, Karpe, Fredrik, Kee, Frank, Khera, Amit V., Klarin, Derek, Koistinen, Heikki A., Kooner, Jaspal S, Kooperberg, Charles, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo, Langenberg, Claudia, Langsted, Anne, Launer, Lenore J., Lauritzen, Torsten, Liewald, David CM, Lin, Li An, Linneberg, Allan, Loos, Ruth J.F., Lu, Yingchang, Lu, Xiangfeng, Mägi, Reedik, Malarstig, Anders, Manichaikul, Ani, Manning, Alisa K., Mäntyselkä, Pekka, Marouli, Eirini, Masca, Nicholas GD, Maschio, Andrea, Meigs, James B., Melander, Olle, Metspalu, Andres, Morris, Andrew P, Morrison, Alanna C., Mulas, Antonella, Müller-Nurasyid, Martina, Munroe, Patricia B., Neville, Matt J, Nielsen, Jonas B., Nielsen, Sune F, Nordestgaard, Børge G, Ordovas, Jose M., Mehran, Roxana, O’Donnell, Christoper J., Orho-Melander, Marju, Molony, Cliona M., Muntendam, Pieter, Padmanabhan, Sandosh, Palmer, Colin NA, Pasko, Dorota, Patel, Aniruddh P., Pedersen, Oluf, Perola, Markus, Peters, Annette, Pisinger, Charlotta, Pistis, Giorgio, Polasek, Ozren, Poulter, Neil, Psaty, Bruce M., Rader, Daniel J., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot, Reiner, Alex P., Renström, Frida, Rich, Stephen S, Ridker, Paul M, Rioux, John D., Robertson, Neil R, Roden, Dan M., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Sanna, Serena, Sattar, Naveed, Schmidt, Ellen M., Scott, Robert A., Sever, Peter, Sevilla, Raquel S., Shaffer, Christian M., Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, Smith, Albert V., Smith, Blair H, Somayajula, Sangeetha, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K., Starr, John M, Stirrups, Kathleen E, Stitziel, Nathan, Strauch, Konstantin, Stringham, Heather M, Surendran, Praveen, Tada, Hayato, Tall, Alan R., Tang, Hua, Tardif, Jean-Claude, Taylor, Kent D, Trompet, Stella, Tsao, Philip S., Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, van Zuydam, Natalie R, Varbo, Anette, Varga, Tibor V, Virtamo, Jarmo, Waldenberger, Melanie, Wang, Nan, Wareham, Nick J., Warren, Helen R, Weeke, Peter E., Weinstock, Joshua, Wessel, Jennifer, Wilson, James G., Wilson, Peter W. F., Xu, Ming, Yaghootkar, Hanieh, Young, Robin, Zeggini, Eleftheria, Zhang, He, Zheng, Neil S., Zhang, Weihua, Zhang, Yan, Zhou, Wei, Zhou, Yanhua, Zoledziewska, Magdalena, Howson, Joanna MM, Danesh, John, McCarthy, Mark I, Cowan, Chad, Abecasis, Goncalo, Deloukas, Panos, Musunuru, Kiran, Willer, Cristen J., and Kathiresan, Sekar

Abstract

We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.

Published
2017
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34. 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, Valérie, 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, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Angelantonio, Emanuele Di, Dörr, Marcus, Drenos, Fotios, Dubé, 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, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T, Hayward, Caroline, Heid, Iris M, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jarvik, Gail P, Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M, Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kovacs, Peter, Krämer, Bernhard K, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas GD, McCarthy, Mark I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Ntalla, Ioanna, O'Connell, Jeffrey R, Owen, Katharine R, Pedersen, Oluf, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T, 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 MA, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André 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, Nicholas 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, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M Carola, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CH, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Rivadeneira, Fernando, Borecki, Ingrid B, Pospisilik, J Andrew, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, Mohlke, Karen L, Rotter, Jerome I, Kutalik, Zoltán, Hirschhorn, Joel N, Cupples, L Adrienne, Loos, Ruth JF, North, Kari E, Lindgren, Cecilia M, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Institute for Molecular Medicine Finland, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Young, Kristin L [0000-0003-0070-6145], Mahajan, Anubha [0000-0001-5585-3420], Winkler, Thomas W [0000-0003-0292-5421], Locke, Adam E [0000-0001-6227-198X], Medina-Gomez, Carolina [0000-0001-7999-5538], Giri, Ayush [0000-0002-7786-4670], Ng, Maggie CY [0000-0002-4133-2007], Heard-Costa, Nancy L [0000-0001-9730-0306], Manning, Alisa K [0000-0003-0247-902X], Alam, Dewan S [0000-0002-2051-3837], Amouyel, Philippe [0000-0001-9088-234X], Bergmann, Sven [0000-0002-6785-9034], Boehnke, Michael [0000-0002-6442-7754], Butterworth, Adam S [0000-0002-6915-9015], Caulfield, Mark J [0000-0001-9295-3594], Collins, Francis S [0000-0002-1023-7410], de Bakker, Paul IW [0000-0001-7735-7858], Dennis, Joe G [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Elliott, Paul [0000-0002-7511-5684], Evangelou, Evangelos [0000-0002-5488-2999], Giedraitis, Vilmantas [0000-0003-3423-2021], Girotto, Giorgia [0000-0003-4507-6589], Grarup, Niels [0000-0001-5526-1070], Gustafsson, Stefan [0000-0001-5894-0351], Hansen, Torben [0000-0001-8748-3831], Hayward, Caroline [0000-0002-9405-9550], Howson, Joanna MM [0000-0001-7618-0050], Ikram, M Arfan [0000-0003-0372-8585], Jackson, Anne U [0000-0002-9672-2547], Justesen, Johanne M [0000-0002-0484-8522], Kovacs, Peter [0000-0002-0290-5423], Kuulasmaa, Kari [0000-0003-2165-1411], Langenberg, Claudia [0000-0002-5017-7344], Lin, Li-An [0000-0003-2731-1346], Linneberg, Allan [0000-0002-0994-0184], Liu, Ching-Ti [0000-0002-0703-0742], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], MacGregor, Stuart [0000-0001-6731-8142], McCarthy, Mark I [0000-0002-4393-0510], Morgan, Anna [0000-0001-6290-445X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Munroe, Patricia B [0000-0002-4176-2947], Narisu, Narisu [0000-0002-8483-1156], Neville, Matt [0000-0002-6004-5433], Reilly, Dermot F [0000-0002-9456-1364], Rudan, Igor [0000-0001-6993-6884], Saleheen, Danish [0000-0001-6193-020X], Salomaa, Veikko [0000-0001-7563-5324], Sim, Xueling [0000-0002-1233-7642], Small, Kerrin S [0000-0003-4566-0005], Smith, Blair H [0000-0002-5362-9430], Smith, Jennifer A [0000-0002-3575-5468], Southam, Lorraine [0000-0002-7546-9650], Stefansson, Kari [0000-0003-1676-864X], Stirrups, Kathleen E [0000-0002-6823-3252], Stringham, Heather M [0000-0002-2991-6392], Teumer, Alexander [0000-0002-8309-094X], Thompson, Deborah J [0000-0003-1465-5799], Vestergaard, Henrik [0000-0003-3090-269X], Vitart, Veronique [0000-0002-4991-3797], Wang, Carol A [0000-0002-4301-3974], Wessel, Jennifer [0000-0002-7031-0085], Willer, Cristen J [0000-0001-5645-4966], Zeggini, Eleftheria [0000-0003-4238-659X], Rivadeneira, Fernando [0000-0001-9435-9441], Pospisilik, J Andrew [0000-0002-9745-0977], Deloukas, Panos [0000-0001-9251-070X], Mohlke, Karen L [0000-0001-6721-153X], Kutalik, Zoltán [0000-0001-8285-7523], Loos, Ruth JF [0000-0002-8532-5087], Lindgren, Cecilia M [0000-0002-4903-9374], Apollo - University of Cambridge Repository, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Medical and Clinical Psychology, Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, 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, Tõnu, 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, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Mark J., Cesana, Giancarlo, Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele Di, Dörr, Marcu, Drenos, Fotio, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelo, 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, Vilmanta, Girotto, Giorgia, Gorski, Mathia, Grallert, Harald, Grarup, Niel, Grove, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jørgensen, 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, Krämer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian’An, Lyytikäinen, Leo-Pekka, Macgregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas G. D., Mccarthy, Mark I., Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, O’Connell, Jeffrey R., Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T., 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., Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André 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, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, Nicholas 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, Yerges-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, Pano, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome I., Kutalik, Zoltán, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., APH - Societal Participation & Health, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Epidemiology and Data Science, and VU University medical center

Subjects
Exome/genetics, Male, ReproGen Consortium, Adipose tissue, Genome-wide association study, Type 2 diabetes, White adipose tissue, Body Mass Index, Animals, Body Fat Distribution, Case-Control Studies, Drosophila, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeostasis, Humans, Lipids, Proteins, Risk Factors, Waist-Hip Ratio, 0302 clinical medicine, Hyperlipidemia, Body fat distribution, 2. Zero hunger, Genetics, 0303 health sciences, INSULIN-RESISTANCE, ADIPOCYTE DIFFERENTIATION, CHD Exome+ Consortium, Genetic Predisposition to Disease/genetics, Drosophila/genetics, RS11209026 POLYMORPHISM, KINASE 7, 1184 Genetics, developmental biology, physiology, T2D-Genes Consortium, 11 Medical And Health Sciences, Body Fat Distribution/methods, RECEPTOR ALK7, ADIPOSE-TISSUE, Gene Frequency/genetics, Genetic Variation/genetics, InterAct, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], genetic association study, RNA splicing, Proteins/genetics, Genome-Wide Association Study/methods, Lipid particle, ExomeBP Consortium, WAIST CIRCUMFERENCE, Waist-Hip Ratio/methods, Biology, EPIC-CVD Consortium, Article, MAGIC Investigators, 03 medical and health sciences, Homeostasis/genetics, Lipids/genetics, All institutes and research themes of the Radboud University Medical Center, medicine, Global Lipids Genetic Consortium, Risk factor, GENOME-WIDE ASSOCIATION, ABDOMINAL ADIPOSITY, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Gene, 030304 developmental biology, 06 Biological Sciences, medicine.disease, Minor allele frequency, GoT2D Genes Consortium, genetics research, TYPE-2 DIABETES SUSCEPTIBILITY, 3111 Biomedicine, Body mass index, 030217 neurology & neurosurgery, Developmental Biology
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 9 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., Editorial summary: A trans-ethnic exome-wide association study for body fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

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35. The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load.

Author

Hornbak, Malene, Banasik, Karina, Justesen, Johanne M., Krarup, Nikolaj T., Sandholt, Camilla H., Andersson, Äsa, Sandbæk, Annelli, Lauritzen, Torsten, Pisinger, Charlotta, Witte, Daniel R., Sørensen, Thorkild I. A., Pedersen, Oluf, and Hansen, Torben

Subjects
INSULIN, GLUCOSE, GENOMES, COENZYMES, TYPE 2 diabetes
Abstract

Background: A genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid β-oxidation. Chronic exposure to fatty acids due to an impaired β-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D. Methods: The variants were genotyped using KASPar® PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (nACADS = 4,324; nACADM = 4,337). The T2D-case-control study involved a total of ∼8,300 Danish individuals (nACADS = 8,313; nACADM = 8,344). Results: In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (β) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (β = 2.9% (0.5%;5.2%), P = 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, P = 0.21). rs11161510 of ACADM did not associate with any indices of glucose-stimulated insulin release or with T2D. Conclusions: In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired β-oxidation of fatty acids. [ABSTRACT FROM AUTHOR]

Published
2011
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37. 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, Valérie, 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, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, De Bakker, Paul IW, Denus, Simon De, Mutsert, Renée De, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Di Angelantonio, Emanuele, Dörr, Marcus, Drenos, Fotios, Dubé, 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, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T, Hayward, Caroline, Heid, Iris M, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jarvik, Gail P, Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M, Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kovacs, Peter, Krämer, Bernhard K, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas GD, McCarthy, Mark I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Ntalla, Ioanna, O'Connell, Jeffrey R, Owen, Katharine R, Pedersen, Oluf, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T, 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 MA, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André 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, Nicholas 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, Yerges-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, Zoltán, Hirschhorn, Joel N, Cupples, L Adrienne, Loos, Ruth JF, North, Kari E, Lindgren, Cecilia M, CHD Exome+ Consortium, Cohorts For Heart And Aging Research In Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, and MAGIC Investigators

Subjects
2. Zero hunger, Male, Waist-Hip Ratio, Genetic Variation, Proteins, Lipids, Body Mass Index, Gene Frequency, Risk Factors, Case-Control Studies, Animals, Body Fat Distribution, Homeostasis, Humans, Drosophila, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
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

38. A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.

Author

Saliba-Gustafsson P, Justesen JM, Ranta A, Sharma D, Bielczyk-Maczynska E, Li J, Najmi LA, Apodaka M, Aspichueta P, Björck HM, Eriksson P, Schurr TM, Franco-Cereceda A, Gloudemans M, Mujica E, den Hoed M, Assimes TL, Quertermous T, Carcamo-Orive I, Park CY, and Knowles JW

Abstract

Background Aims: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD., Approach Results: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD., Conclusions: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2024
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39. A functional genomic framework to elucidate novel causal non-alcoholic fatty liver disease genes.

Author

Saliba-Gustafsson P, Justesen JM, Ranta A, Sharma D, Bielczyk-Maczynska E, Li J, Najmi LA, Apodaka M, Aspichueta P, Björck HM, Eriksson P, Franco-Cereceda A, Gloudemans M, Mujica E, den Hoed M, Assimes TL, Quertermous T, Carcamo-Orive I, Park CY, and Knowles JW

Abstract

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD., Approach & Results: We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD., Conclusions: Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.

Published
2024
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40. Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals With Atrial Fibrillation.

Author

O'Sullivan JW, Shcherbina A, Justesen JM, Turakhia M, Perez M, Wand H, Tcheandjieu C, Clarke SL, Rivas MA, and Ashley EA

Subjects
Aged, Female, Humans, Male, Middle Aged, Risk Assessment, Atrial Fibrillation complications, Atrial Fibrillation genetics, Atrial Fibrillation physiopathology, Genome-Wide Association Study, Ischemic Stroke etiology, Ischemic Stroke genetics, Ischemic Stroke physiopathology
Abstract

Background: Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable; however, current risk stratification tools (CHA 2 DS 2 -VASc) do not include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS)., Methods: Using data from the largest available genome-wide association study in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank, both independently and integrated with clinical risk factors. The integrated PRS and clinical risk factors risk tool had the greatest predictive ability., Results: Compared with the currently recommended risk tool (CHA 2 DS 2 -VASc), the integrated tool significantly improved Net Reclassification Index (2.3% [95% CI, 1.3%-3.0%]) and fit (χ 2 P =0.002). Using this improved tool, >115 000 people with AF would have improved risk classification in the United States. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (hazard ratio, 1.13 per 1 SD [95% CI, 1.06-1.23]). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson correlation coefficient, -0.018)., Conclusions: In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors; however, the prediction of stroke remains challenging.

Published
2021
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41. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

Author

Kato N, Loh M, Takeuchi F, Verweij N, Wang X, Zhang W, Kelly TN, Saleheen D, Lehne B, Leach IM, Drong AW, Abbott J, Wahl S, Tan ST, Scott WR, Campanella G, Chadeau-Hyam M, Afzal U, Ahluwalia TS, Bonder MJ, Chen P, Dehghan A, Edwards TL, Esko T, Go MJ, Harris SE, Hartiala J, Kasela S, Kasturiratne A, Khor CC, Kleber ME, Li H, Yu Mok Z, Nakatochi M, Sapari NS, Saxena R, Stewart AFR, Stolk L, Tabara Y, Teh AL, Wu Y, Wu JY, Zhang Y, Aits I, Da Silva Couto Alves A, Das S, Dorajoo R, Hopewell JC, Kim YK, Koivula RW, Luan J, Lyytikäinen LP, Nguyen QN, Pereira MA, Postmus I, Raitakari OT, Scannell Bryan M, Scott RA, Sorice R, Tragante V, Traglia M, White J, Yamamoto K, Zhang Y, Adair LS, Ahmed A, Akiyama K, Asif R, Aung T, Barroso I, Bjonnes A, Braun TR, Cai H, Chang LC, Chen CH, Cheng CY, Chong YS, Collins R, Courtney R, Davies G, Delgado G, Do LD, Doevendans PA, Gansevoort RT, Gao YT, Grammer TB, Grarup N, Grewal J, Gu D, Wander GS, Hartikainen AL, Hazen SL, He J, Heng CK, Hixson JE, Hofman A, Hsu C, Huang W, Husemoen LLN, Hwang JY, Ichihara S, Igase M, Isono M, Justesen JM, Katsuya T, Kibriya MG, Kim YJ, Kishimoto M, Koh WP, Kohara K, Kumari M, Kwek K, Lee NR, Lee J, Liao J, Lieb W, Liewald DCM, Matsubara T, Matsushita Y, Meitinger T, Mihailov E, Milani L, Mills R, Mononen N, Müller-Nurasyid M, Nabika T, Nakashima E, Ng HK, Nikus K, Nutile T, Ohkubo T, Ohnaka K, Parish S, Paternoster L, Peng H, Peters A, Pham ST, Pinidiyapathirage MJ, Rahman M, Rakugi H, Rolandsson O, Ann Rozario M, Ruggiero D, Sala CF, Sarju R, Shimokawa K, Snieder H, Sparsø T, Spiering W, Starr JM, Stott DJ, Stram DO, Sugiyama T, Szymczak S, Tang WHW, Tong L, Trompet S, Turjanmaa V, Ueshima H, Uitterlinden AG, Umemura S, Vaarasmaki M, van Dam RM, van Gilst WH, van Veldhuisen DJ, Viikari JS, Waldenberger M, Wang Y, Wang A, Wilson R, Wong TY, Xiang YB, Yamaguchi S, Ye X, Young RD, Young TL, Yuan JM, Zhou X, Asselbergs FW, Ciullo M, Clarke R, Deloukas P, Franke A, Franks PW, Franks S, Friedlander Y, Gross MD, Guo Z, Hansen T, Jarvelin MR, Jørgensen T, Jukema JW, Kähönen M, Kajio H, Kivimaki M, Lee JY, Lehtimäki T, Linneberg A, Miki T, Pedersen O, Samani NJ, Sørensen TIA, Takayanagi R, Toniolo D, Ahsan H, Allayee H, Chen YT, Danesh J, Deary IJ, Franco OH, Franke L, Heijman BT, Holbrook JD, Isaacs A, Kim BJ, Lin X, Liu J, März W, Metspalu A, Mohlke KL, Sanghera DK, Shu XO, van Meurs JBJ, Vithana E, Wickremasinghe AR, Wijmenga C, Wolffenbuttel BHW, Yokota M, Zheng W, Zhu D, Vineis P, Kyrtopoulos SA, Kleinjans JCS, McCarthy MI, Soong R, Gieger C, Scott J, Teo YY, He J, Elliott P, Tai ES, van der Harst P, Kooner JS, and Chambers JC

Subjects
Adult, Aged, Aged, 80 and over, Asian People genetics, Cardiovascular Diseases blood, Cardiovascular Diseases ethnology, Cardiovascular Diseases genetics, Female, Genetic Predisposition to Disease ethnology, Genetic Predisposition to Disease genetics, Genetic Variation, Genotype, Humans, Male, Middle Aged, Natriuretic Peptide, Brain blood, Peptide Fragments blood, Polymorphism, Single Nucleotide, Regression Analysis, Risk Factors, White People genetics, Blood Pressure genetics, DNA Methylation, Genetic Loci genetics, Genome-Wide Association Study methods
Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Published
2015
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