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Your search keyword '"Lyytikäinen, Leo-Pekka"' showing total 38 results
Start Over Author "Lyytikäinen, Leo-Pekka" Publisher nature publishing group
38 results on '"Lyytikäinen, Leo-Pekka"'

1. Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

Author

Musolf, Anthony M., Haarman, Annechien E. G., Luben, Robert N., Ong, Jue-Sheng, Patasova, Karina, Trapero, Rolando Hernandez, Marsh, Joseph, Jain, Ishika, Jain, Riya, Wang, Paul Zhiping, Lewis, Deyana D., Tedja, Milly S., Iglesias, Adriana I., Li, Hengtong, Cowan, Cameron S., Baird, Paul Nigel, Veluchamy, Amutha Barathi, Burdon, Kathryn P., Campbell, Harry, Chen, Li Jia, Cheng, Ching-Yu, Chew, Emily Y., Craig, Jamie E., Cumberland, Phillippa M., Deangelis, Margaret M., Delcourt, Cécile, Ding, Xiaohu, Evans, David M., Fan, Qiao, Fossarello, Maurizio, Foster, Paul J., Gharahkhani, Puya, Guggenheim, Jeremy A., Guo, Xiaobo, Han, Xikun, He, Mingguang, Hewitt, Alex W., Hoang, Quan V., Iyengar, Sudha K., Jonas, Jost B., Kähönen, Mika, Kaprio, Jaakko, Klein, Barbara E., Lass, Jonathan H., Lee, Kris, Lehtimäki, Terho, Lewis, Deyana, Li, Qing, Li, Shi-Ming, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mackey, David A., Martin, Nicholas G., Meguro, Akira, Middlebrooks, Candace, Miyake, Masahiro, Mizuki, Nobuhisa, Musolf, Anthony, Nickels, Stefan, Oexle, Konrad, Pang, Chi Pui, Paterson, Andrew D., Pennell, Craig, Pfeiffer, Norbert, Polasek, Ozren, Rahi, Jugnoo S., Raitakari, Olli, Rudan, Igor, Sahebjada, Srujana, Simpson, Claire L., Tai, E-Shyong, Tideman, J. Willem L., Tsujikawa, Akitaka, Wang, Ningli, Bin, Wei Wen, Williams, Cathy, Williams, Katie M., Wilson, James F., Wojciechowski, Robert, Wang, Ya Xing, Yamashiro, Kenji, Yam, Jason C. S., Yap, Maurice K. H., Yazar, Seyhan, Yip, Shea Ping, Young, Terri L., Zhou, Xiangtian, Biino, Ginevra, Klein, Alison P., Duggal, Priya, Hayward, Caroline, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Pärssinen, Olavi, Saw, Seang-Mei, Stambolian, Dwight, Hysi, Pirro G., Khawaja, Anthony P., Vitart, Veronique, Hammond, Christopher J., van Duijn, Cornelia M., Verhoeven, Virginie J. M., Klaver, Caroline C. W., and Bailey-Wilson, Joan E.

Subjects
genetic predisposition to disease, perinnölliset taudit, ympäristötekijät, taittovirheet, perinnöllisyyslääketiede, riskitekijät, quantitative trait, periytyvyys, genome-wide association studies, quantitative trait loci, perimä, silmätaudit, microarrays, perinnöllisyys
Abstract

Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP, the circadian rhythm gene PER3, and P4HTM, which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions. peerReviewed

Published
2023

2. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Qiao, Pozarickij, Alfred, Tan, Nicholas Y. Q., Guo, Xiaobo, Verhoeven, Virginie J. M., Vitart, Veronique, Guggenheim, Jeremy A., Miyake, Masahiro, Tideman, J. Willem L., Khawaja, Anthony P., Zhang, Liang, MacGregor, Stuart, Höhn, René, Chen, Peng, Biino, Ginevra, Wedenoja, Juho, Saffari, Seyed Ehsan, Tedja, Milly S., Xie, Jing, Lanca, Carla, Wang, Ya Xing, Sahebjada, Srujana, Mazur, Johanna, Mirshahi, Alireza, Martin, Nicholas G., Yazar, Seyhan, Pennell, Craig E., Yap, Maurice, Haarman, Annechien E. G., Enthoven, Clair A., Polling, JanRoelof, Bailey-Wilson, Joan E., Veluchamy, Amutha Barathi, Burdon, Kathryn P., Campbell, Harry, Chen, Li Jia, Chew, Emily Y., Craig, Jamie E., Cumberland, Phillippa M., Deangelis, Margaret M., Delcourt, Cécile, Ding, Xiaohu, Evans, David M., Gharahkhani, Puya, Iglesias, Adriana I., Haller, Toomas, Han, Xikun, Hoang, Quan, Igo, Robert P., Iyengar, Sudha K., Kähönen, Mika, Kaprio, Jaakko, Klein, Barbara E., Klein, Ronald, Lass, Jonathan H., Lee, Kris, Lehtimäki, Terho, Lewis, Deyana D., Li, Qing, Li, Shi-Ming, Lyytikäinen, Leo-Pekka, Meguro, Akira, Metspalu, Andres, Middlebrooks, Candace D., Mizuki, Nobuhisa, Musolf, Anthony M., Nickels, Stefan, Oexle, Konrad, Pang, Chi Pui, Paterson, Andrew D., Rahi, Jugnoo S., Raitakari, Olli, Rudan, Igor, Stambolian, Dwight, Simpson, Claire L., Wang, Ningli, Bin Wei, Wen, Williams, Katie M., Wilson, James F., Wojciechowski, Robert, Yamashiro, Kenji, Yam, Jason C. S., Zhou, Xiangtian, Aslam, Tariq, Barman, Sarah A., Barrett, Jenny H., Bishop, Paul, Blows, Peter, Bunce, Catey, Carare, Roxana O., Chakravarthy, Usha, Chan, Michelle, Chua, Sharon Y. L., Crabb, David P., Cumberland, Philippa M., Day, Alexander, Desai, Parul, Dhillon, Bal, Dick, Andrew D., Egan, Cathy, Ennis, Sarah, Fruttiger, Marcus, Gallacher, John E. J., Garway-Heath, David F., Gibson, Jane, Gore, Dan, Hardcastle, Alison, Harding, Simon P., Hogg, Ruth E., Keane, Pearse A., Khaw, Sir Peng T., Lascaratos, Gerassimos, Lotery, Andrew J., Macgillivray, Tom, Mackie, Sarah, Martin, Keith, McGaughey, Michelle, McGuinness, Bernadette, McKay, Gareth J., McKibbin, Martin, Mitry, Danny, Moore, Tony, Morgan, James E., Muthy, Zaynah A., O’Sullivan, Eoin, Owen, Chris G., Patel, Praveen, Paterson, Euan, Peto, Tunde, Petzold, Axel, Rudnikca, Alicja R., Self, Jay, Sivaprasad, Sobha, Steel, David, Stratton, Irene, Strouthidis, Nicholas, Sudlow, Cathie, Thomas, Dhanes, Trucco, Emanuele, Tufail, Adnan, Vernon, Stephen A., Viswanathan, Ananth C., Williams, Katie, Woodside, Jayne V., Yates, Max M., Yip, Jennifer, Zheng, Yalin, Hewitt, Alex W., Jaddoe, Vincent W. V., van Duijn, Cornelia M., Hayward, Caroline, Polasek, Ozren, Tai, E-Shyong, Yoshikatsu, Hosoda, Hysi, Pirro G., Young, Terri L., Tsujikawa, Akitaka, Wang, Jie Jing, Mitchell, Paul, Pfeiffer, Norbert, Pärssinen, Olavi, Foster, Paul J., Fossarello, Maurizio, Yip, Shea Ping, Williams, Cathy, Hammond, Christopher J., Jonas, Jost B., He, Mingguang, Mackey, David A., Wong, Tien-Yin, Klaver, Caroline C. W., Saw, Seang-Mei, Baird, Paul N., and Cheng, Ching-Yu

Subjects
genetic structures, likinäköisyys, sense organs, geneettiset tekijät, eye diseases
Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia. peerReviewed

Published
2020

3. A catalog of genetic loci associated with kidney function from analyses of a million individuals

Author

Wuttke, Matthias, Li, Yong, Li, Man, Sieber, Karsten B., Feitosa, Mary F., Gorski, Mathias, Tin, Adrienne, Wang, Lihua, Chu, Audrey Y., Hoppmann, Anselm, Kirsten, Holger, Giri, Ayush, Chai, Jin-Fang, Sveinbjornsson, Gardar, Tayo, Bamidele O., Nutile, Teresa, Fuchsberger, Christian, Marten, Jonathan, Cocca, Massimiliano, Ghasemi, Sahar, Xu, Yizhe, Horn, Katrin, Noce, Damia, van der Most, Peter J., Sedaghat, Sanaz, Yu, Zhi, Akiyama, Masato, Afaq, Saima, Ahluwalia, Tarunveer S., Almgren, Peter, Amin, Najaf, Ärnlöv, Johan, Bakker, Stephan J. L., Bansal, Nisha, Baptista, Daniela, Bergmann, Sven, Biggs, Mary L., Biino, Ginevra, Boehnke, Michael, Boerwinkle, Eric, Boissel, Mathilde, Bottinger, Erwin P., Boutin, Thibaud S., Brenner, Hermann, Brumat, Marco, Burkhardt, Ralph, Butterworth, Adam S., Campana, Eric, Campbell, Archie, Campbell, Harry, Canouil, Mickaël, Carroll, Robert J., Catamo, Eulalia, Chambers, John C., Chee, Miao-Ling, Chee, Miao-Li, Chen, Xu, Cheng, Ching-Yu, Cheng, Yurong, Christensen, Kaare, Cifkova, Renata, Ciullo, Marina, Pina Concas, Maria, Cook, James P., Coresh, Josef, Corre, Tanguy, Sala, Cinzia Felicita, Cusi, Daniele, Danesh, John, Daw, E. Warwick, de Borst, Martin H., De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko P. J., Degenhardt, Frauke, Delgado, Graciela, Demirkan, Ayse, Di Angelantonio, Emanuele, Dittrich, Katalin, Divers, Jasmin, Dorajoo, Rajkumar, Eckardt, Kai-Uwe, Ehret, Georg, Elliott, Paul, Endlich, Karlhans, Evans, Michele K., Felix, Janine F., Foo, Valencia Hui Xian, Franco, Oscar H., Franke, Andre, Freedman, Barry I., Freitag-Wolf, Sandra, Friedlander, Yechiel, Froguel, Philippe, Gansevoort, Ron T., Gao, He, Gasparini, Paolo, Gaziano, J. Michael, Giedraitis, Vilmantas, Gieger, Christian, Girotto, Giorgia, Giulianini, Franco, Gögele, Martin, Gordon, Scott D., Gudbjartsson, Daniel F., Gudnason, Vilmundur, Haller, Toomas, Hamet, Pavel, Harris, Tamara B., Hartman, Catharina A., Hayward, Caroline, Hellwege, Jacklyn N., Heng, Chew-Kiat, Hickst, Andrew A., Hofer, Edith, Huang, Wei, Hutri-Kähönen, Nina, Hwang, Shih-Jen, ikram, M. Arfan, indridason, Olafur S., Ingelsson, Erik, ising, Marcus, Jaddoe, Vincent W. V., Jakobsdottir, Johanna, Jonas, Jost B, Joshi, Peter K., Shilpa Josyula, Navya, Jung, Bettina, Kähönen, Mika, Kamatani, Yoichiro, Kammerer, Candace M., Kanai, Masahiro, Kastarinen, Mika, Kerr, Shona M., Khor, Chiea-Chuen, Kiess, Wieland, Kleber, Marcus E., Koenig, Wolfgang, Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kraja, Aldi T., Krajcoviechova, Alena, Kramer, Holly, Krämer, Bernhard K., Kronenberg, Florian, Kubo, Michiaki, Kühnel, Brigitte, Kuokkanen, Mikko, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lange, Leslie A., Langefeld, Carl D., Jen-Mai Lee, Jeannette, Lehne, Benjamin, Lehtimäki, Terho, Lieb, Wolfgang, Cohort Study, Lifelines, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M., Liu, Jun, Liu, Jianjun, Loeffler, Markus, Loos, Ruth J. F., Lucae, Susanne, Ann Lukas, Mary, Lyytikäinen, Leo-Pekka, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Martins, Jade, März, Winfried, Mascalzoni, Deborah, Matsuda, Koichi, Christa Meisinger, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mikaelsdottir, Evgenia K., Milaneschi, Yuri, Miliku, Kozeta, Mishra, Pashupati P., Veteran Program, V. A. Million, Mohlke, Karen L., Mononen, Nina, Montgomery, Grant W., Mook-Kanamori, Dennis O., Mychaleckyj, Josyf C., Nadkarni, Girish N, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, ilja M., Noordam, Raymond, O’Connell, Jeffrey, O’Donoghue, Michelle L., Olafsson, Isleifur, Oldehinkel, Albertine J., Orho-Melander, Marju, Ouwehand, Willem H., Padmanabhan, Sandosh, Palmer, Nicholette D., Palsson, Runolfur, Penninx, Brenda W. J. H., Perls, Thomas, Perola, Markus, Pirastu, Mario, Pirastu, Nicola, Pistis, Giorgio, Podgornaia, Anna I., Polasek, Ozren, Ponte, Belen, Porteous, David J., Poulain, Tanja, Pramstaller, Peter P., Preuss, Michael H., Prins, Bram P., Province, Michael A., Rabelink, Ton J., Raffield, Laura M., Raitakari, Olli T., Reilly, Dermot F., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Ridker, Paul M., Rivadeneira, Fernando, Rizzi, Federica, Roberts, David J., Robino, Antonietta, Rossing, Peter, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Ryan, Kathleen A., Saba, Yasaman, Sabanayagam, Charumathi, Salomaa, Veikko, Salvi, Erika, Saum, Kai-Uwe, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Schupf, Nicole, Shaffer, Christian M., Shi, Yuan, Smith, Albert V., Smith, Blair H., Soranzo, Nicole, Spracklen, Cassandra N., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Svensson, Per O., Szymczak, Silke, Tai, E-Shyong, Tajuddin, Salman M., Tan, Nicholas Y. Q., Taylor, Kent D., Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H. L., Thomsen, Hauke, Thorleifsson, Gudmar, Toniolo, Daniela, Tönjes, Anke, Tremblay, Johanne, Tzoulaki, Ioanna, Uitterlinden, André G., Vaccargiu, Simona, van Dam, Rob M., van der Harst, Pim, van Duijn, Cornelia M., Velez Edward, Digna R., Verweij, Niek, Vogelezang, suzanne, Völker, üwe, Vollenweider, Peter, Waeber, Gerard, Waldenberger, Melanie, Wallentin, Lars, Wang, Ya Xing, Wang, Chaolong, Waterworth, Dawn M., Bin Wei, Wen, White, Harvey, Whitfield, John B., Wild, Sarah H., Wilson, James F., Wojczynski, Mary K., Wong, Charlene, Wong, Tien-Yin, Xu, Liang, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Weihua, Zonderman, Alan B., Rotter, Jerome I., Bochud, Murielle, Psaty, Bruce M., Vitart, Veronique, Wilson, James G., Dehghan, Abbas, Parsa, Afshin, Chasman, Daniel I., Ho, Kevin, Morris, Andrew P., Devuyst, Olivier, Akilesh, Shreeram, Pendergrass, Sarah A., Sim, Xueling, Böger, Carsten A., Okada, Yukinori, Edwards, Todd L., Snieder, Harold, Stefansson, Kari, Hung, Adriana M., Heid, Iris M., Markus Scholz, Teumer, Alexander, Köttgen, Anna, Pattaro, Cristian, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Internal Medicine, Epidemiology, Erasmus MC other, Pediatrics, Psychiatry, APH - Mental Health, APH - Digital Health, Wuttke, M, Li, Y, Li, M, Sieber, Kb, Feitosa, Mf, Gorski, M, Tin, A, Wang, L, Chu, Ay, Hoppmann, A, Kirsten, H, Giri, A, Chai, Jf, Sveinbjornsson, G, Tayo, Bo, Nutile, T, Fuchsberger, C, Marten, J, Cocca, M, Ghasemi, S, Xu, Y, Horn, K, Noce, D, van der Most, Pj, Sedaghat, S, Yu, Z, Akiyama, M, Afaq, S, Ahluwalia, T, Almgren, P, Amin, N, Ärnlöv, J, Bakker, Sjl, Bansal, N, Baptista, D, Bergmann, S, Biggs, Ml, Biino, G, Boehnke, M, Boerwinkle, E, Boissel, M, Bottinger, Ep, Boutin, T, Brenner, H, Brumat, M, Burkhardt, R, Butterworth, A, Campana, Eric, Campbell, A, Campbell, H, Canouil, M, Carroll, Rj, Catamo, E, Chambers, Jc, Chee, Ml, Chen, X, Cheng, Cy, Cheng, Y, Christensen, K, Cifkova, R, Ciullo, M, Concas, Mp, Cook, Jp, Coresh, J, Corre, T, Sala, Cf, Cusi, D, Danesh, J, Daw, Ew, de Borst, Mh, De Grandi, A, de Mutsert, R, de Vries, Apj, Degenhardt, F, Delgado, G, Demirkan, A, Di Angelantonio, E, Dittrich, K, Divers, J, Dorajoo, R, Eckardt, Ku, Ehret, G, Elliott, P, Endlich, K, Evans, Mk, Felix, Jf, Foo, Vhx, Franco, Oh, Franke, A, Freedman, Bi, Freitag-Wolf, S, Friedlander, Y, Froguel, P, Gansevoort, Rt, Gao, H, Gasparini, P, Gaziano, Jm, Giedraitis, V, Gieger, C, Girotto, G, Giulianini, F, Gögele, M, Gordon, Sd, Gudbjartsson, Df, Gudnason, V, Haller, T, Hamet, P, Harris, Tb, Hartman, Ca, Hayward, C, Hellwege, Jn, Heng, Ck, Hicks, Aa, Hofer, E, Huang, W, Hutri-Kähönen, N, Hwang, Sj, Ikram, Ma, Indridason, O, Ingelsson, E, Ising, M, Jaddoe, Vwv, Jakobsdottir, J, Jonas, Jb, Joshi, Pk, Josyula, N, Jung, B, Kähönen, M, Kamatani, Y, Kammerer, Cm, Kanai, M, Kastarinen, M, Kerr, Sm, Khor, Cc, Kiess, W, Kleber, Me, Koenig, W, Kooner, J, Körner, A, Kovacs, P, Kraja, At, Krajcoviechova, A, Kramer, H, Krämer, Bk, Kronenberg, F, Kubo, M, Kühnel, B, Kuokkanen, M, Kuusisto, J, La Bianca, M, Laakso, M, Lange, La, Langefeld, Cd, Lee, Jj, Lehne, B, Lehtimäki, T, Lieb, W, Lifelines Cohort, Study, Lim, Sc, Lind, L, Lindgren, Cm, Liu, J, Loeffler, M, Loos, Rjf, Lucae, S, Lukas, Ma, Lyytikäinen, Lp, Mägi, R, Magnusson, Pke, Mahajan, A, Martin, Ng, Martins, J, März, W, Mascalzoni, D, Matsuda, K, Meisinger, C, Meitinger, T, Melander, O, Metspalu, A, Mikaelsdottir, Ek, Milaneschi, Y, Miliku, K, Mishra, Pp, V. A., Million Veteran Program, Mohlke, Kl, Mononen, N, Montgomery, Gw, Mook-Kanamori, Do, Mychaleckyj, Jc, Nadkarni, Gn, Nalls, Ma, Nauck, M, Nikus, K, Ning, B, Nolte, Im, Noordam, R, O'Connell, J, O'Donoghue, Ml, Olafsson, I, Oldehinkel, Aj, Orho-Melander, M, Ouwehand, Wh, Padmanabhan, S, Palmer, Nd, Palsson, R, Penninx, Bwjh, Perls, T, Perola, M, Pirastu, M, Pirastu, N, Pistis, G, Podgornaia, Ai, Polasek, O, Ponte, B, Porteous, Dj, Poulain, T, Pramstaller, Pp, Preuss, Mh, Prins, Bp, Province, Ma, Rabelink, Tj, Raffield, Lm, Raitakari, Ot, Reilly, Df, Rettig, R, Rheinberger, M, Rice, Km, Ridker, Pm, Rivadeneira, F, Rizzi, F, Roberts, Dj, Robino, A, Rossing, P, Rudan, I, Rueedi, R, Ruggiero, D, Ryan, Ka, Saba, Y, Sabanayagam, C, Salomaa, V, Salvi, E, Saum, Ku, Schmidt, H, Schmidt, R, Schöttker, B, Schulz, Ca, Schupf, N, Shaffer, Cm, Shi, Y, Smith, Av, Smith, Bh, Soranzo, N, Spracklen, Cn, Strauch, K, Stringham, Hm, Stumvoll, M, Svensson, Po, Szymczak, S, Tai, E, Tajuddin, Sm, Tan, Nyq, Taylor, Kd, Teren, A, Tham, Yc, Thiery, J, Thio, Chl, Thomsen, H, Thorleifsson, G, Toniolo, D, Tönjes, A, Tremblay, J, Tzoulaki, I, Uitterlinden, Ag, Vaccargiu, S, van Dam, Rm, van der Harst, P, van Duijn, Cm, Velez Edward, Dr, Verweij, N, Vogelezang, S, Völker, U, Vollenweider, P, Waeber, G, Waldenberger, M, Wallentin, L, Wang, Yx, Wang, C, Waterworth, Dm, Bin Wei, W, White, H, Whitfield, Jb, Wild, Sh, Wilson, Jf, Wojczynski, Mk, Wong, C, Wong, Ty, Xu, L, Yang, Q, Yasuda, M, Yerges-Armstrong, Lm, Zhang, W, Zonderman, Ab, Rotter, Ji, Bochud, M, Psaty, Bm, Vitart, V, Wilson, Jg, Dehghan, A, Parsa, A, Chasman, Di, Ho, K, Morris, Ap, Devuyst, O, Akilesh, S, Pendergrass, Sa, Sim, X, Böger, Ca, Okada, Y, Edwards, Tl, Snieder, H, Stefansson, K, Hung, Am, Heid, Im, Scholz, M, Teumer, A, Köttgen, A, and Pattaro, C.

Subjects
catalog, Inheritance Patterns, Hasso-Plattner-Institut für Digital Engineering GmbH, Genome-wide association study, Disease, Kidney Function Tests, Bioinformatics, DISEASE, 0302 clinical medicine, Uromodulin/urine, kidney function, 11 Medical and Health Sciences, Genetics & Heredity, ddc:616, 0303 health sciences, Kidney, Genome-wide association, HERITABILITY, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, RENAL-FUNCTION, TRANS-EQTLS, METAANALYSIS, TRANSPORTER, CLASSIFICATION, INTEGRATION, Chromosome Mapping, 3. Good health, Phenotype, medicine.anatomical_structure, Medical genetics, Common variants, Renal function, Trans-EQTLS, Metaanalysis, Heritability, Transporter, Life Sciences & Biomedicine, Glomerular Filtration Rate, Metaanalysi, medicine.medical_specialty, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Common variant, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, White People, V. A. Million Veteran Program, 03 medical and health sciences, Quantitative Trait, Heritable, Lifelines Cohort Study, Uromodulin, Genetics, medicine, Humans, Genetic Predisposition to Disease, Renal Insufficiency, Chronic, Genetic Association Studies, 030304 developmental biology, Genetic association, Science & Technology, urogenital system, association, genetic loci, 06 Biological Sciences, medicine.disease, Renal Insufficiency, Chronic/genetics/physiopathology/urine, Genetic Association Studies/methods, ddc:000, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study, Kidney disease
Abstract

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Published
2019

4. 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

Author

Gorski, Mathias, van der Most, Peter J., Teumer, Alexander, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Nolte, Ilja M., Cocca, Massimiliano, Taliun, Daniel, Gomez, Felicia, Li, Yong, Tayo, Bamidele, Tin, Adrienne, Feitosa, Mary F., Aspelund, Thor, Attia, John, Biffar, Reiner, Bochud, Murielle, Boerwinkle, Eric, Borecki, Ingrid, Bottinger, Erwin P., Chen, Ming-Huei, Chouraki, Vincent, Ciullo, Marina, Coresh, Josef, Cornelis, Marilyn C., Curhan, Gary C., d’Adamo, Adamo Pio, Dehghan, Abbas, Dengler, Laura, Ding, Jingzhong, Eiriksdottir, Gudny, Endlich, Karlhans, Enroth, Stefan, Esko, Tõnu, Franco, Oscar H., Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Gottesman, Omri, Gudnason, Vilmundur, Gyllensten, Ulf, Hancock, Stephen J., Harris, Tamara B., Helmer, Catherine, Höllerer, Simon, Hofer, Edith, Hofman, Albert, Holliday, Elizabeth G., Homuth, Georg, Hu, Frank B., Huth, Cornelia, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Imboden, Medea, Johansson, Åsa, Kähönen, Mika, König, Wolfgang, Kramer, Holly, Krämer, Bernhard K., Kumar, Ashish, Kutalik, Zoltan, Lambert, Jean-Charles, Launer, Lenore J., Lehtimäki, Terho, de Borst, Martin, Navis, Gerjan, Swertz, Morris, Liu, Yongmei, Lohman, Kurt, Loos, Ruth J. F., Lu, Yingchang, Lyytikäinen, Leo-Pekka, McEvoy, Mark A., Meisinger, Christa, Meitinger, Thomas, Metspalu, Andres, Metzger, Marie, Mihailov, Evelin, Mitchell, Paul, Nauck, Matthias, Oldehinkel, Albertine J., Olden, Matthias, Penninx, Brenda W. J. H., Pistis, Giorgio, Pramstaller, Peter P., Probst-Hensch, Nicole, Raitakari, Olli T., Rettig, Rainer, Ridker, Paul M., Rivadeneira, Fernando, Robino, Antonietta, Rosas, Sylvia E., Ruderfer, Douglas, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia, Schmidt, Helena, Schmidt, Reinhold, Scott, Rodney J., Sedaghat, Sanaz, Smith, Albert V., Sorice, Rossella, Stengel, Benedicte, Stracke, Sylvia, Strauch, Konstantin, Toniolo, Daniela, Uitterlinden, Andre G., Ulivi, Sheila, Viikari, Jorma S., Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Vuckovic, Dragana, Waldenberger, Melanie, Jin Wang, Jie, Yang, Qiong, Chasman, Daniel I., Tromp, Gerard, Snieder, Harold, Heid, Iris M., Fox, Caroline S., Köttgen, Anna, Pattaro, Cristian, Böger, Carsten A., Fuchsberger, Christian, Teumer, Alexander [0000-0002-8309-094X], Cocca, Massimiliano [0000-0002-1127-7596], Feitosa, Mary F [0000-0002-0933-2410], Aspelund, Thor [0000-0002-7998-5433], Chouraki, Vincent [0000-0002-4698-1794], Ciullo, Marina [0000-0002-9621-9984], d'Adamo, Adamo Pio [0000-0001-9367-4909], Endlich, Karlhans [0000-0001-6052-6061], Enroth, Stefan [0000-0002-5056-9137], Franco, Oscar H [0000-0002-4606-4929], Gasparini, Paolo [0000-0002-0859-0856], Girotto, Giorgia [0000-0003-4507-6589], Gottesman, Omri [0000-0002-1840-8464], Gudnason, Vilmundur [0000-0001-5696-0084], Huth, Cornelia [0000-0003-2421-433X], Johansson, Åsa [0000-0002-2915-4498], Kähönen, Mika [0000-0002-4510-7341], Lambert, Jean-Charles [0000-0003-0829-7817], de Borst, Martin [0000-0002-4127-8733], Loos, Ruth JF [0000-0002-8532-5087], Metzger, Marie [0000-0003-3597-5409], Pramstaller, Peter P [0000-0002-9831-8302], Robino, Antonietta [0000-0003-2152-2353], Ruggiero, Daniela [0000-0003-3898-7827], Smith, Albert V [0000-0003-1942-5845], Stengel, Benedicte [0000-0001-9469-0804], Völker, Uwe [0000-0002-5689-3448], Vuckovic, Dragana [0000-0001-9343-6142], Tromp, Gerard [0000-0002-7761-0806], Apollo - University of Cambridge Repository, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Gorski, Mathia, van der Most, Peter J, Teumer, Alexander, Chu, Audrey Y, Li, Man, Mijatovic, Vladan, Nolte, Ilja M, Cocca, Massimiliano, Taliun, Daniel, Gomez, Felicia, Li, Yong, Tayo, Bamidele, Tin, Adrienne, Feitosa, Mary F, Aspelund, Thor, Attia, John, Biffar, Reiner, Bochud, Murielle, Boerwinkle, Eric, Borecki, Ingrid, Bottinger, Erwin P, Chen, Ming Huei, Chouraki, Vincent, Ciullo, Marina, Coresh, Josef, Cornelis, Marilyn C, Curhan, Gary C, D'Adamo, ADAMO PIO, Dehghan, Abba, Dengler, Laura, Ding, Jingzhong, Eiriksdottir, Gudny, Endlich, Karlhan, Enroth, Stefan, Esko, Tõnu, Franco, Oscar H, Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Gottesman, Omri, Gudnason, Vilmundur, Gyllensten, Ulf, Hancock, Stephen J, Harris, Tamara B, Helmer, Catherine, Höllerer, Simon, Hofer, Edith, Hofman, Albert, Holliday, Elizabeth G, Homuth, Georg, Hu, Frank B, Huth, Cornelia, Hutri Kähönen, Nina, Hwang, Shih Jen, Imboden, Medea, Johansson, Åsa, Kähönen, Mika, König, Wolfgang, Kramer, Holly, Krämer, Bernhard K, Kumar, Ashish, Kutalik, Zoltan, Lambert, Jean Charle, Launer, Lenore J, Lehtimäki, Terho, de Borst, Martin, Navis, Gerjan, Swertz, Morri, Liu, Yongmei, Lohman, Kurt, Loos, Ruth J. F, Lu, Yingchang, Lyytikäinen, Leo Pekka, Mcevoy, Mark A, Meisinger, Christa, Meitinger, Thoma, Metspalu, Andre, Metzger, Marie, Mihailov, Evelin, Mitchell, Paul, Nauck, Matthia, Oldehinkel, Albertine J, Olden, Matthia, Wjh Penninx, Brenda, Pistis, Giorgio, Pramstaller, Peter P, Probst Hensch, Nicole, Raitakari, Olli T, Rettig, Rainer, Ridker, Paul M, Rivadeneira, Fernando, Robino, Antonietta, Rosas, Sylvia E, Ruderfer, Dougla, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia, Schmidt, Helena, Schmidt, Reinhold, Scott, Rodney J, Sedaghat, Sanaz, Smith, Albert V, Sorice, Rossella, Stengel, Benedicte, Stracke, Sylvia, Strauch, Konstantin, Toniolo, Daniela, Uitterlinden, Andre G, Ulivi, Sheila, Viikari, Jorma S, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Vuckovic, Dragana, Waldenberger, Melanie, Jin Wang, Jie, Yang, Qiong, Chasman, Daniel I, Tromp, Gerard, Snieder, Harold, Heid, Iris M, Fox, Caroline S, Köttgen, Anna, Pattaro, Cristian, Böger, Carsten A, Fuchsberger, Christian, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Value, Affordability and Sustainability (VALUE), and Groningen Institute for Organ Transplantation (GIOT)

Subjects
kidney, Medicin och hälsovetenskap, Genotyping Techniques, 610 Medizin, HapMap based genome-wide association studies, genome sequencing, The 1000 Genomes project, meta-analysis, kidney function, VARIANTS, GENOTYPE IMPUTATION, Kidney, GLOMERULAR-FILTRATION-RATE, Medical and Health Sciences, Genome-wide association studies, Polymorphism, Single Nucleotide, DISEASE, Article, genome-wide, Gene Frequency, Chronic kidney disease, WIDE ASSOCIATION, Erfðafræði, GWAS, Humans, ddc:610, SERUM CREATININE, LINKAGE ANALYSIS, HERITABILITY, Genome, Human, COMMUNITY-BASED POPULATION, Computational Biology, Rannsóknir, Arfgengi, Genetic Loci, Nýrnasjúkdómar, INTEGRATION, Genome-Wide Association Study
Abstract

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value, 3C. Three-City Study. The work was made possible by the participation of the control subjects, the patients, and their families. We thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The 3C Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai. AGES. Age, Gene/Environment Susceptibility-Reykjavik Study. This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC. Atherosclerosis Risk in Communities study. The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This work as well as YL and AK were supported by the German Research Foundation (KO 3598/2-1, KO 3598/3-1 and CRC1140 A05 to AK). ASPS. Austrian Stroke Prevention Study. The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS. The authors thank the staff and the participants of the ASPS for their valuable contributions. We thank Birgit Reinhart for her long-term administrative commitment and Ing Johann Semmler for the technical assistance at creating the DNA-bank. BMES. Blue Mountains Eye Study. The BMES has been supported by the Australian RADGAC grant (1992- 94) and Australian National Health & Medical Research Council, Canberra Australia (Grant Nos: 974159, 211069, 991407, 457349). The GWAS studies of Blue Mountains Eye Study population are supported by the Australian National Health & Medical Research Council (Grant Nos: 512423, 475604, 529912) and the Wellcome Trust, UK (2008). EGH and JJW are funded by the Australian National Health & Medical Research Council Fellowship Schemes. CILENTO. Italian Network on Genetic Isolates – Cilento. We thank the populations of Cilento for their participation in the study. The study was supported by the Italian Ministry of Universities and CNR 36 (PON03PE_00060_7, Interomics Flagship Project), the Assessorato Ricerca Regione Campania, the Fondazione con il SUD (2011-PDR-13), and the Istituto Banco di Napoli - Fondazione to MC. COLAUS. The CoLaus authors thank Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey and Sylvie Mermoud for data collection. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, the Swiss National Science Foundation (33CSCO- 122661, 3200BO-111361/2, 3100AO-116323/1, 310000-112552). The computations for CoLaus imputation were performed in part at the Vital-IT center for high performance computing of the Swiss Institute of Bioinformatics. We thank Vincent Mooser for his contribution to the CoLaus study. EGCUT. Estonian Genome Center University of Tartu. EGCUT received financing from FP7 grants (278913, 306031, 313010) and targeted financing from Estonian Government (SF0180142s08). EGCUT studies were covered from Infra-structure grant no. 3.2.0304.11-0312 funded mostly by the European Regional Development Fund, Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG). We acknowledge EGCUT technical personnel, especially Mr V. Soo and S. Smit. Data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. FamHS. Family Heart Study. The FHS work was supported in part by NIH grants 5R01HL08770003, 5R01HL08821502 (Michael A. Province) from the NHLBI and 5R01DK07568102, 5R01DK06833603 from the NIDDK (I.B.B.). The authors thank the staff and participants of the FamHS for their important contributions. FHS. Framingham Heart Study. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. GENDIAN. GENetics of DIAbetic Nephropathy study. The support of the physicians, the patients, and the staff of the Diabetes Zentrum Mergentheim (Head: Prof. Dr. Thomas Haak), the diabetes outpatient clinic Dr Nusser - Dr Kreisel, the dialysis centers KfH Amberg, KfH Bayreuth, KfH Deggendorf, KfH Donauwörth, KfH Freising, KfH Freyung, KfH Fürth, KfH Hof, KfH Ingolstadt, KfH Kelheim, KfH München Elsenheimerstraße, KfH München-Schwabing, KfH Neumarkt, KfH Neusäß, KfH Oberschleißheim, KfH Passau, KfH Plauen, KfH Regensburg Günzstraße, KfH Regensburg Caritas-Krankenhaus, KfH Straubing, KfH Sulzbach-Rosenberg, KfH Weiden, Dialysezentrum Augsburg Dr. Kirschner, Dialysezentrum Bad Alexandersbad, KfH Bamberg, Dialysezentrum Emmering, Dialysezentrum Klinikum Landshut, Dialysezentrum Landshut, Dialysezentrum Pfarrkirchen, Dialysezentrum Schwandorf, Dr. Angela Götz, the medical doctoral student Johanna Christ and the Study Nurse Ingrid Lugauer. The expert technical assistance of Claudia Strohmeier is acknowledged. Phenotyping was funded by the Dr. Robert PflegerStiftung (Dr Carsten A. Böger), the MSD Stipend Diabetes (Dr Carsten A. Böger) and the University Hospital of Regensburg (intramural grant ReForM A to Dr. A. Götz, ReForM C to Dr. Carsten Böger). Genome-wide genotyping was funded by the KfH Stiftung Präventivmedizin e.V. (Dr. Carsten A. Böger, Dr. Jens Brüning), the Else Kröner-Fresenius-Stiftung (2012_A147 to Dr Carsten A. Böger and Dr Iris M. Heid) and the University Hospital Regensburg (Dr Carsten A. Böger). Data analysis was funded by the Else 37 Kröner-Fresenius Stiftung (Dr. Iris M. Heid and Dr. Carsten A. Böger: 2012_A147; Dr. Carsten A. Böger and Dr. Bernhard K. Krämer: P48/08//A11/08). GENDIAN Study Group: Mathias Gorski, Iris M. Heid, Bernhard K. Krämer, Myriam Rheinberger, Michael Broll, Alexander Lammert, Jens Brüning, Matthias Olden, Klaus Stark, Claudia Strohmeier, Simone Neumeier, Sarah Hufnagel, Petra Jackermeier, Emilia Ruff, Johanna Christ, Peter Nürnberg, Thomas Haak, Carsten A. Böger. HABC. Health Aging and Body Composition Study. The HABC study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HCS. Hunter Community Study. The University of Newcastle provided $300,000 from its Strategic Initiatives Fund, and $600,000 from the Gladys M Brawn Senior Research Fellowship scheme; Vincent Fairfax Family Foundation, a private philanthropic trust, provided $195,000; The Hunter Medical Research Institute provided media support during the initial recruitment of participants; and Dr Anne Crotty, Prof. Rodney Scott and Associate Prof. Levi provided financial support towards freezing costs for the long-term storage of participant blood samples. The authors would like to thank the men and women participating in the HCS as well as all the staff, investigators and collaborators who have supported or been involved in the project to date. A special thank you should go to Alison Koschel and Debbie Quain who were instrumental in setting up the pilot study and initial phase of the project. HPFS. Health Professionals Follow-Up Study. The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental & Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease”(HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). We thank the staff and participants of the NHS and HPFS for their dedication and commitment. INGI-CARLANTINO. Italian Network on Genetic Isolates – Carlantino. We thank Anna Morgan and Angela D’Eustacchio for technical support. We are grateful to the municipal administrators for their collaboration on the project and for logistic support. We thank all participants to this study. INGI-FVG. Italian Network on Genetic Isolates – Friuli Venezia-Giulia. We thank Anna Morgan and Angela D’Eustacchio for technical support. We are grateful to the municipal administrators for their collaboration on the project and for logistic support. We thank all participants to this study. 38 INGI-VAL BORBERA. Italian Network on Genetic Isolates – Val Borbera. We thank the inhabitants of the Val Borbera who made this study possible, the local administrations and the ASL-Novi Ligure (Al) for support. We also thank Clara Camaschella for data collection supervision and organization of the clinical data collection, Fiammetta Vigano` for technical help and Corrado Masciullo for building the analysis platform. The research was supported by funds from Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy and Ministry of Health, Ricerca Finalizzata 2008 and 2011/2012, CCM 2010, PRIN 2009 and Telethon, Italy to DT. IPM. Mount Sinai BioMe Biobank Program. The Mount Sinai BioMe Biobank Program is supported by The Andrea and Charles Bronfman Philanthropies. KORA-F3 and F4. The genetic epidemiological work was funded by the NIH subcontract from the Children’s Hospital, Boston, US, (H.E.W., I.M.H, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (H.E.W. 01GS0823; WK project A3, number 01GS0834), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else KrönerFresenius-Stiftung (P48/08//A11/08; C.A.B., B.K.K; 2012_A147 to CAB and IMH.). The Genetic Epidemiology at the University of Regensburg received financial contributions from the BMBF (01ER1206 and 01ER1507). The kidney parameter measurements in F3 were funded by the Else Kröner-FreseniusStiftung (C.A.B., B.K.K.) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (W.K.). Genome wide genotyping costs in F3 and F4 were in part funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). De novo genotyping in F3 and F4 were funded by the Else Kröner-Fresenius-Stiftung (C.A.B., B.K.K.). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum München. The LINUX platform for computation were funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center. LIFELINES. The authors wish to acknowledge the services of the Lifelines Cohort Study, the contributing research centers delivering data to Lifelines, and all the study participants. Lifelines group authors: Behrooz Z Alizadeh1 , H Marike Boezen1 , Lude Franke2 , Pim van der Harst3 , Gerjan Navis4 , Marianne Rots5 , Harold Snieder1 , Morris Swertz2 , Bruce HR Wolffenbuttel6 and Cisca Wijmenga2 1. Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands 2. Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands 3. Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands 4. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands 5. Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands 6. Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands MESA. Multi-Ethnic Study of Atherosclerosis. University of Washington (N01-HC-95159),Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University 39 (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC- 95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL- 071205) MICROS. Microisolates in South Tyrol study. We owe a debt of gratitude to all participants. We thank the primary care practitioners R. Stocker, S. Waldner, T. Pizzecco, J. Plangger, U. Marcadent and the personnel of the Hospital of Silandro (Department of Laboratory Medicine) for their participation and collaboration in the research project. In South Tyrol, the study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). NESDA. The Netherlands Study of Depression and Anxiety. The infrastructure for the NESDA study is funded through the Geestkracht programme of the Dutch Scientific Organization (ZON-MW, grant number 10-000-1002) and matching funds from participating universities and mental health care organizations. Genotyping in NESDA was funded by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health. NHS. Nurses' Health Study. The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental & Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease”(HHSN268200782096C). The NHS renal function and albuminuria work was supported by DK66574. Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). We thank the staff and participants of the NHS and HPFS for their dedication and commitment. NSPHS. The Northern Swedish Population Health Study. The NSPHS was supported by grants from the Swedish Natural Sciences Research Council, the European Union through the EUROSPAN project (contract no. LSHG-CT-2006-018947), the Foundation for Strategic Research (SSF) and the Linneaus Centre for Bioinformatics (LCB). We are also grateful for the contribution of samples from the Medical Biobank in Umeå and for the contribution of the district nurse Svea Hennix in the Karesuando study. RS-I. The Rotterdam Study. The GWA study was funded by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Dr Michael 40 Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the GWAS database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are very grateful to the participants and staff from the Rotterdam Study, the participating general practitioners and the pharmacists. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G, for access to their grid resources. Abbas Dehghan is supported by NWO grant (vici, 918-76-619). SAPALDIA. Swiss Study on Air Pollution and Lung Diseases in Adults. The SAPALDIA Team: Study directorate: T Rochat (p), NM Probst Hensch (e/g), N Künzli (e/exp), C Schindler (s), JM Gaspoz (c) Scientific team: JC Barthélémy (c), W Berger (g), R Bettschart (p), A Bircher (a), O Brändli (p), C Brombach (n), M Brutsche (p), L Burdet (p), M Frey (p), U Frey (pd), MW Gerbase (p), D Gold (e/c/p), E de Groot (c), W Karrer (p), R Keller (p), B Martin (pa), D Miedinger (o), U Neu (exp), L Nicod (p), M Pons (p), F Roche (c), T Rothe (p), E Russi (p), P Schmid-Grendelmeyer (a), A Schmidt-Trucksäss (pa), A Turk (p), J Schwartz (e), D. Stolz (p), P Straehl (exp), JM Tschopp (p), A von Eckardstein (cc), E Zemp Stutz (e). Scientific team at coordinating centers: M Adam (e/g), C Autenrieth (pa), PO Bridevaux (p), D Carballo (c), E Corradi (exp), I Curjuric (e), J Dratva (e), A Di Pasquale (s), E Dupuis Lozeron (s), E Fischer (e), M Germond (s), L Grize (s), D Keidel (s), S Kriemler (pa), A Kumar (g), M Imboden (g), N Maire (s), A Mehta (e), H Phuleria (exp), E Schaffner (s), GA Thun (g) A Ineichen (exp), M Ragettli (e), M Ritter (exp), T Schikowski (e), M Tarantino (s), M Tsai (exp) (a) allergology, (c) cardiology, (cc) clinical chemistry, (e) epidemiology, (exp) exposure, (g) genetic and molecular biology, (m) meteorology, (n) nutrition, (o) occupational health, (p) pneumology, (pa) physical activity, (pd) pediatrics, (s) statistics. Funding: The Swiss National Science Foundation (grants no 33CSCO-134276/1, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO- 104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099), the Federal Office for Forest, Environment and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton's Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais and Zurich, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA. The study could not have been done without the help of the study participants, technical and administrative support and the medical teams and field workers at the local study sites. Local fieldworkers : Aarau: S Brun, G Giger, M Sperisen, M Stahel, Basel: C Bürli, C Dahler, N Oertli, I Harreh, F Karrer, G Novicic, N Wyttenbacher, Davos: A Saner, P Senn, R Winzeler, Geneva: F Bonfils, B Blicharz, C Landolt, J Rochat, Lugano: S Boccia, E Gehrig, MT Mandia, G Solari, B Viscardi, Montana: AP Bieri, C Darioly, M Maire, Payerne: F Ding, P Danieli A Vonnez, Wald: D Bodmer, E Hochstrasser, R Kunz, C Meier, J Rakic, U Schafroth, A Walder. Administrative staff: C Gabriel, R Gutknecht. SHIP and SHIP-TREND. The Study of Health in Pomerania. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 41 ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. The SHIP authors are grateful to Mario Stanke for the opportunity to use his Server Cluster for the SNP imputation as well as to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum München) for the genotyping of the SHIP-TREND cohort. TRAILS. TRacking Adolescents' Individual Lives. Trails is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60- 60600-98-018 and 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 457-03-018, GB-MaGW 452-04-314, and GB-MaGW 452-06- 004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013); the Sophia Foundation for Medical Research (projects 301 and 393), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), and the participating universities. We are grateful to all adolescents, their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. WGHS. Women’s Genome Health Study. The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen. YFS. Young Finns Study. The YFS has been financially supported by the Academy of Finland: grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 and 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (T.L). The technical assistance in the statistical analyses by Ville Aalto and Irina Lisinen is acknowledged.

Published
2017
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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 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.

Published
2018

6. Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

Author

van Leeuwen, Elisabeth M, Huffman, Jennifer E, Bis, Joshua C, Isaacs, Aaron, Mulder, Monique, Sabo, Aniko, Smith, Albert V, Demissie, Serkalem, Manichaikul, Ani, Brody, Jennifer A, Feitosa, Mary F, Duan, Qing, Schraut, Katharina E, Navarro, Pau, van Vliet-Ostaptchouk, Jana V, Zhu, Gu, Mbarek, Hamdi, Trompet, Stella, Verweij, Niek, Lyytikäinen, Leo-Pekka, Deelen, Joris, Nolte, Ilja M, van der Laan, Sander W, Davies, Gail, Vermeij-Verdoold, Andrea Jm, van Oosterhout, Andy Alj, Vergeer-Drop, Jeannette M, Arking, Dan E, Trochet, Holly, Medina-Gomez, Carolina, Rivadeneira, Fernando, Uitterlinden, Andre G, Dehghan, Abbas, Franco, Oscar H, Sijbrands, Eric J, Hofman, Albert, White, Charles C, Mychaleckyj, Josyf C, Peloso, Gina M, Swertz, Morris A, Willemsen, Gonneke, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda Wjh, Ford, Ian, Buckley, Brendan M, de Craen, Anton Jm, Starr, John M, Deary, Ian J, Pasterkamp, Gerard, Oldehinkel, Albertine J, Snieder, Harold, Slagboom, P Eline, Nikus, Kjell, Kähönen, Mika, Lehtimäki, Terho, Viikari, Jorma S, Raitakari, Olli T, van der Harst, Pim, Jukema, J Wouter, Hottenga, Jouke-Jan, Boomsma, Dorret I, Whitfield, John B, Montgomery, Grant, Martin, Nicholas G, Polasek, Ozren, Vitart, Veronique, Hayward, Caroline, Kolcic, Ivana, Wright, Alan F, Rudan, Igor, Joshi, Peter K, Wilson, James F, Lange, Leslie A, Wilson, James G, Gudnason, Vilmundur, Harris, Tamar B, Morrison, Alanna C, Borecki, Ingrid B, Rich, Stephen S, Padmanabhan, Sandosh, Psaty, Bruce M, Rotter, Jerome I, Smith, Blair H, Boerwinkle, Eric, Cupples, L Adrienne, and van Duijn, Cornelia

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10(-509)), βadjusted=0.859 mg/dl (P value=9.51×10(-25))), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

Published
2015

7. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author

Justice, Anne E., Winkler, Thomas W., Feitosa, Mary F., Graff, Misa, Fisher, Virginia A., Young, Kristin, Barata, Llilda, Deng, Xuan, Czajkowski, Jacek, Hadley, David, Ngwa, Julius S., Ahluwalia, Tarunveer S., Chu, Audrey Y., Heard-Costa, Nancy L., Lim, Elise, Perez, Jeremiah, Eicher, John D., Kutalik, Zoltán, Xue, Luting, Mahajan, Anubha, Renström, Frida, Wu, Joseph, Qi, Qibin, Ahmad, Shafqat, Alfred, Tamuno, Amin, Najaf, Bielak, Lawrence F., Bonnefond, Amelie, Bragg, Jennifer, Cadby, Gemma, Chittani, Martina, Coggeshall, Scott, Corre, Tanguy, Direk, Nese, Eriksson, Joel, Fischer, Krista, Gorski, Mathias, Neergaard Harder, Marie, Horikoshi, Momoko, Huang, Tao, Huffman, Jennifer E., Jackson, Anne U., Justesen, Johanne Marie, Kanoni, Stavroula, Kinnunen, Leena, Kleber, Marcus E., Komulainen, Pirjo, Kumari, Meena, Lim, Unhee, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Middelberg, Rita P. S., Müller-Nurasyid, Martina, Navarro, Pau, Pérusse, Louis, Pervjakova, Natalia, Sarti, Cinzia, Smith, Albert Vernon, Smith, Jennifer A., Stančáková, Alena, Strawbridge, Rona J., Stringham, Heather M., Sung, Yun Ju, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, van der Laan, Sander W., van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Vedantam, Sailaja L., Verweij, Niek, Vink, Jacqueline M., Vitart, Veronique, Wu, Ying, Yengo, Loic, Zhang, Weihua, Hua Zhao, Jing, Zimmermann, Martina E., Zubair, Niha, Abecasis, Gonçalo R., Adair, Linda S., Afaq, Saima, Afzal, Uzma, Bakker, Stephan J. L., Bartz, Traci M., Beilby, John, Bergman, Richard N., Bergmann, Sven, Biffar, Reiner, Blangero, John, Boerwinkle, Eric, Bonnycastle, Lori L., Bottinger, Erwin, Braga, Daniele, Buckley, Brendan M., Buyske, Steve, Campbell, Harry, Chambers, John C., Collins, Francis S., Curran, Joanne E., de Borst, Gert J., de Craen, Anton J. M., de Geus, Eco J. C., Dedoussis, George, Delgado, Graciela E., den Ruijter, Hester M., Eiriksdottir, Gudny, Eriksson, Anna L., Esko, Tõnu, Faul, Jessica D., Ford, Ian, Forrester, Terrence, Gertow, Karl, Gigante, Bruna, Glorioso, Nicola, Gong, Jian, Grallert, Harald, Grammer, Tanja B., Grarup, Niels, Haitjema, Saskia, Hallmans, Göran, Hamsten, Anders, Hansen, Torben, Harris, Tamara B., Hartman, Catharina A., Hassinen, Maija, Hastie, Nicholas D., Heath, Andrew C., Hernandez, Dena, Hindorff, Lucia, Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Homuth, Georg, Jan Hottenga, Jouke, Huang, Jie, Hung, Joseph, Hutri-Kähönen, Nina, Ingelsson, Erik, James, Alan L., Jansson, John-Olov, Jarvelin, Marjo-Riitta, Jhun, Min A., Jørgensen, Marit E., Juonala, Markus, Kähönen, Mika, Karlsson, Magnus, Koistinen, Heikki A., Kolcic, Ivana, Kolovou, Genovefa, Kooperberg, Charles, Krämer, Bernhard K., Kuusisto, Johanna, Kvaløy, Kirsti, Lakka, Timo A., Langenberg, Claudia, Launer, Lenore J., Leander, Karin, Lee, Nanette R., Lind, Lars, Lindgren, Cecilia M., Linneberg, Allan, Lobbens, Stephane, Loh, Marie, Lorentzon, Mattias, Luben, Robert, Lubke, Gitta, Ludolph-Donislawski, Anja, Lupoli, Sara, Madden, Pamela A. F., Männikkö, Reija, Marques-Vidal, Pedro, Martin, Nicholas G., McKenzie, Colin A., McKnight, Barbara, Mellström, Dan, Menni, Cristina, Montgomery, Grant W., Musk, AW (Bill), Narisu, Narisu, Nauck, Matthias, Nolte, Ilja M., Oldehinkel, Albertine J., Olden, Matthias, Ong, Ken K., Padmanabhan, Sandosh, Peyser, Patricia A., Pisinger, Charlotta, Porteous, David J., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rasmussen-Torvik, Laura J., Rawal, Rajesh, Rice, Treva, Ridker, Paul M., Rose, Lynda M., Bien, Stephanie A., Rudan, Igor, Sanna, Serena, Sarzynski, Mark A., Sattar, Naveed, Savonen, Kai, Schlessinger, David, Scholtens, Salome, Schurmann, Claudia, Scott, Robert A., Sennblad, Bengt, Siemelink, Marten A., Silbernagel, Günther, Slagboom, P Eline, Snieder, Harold, Staessen, Jan A., Stott, David J., Swertz, Morris A., Swift, Amy J., Taylor, Kent D., Tayo, Bamidele O., Thorand, Barbara, Thuillier, Dorothee, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vandenput, Liesbeth, Vohl, Marie-Claude, Völzke, Henry, Vonk, Judith M., Waeber, Gérard, Waldenberger, Melanie, Westendorp, R. G. J., Wild, Sarah, Willemsen, Gonneke, Wolffenbuttel, Bruce H. R., Wong, Andrew, Wright, Alan F., Zhao, Wei, Zillikens, M Carola, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Böger, Carsten A., Boomsma, Dorret I., Bouchard, Claude, Bruinenberg, Marcel, Chasman, Daniel I., Chen, Yii-DerIda, Chines, Peter S., Cooper, Richard S., Cucca, Francesco, Cusi, Daniele, Faire, Ulf de, Ferrucci, Luigi, Franks, Paul W., Froguel, Philippe, Gordon-Larsen, Penny, Grabe, Hans- Jörgen, Gudnason, Vilmundur, Haiman, Christopher A., Hayward, Caroline, Hveem, Kristian, Johnson, Andrew D., Wouter Jukema, J, Kardia, Sharon L. R., Kivimaki, Mika, Kooner, Jaspal S., Kuh, Diana, Laakso, Markku, Lehtimäki, Terho, Marchand, Loic Le, März, Winfried, McCarthy, Mark I., Metspalu, Andres, Morris, Andrew P., Ohlsson, Claes, Palmer, Lyle J., Pasterkamp, Gerard, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Psaty, Bruce M., Qi, Lu, Rauramaa, Rainer, Smith, Blair H., Sørensen, Thorkild I. A., Strauch, Konstantin, Tiemeier, Henning, Tremoli, Elena, van der Harst, Pim, Vestergaard, Henrik, Vollenweider, Peter, Wareham, Nicholas J., Weir, David R., Whitfield, John B., Wilson, James F., Tyrrell, Jessica, Frayling, Timothy M., Barroso, Inês, Boehnke, Michael, Deloukas, Panagiotis, Fox, Caroline S., Hirschhorn, Joel N., Hunter, David J., Spector, Tim D., Strachan, David P., van Duijn, Cornelia M., Heid, Iris M., Mohlke, Karen L., Marchini, Jonathan, Loos, Ruth J. F., Kilpeläinen, Tuomas O., Liu, Ching-Ti, Borecki, Ingrid B., North, Kari E., and Cupples, L Adrienne

Abstract

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Published
2017
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8. No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

Author

Loley, Christina, Alver, Maris, Assimes, Themistocles L., Bjonnes, Andrew, Goel, Anuj, Gustafsson, Stefan, Hernesniemi, Jussi, Hopewell, Jemma C., Kanoni, Stavroula, Kleber, Marcus E., Lau, King Wai, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Nelson, Christopher P., Nikpay, Majid, Qu, Liming, Salfati, Elias, Scholz, Markus, Tukiainen, Taru, Willenborg, Christina, Won, Hong-Hee, Zeng, Lingyao, Zhang, Weihua, Anand, Sonia S., Beutner, Frank, Bottinger, Erwin P., Clarke, Robert, Dedoussis, George, Do, Ron, Esko, Tõnu, Eskola, Markku, Farrall, Martin, Gauguier, Dominique, Giedraitis, Vilmantas, Granger, Christopher B., Hall, Alistair S., Hamsten, Anders, Hazen, Stanley L., Huang, Jie, Kähönen, Mika, Kyriakou, Theodosios, Laaksonen, Reijo, Lind, Lars, Lindgren, Cecilia, Magnusson, Patrik K. E., Marouli, Eirini, Mihailov, Evelin, Morris, Andrew P., Nikus, Kjell, Pedersen, Nancy, Rallidis, Loukianos, Salomaa, Veikko, Shah, Svati H., Stewart, Alexandre F. R., Thompson, John R., Zalloua, Pierre A., Chambers, John C., Collins, Rory, Ingelsson, Erik, Iribarren, Carlos, Karhunen, Pekka J., Kooner, Jaspal S., Lehtimäki, Terho, Loos, Ruth J. F., März, Winfried, McPherson, Ruth, Metspalu, Andres, Reilly, Muredach P., Ripatti, Samuli, Sanghera, Dharambir K., Thiery, Joachim, Watkins, Hugh, Deloukas, Panos, Kathiresan, Sekar, Samani, Nilesh J., Schunkert, Heribert, Erdmann, Jeanette, and König, Inke R.

Abstract

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Published
2016
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9. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Author

Kettunen, Johannes, Demirkan, Ayşe, Würtz, Peter, Draisma, Harmen H.M., Haller, Toomas, Rawal, Rajesh, Vaarhorst, Anika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Pirinen, Matti, Pool, René, Sarin, Antti-Pekka, Soininen, Pasi, Tukiainen, Taru, Wang, Qin, Tiainen, Mika, Tynkkynen, Tuulia, Amin, Najaf, Zeller, Tanja, Beekman, Marian, Deelen, Joris, van Dijk, Ko Willems, Esko, Tõnu, Hottenga, Jouke-Jan, van Leeuwen, Elisabeth M, Lehtimäki, Terho, Mihailov, Evelin, Rose, Richard J., de Craen, Anton J.M., Gieger, Christian, Kähönen, Mika, Perola, Markus, Blankenberg, Stefan, Savolainen, Markku J., Verhoeven, Aswin, Viikari, Jorma, Willemsen, Gonneke, Boomsma, Dorret I., van Duijn, Cornelia M., Eriksson, Johan, Jula, Antti, Järvelin, Marjo-Riitta, Kaprio, Jaakko, Metspalu, Andres, Raitakari, Olli, Salomaa, Veikko, Slagboom, P. Eline, Waldenberger, Melanie, Ripatti, Samuli, and Ala-Korpela, Mika

Abstract

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.

Published
2016
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10. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Author

Lu, Yingchang, Day, Felix R., Gustafsson, Stefan, Buchkovich, Martin L., Na, Jianbo, Bataille, Veronique, Cousminer, Diana L., Dastani, Zari, Drong, Alexander W., Esko, Tõnu, Evans, David M., Falchi, Mario, Feitosa, Mary F., Ferreira, Teresa, Hedman, Åsa K., Haring, Robin, Hysi, Pirro G., Iles, Mark M., Justice, Anne E., Kanoni, Stavroula, Lagou, Vasiliki, Li, Rui, Li, Xin, Locke, Adam, Lu, Chen, Mägi, Reedik, Perry, John R. B., Pers, Tune H., Qi, Qibin, Sanna, Marianna, Schmidt, Ellen M., Scott, William R., Shungin, Dmitry, Teumer, Alexander, Vinkhuyzen, Anna A. E., Walker, Ryan W., Westra, Harm-Jan, Zhang, Mingfeng, Zhang, Weihua, Zhao, Jing Hua, Zhu, Zhihong, Afzal, Uzma, Ahluwalia, Tarunveer Singh, Bakker, Stephan J. L., Bellis, Claire, Bonnefond, Amélie, Borodulin, Katja, Buchman, Aron S., Cederholm, Tommy, Choh, Audrey C., Choi, Hyung Jin, Curran, Joanne E., de Groot, Lisette C. P. G. M., De Jager, Philip L., Dhonukshe-Rutten, Rosalie A. M., Enneman, Anke W., Eury, Elodie, Evans, Daniel S., Forsen, Tom, Friedrich, Nele, Fumeron, Frédéric, Garcia, Melissa E., Gärtner, Simone, Han, Bok-Ghee, Havulinna, Aki S., Hayward, Caroline, Hernandez, Dena, Hillege, Hans, Ittermann, Till, Kent, Jack W., Kolcic, Ivana, Laatikainen, Tiina, Lahti, Jari, Leach, Irene Mateo, Lee, Christine G., Lee, Jong-Young, Liu, Tian, Liu, Youfang, Lobbens, Stéphane, Loh, Marie, Lyytikäinen, Leo-Pekka, Medina-Gomez, Carolina, Michaëlsson, Karl, Nalls, Mike A., Nielson, Carrie M., Oozageer, Laticia, Pascoe, Laura, Paternoster, Lavinia, Polašek, Ozren, Ripatti, Samuli, Sarzynski, Mark A., Shin, Chan Soo, Narančić, Nina Smolej, Spira, Dominik, Srikanth, Priya, Steinhagen-Thiessen, Elisabeth, Sung, Yun Ju, Swart, Karin M. A., Taittonen, Leena, Tanaka, Toshiko, Tikkanen, Emmi, van der Velde, Nathalie, van Schoor, Natasja M., Verweij, Niek, Wright, Alan F., Yu, Lei, Zmuda, Joseph M., Eklund, Niina, Forrester, Terrence, Grarup, Niels, Jackson, Anne U., Kristiansson, Kati, Kuulasmaa, Teemu, Kuusisto, Johanna, Lichtner, Peter, Luan, Jian'an, Mahajan, Anubha, Männistö, Satu, Palmer, Cameron D., Ried, Janina S., Scott, Robert A., Stancáková, Alena, Wagner, Peter J., Demirkan, Ayse, Döring, Angela, Gudnason, Vilmundur, Kiel, Douglas P., Kühnel, Brigitte, Mangino, Massimo, Mcknight, Barbara, Menni, Cristina, O'Connell, Jeffrey R., Oostra, Ben A., Shuldiner, Alan R., Song, Kijoung, Vandenput, Liesbeth, van Duijn, Cornelia M., Vollenweider, Peter, White, Charles C., Boehnke, Michael, Boettcher, Yvonne, Cooper, Richard S., Forouhi, Nita G., Gieger, Christian, Grallert, Harald, Hingorani, Aroon, Jørgensen, Torben, Jousilahti, Pekka, Kivimaki, Mika, Kumari, Meena, Laakso, Markku, Langenberg, Claudia, Linneberg, Allan, Luke, Amy, Mckenzie, Colin A., Palotie, Aarno, Pedersen, Oluf, Peters, Annette, Strauch, Konstantin, Tayo, Bamidele O., Wareham, Nicholas J., Bennett, David A., Bertram, Lars, Blangero, John, Blüher, Matthias, Bouchard, Claude, Campbell, Harry, Cho, Nam H., Cummings, Steven R., Czerwinski, Stefan A., Demuth, Ilja, Eckardt, Rahel, Eriksson, Johan G., Ferrucci, Luigi, Franco, Oscar H., Froguel, Philippe, Gansevoort, Ron T., Hansen, Torben, Harris, Tamara B., Hastie, Nicholas, Heliövaara, Markku, Hofman, Albert, Jordan, Joanne M., Jula, Antti, Kähönen, Mika, Kajantie, Eero, Knekt, Paul B., Koskinen, Seppo, Kovacs, Peter, Lehtimäki, Terho, Lind, Lars, Liu, Yongmei, Orwoll, Eric S., Osmond, Clive, Perola, Markus, Pérusse, Louis, Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Rivadeneira, Fernando, Rudan, Igor, Salomaa, Veikko, Sørensen, Thorkild I. A., Stumvoll, Michael, Tönjes, Anke, Towne, Bradford, Tranah, Gregory J., Tremblay, Angelo, Uitterlinden, André G., van der Harst, Pim, Vartiainen, Erkki, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Völzke, Henry, Walker, Mark, Wallaschofski, Henri, Wild, Sarah, Wilson, James F., Yengo, Loïc, Bishop, D. Timothy, Borecki, Ingrid B., Chambers, John C., Cupples, L. Adrienne, Dehghan, Abbas, Deloukas, Panos, Fatemifar, Ghazaleh, Fox, Caroline, Furey, Terrence S., Franke, Lude, Han, Jiali, Hunter, David J., Karjalainen, Juha, Karpe, Fredrik, Kaplan, Robert C., Kooner, Jaspal S., McCarthy, Mark I., Murabito, Joanne M., Morris, Andrew P., Bishop, Julia A. N., North, Kari E., Ohlsson, Claes, Ong, Ken K., Prokopenko, Inga, Richards, J. Brent, Schadt, Eric E., Spector, Tim D., Widén, Elisabeth, Willer, Cristen J., Yang, Jian, Ingelsson, Erik, Mohlke, Karen L., Hirschhorn, Joel N., Pospisilik, John Andrew, Zillikens, M. Carola, Lindgren, Cecilia, Kilpeläinen, Tuomas Oskari, and Loos, Ruth J. F.

Abstract

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

Published
2016
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11. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Author

Kilpeläinen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F, Hedman, Åsa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltán, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikäinen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Greco M, Fabiola Del, Pasko, Dorota, Renström, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Pérusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Ju Sung, Yun, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Inês, Bellis, Claire, Blangero, John, Buckley, Brendan M., Böhringer, Stefan, I Chen, Yii-Der, de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Göran, Hankinson, Susan E., Havulinna, Aki S, Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jørgensen, Marit E., Jørgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Männistö, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Brent Richards, J, Ridker, Paul M., Sattar, Naveed, Savage, David B., Söderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widén, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sørensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, André G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliövaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kähönen, Mika, Lehtimäki, Terho, Raitakari, Olli T., Mellström, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, März, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gérard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Eline Slagboom, P, Grallert, Harald, Spector, Tim D., Jukema, J.W., Klein, Robert J., Schadt, Erik E, Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., and Loos, Ruth J. F.

Abstract

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Published
2016
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12. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Pattaro, Cristian, Teumer, Alexander, Gorski, Mathias, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthias, Foster, Meredith, Yang, Qiong, Chen, Ming-Huei, Pers, Tune H., Johnson, Andrew D., Ko, Yi-An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F., Isaacs, Aaron, Dehghan, Abbas, d'Adamo, Pio, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B., Nolte, Ilja M., van der Most, Peter J., Wright, Alan F., Shuldiner, Alan R., Morrison, Alanna C., Hofman, Albert, Smith, Albert V., Dreisbach, Albert W., Franke, Andre, Uitterlinden, Andre G., Metspalu, Andres, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I., Ponte, Belen, Oostra, Ben A., Paulweber, Bernhard, Krämer, Bernhard K., Mitchell, Braxton D., Buckley, Brendan M., Peralta, Carmen A., Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N., Shaffer, Christian M., Müller, Christian, Sala, Cinzia, van Duijn, Cornelia M., Saint-Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S., Ruderfer, Douglas, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J., Holliday, Elizabeth G., Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B., Navis, Gerjan J., Curhan, Gary C., Ehret, George B., Homuth, Georg, Coassin, Stefan, Thun, Gian-Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W., Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H-Erich, Campbell, Harry, Schmidt, Helena, Wallaschofski, Henri, Völzke, Henry, Brenner, Hermann, Kroemer, Heyo K., Kramer, Holly, Lin, Honghuang, Leach, I. Mateo, Ford, Ian, Guessous, Idris, Rudan, Igor, Prokopenko, Inga, Borecki, Ingrid, Heid, Iris M., Kolcic, Ivana, Persico, Ivana, Jukema, J. Wouter, Wilson, James F., Felix, Janine F., Divers, Jasmin, Lambert, Jean-Charles, Stafford, Jeanette M., Gaspoz, Jean-Michel, Smith, Jennifer A., Faul, Jessica D., Wang, Jie Jin, Ding, Jingzhong, Hirschhorn, Joel N., Attia, John, Whitfield, John B., Chalmers, John, Viikari, Jorma, Coresh, Josef, Denny, Joshua C., Karjalainen, Juha, Fernandes, Jyotika K., Endlich, Karlhans, Butterbach, Katja, Keene, Keith L., Lohman, Kurt, Portas, Laura, Launer, Lenore J., Lyytikäinen, Leo-Pekka, Yengo, Loic, Franke, Lude, Ferrucci, Luigi, Rose, Lynda M., Kedenko, Lyudmyla, Rao, Madhumathi, Struchalin, Maksim, Kleber, Marcus E., Cavalieri, Margherita, Haun, Margot, Cornelis, Marilyn C., Ciullo, Marina, Pirastu, Mario, de Andrade, Mariza, McEvoy, Mark A., Woodward, Mark, Adam, Martin, Cocca, Massimiliano, Nauck, Matthias, Imboden, Medea, Waldenberger, Melanie, Pruijm, Menno, Metzger, Marie, Stumvoll, Michael, Evans, Michele K., Sale, Michele M., Kähönen, Mika, Boban, Mladen, Bochud, Murielle, Rheinberger, Myriam, Verweij, Niek, Bouatia-Naji, Nabila, Martin, Nicholas G., Hastie, Nick, Probst-Hensch, Nicole, Soranzo, Nicole, Devuyst, Olivier, Raitakari, Olli, Gottesman, Omri, Franco, Oscar H., Polasek, Ozren, Gasparini, Paolo, Munroe, Patricia B., Ridker, Paul M., Mitchell, Paul, Muntner, Paul, Meisinger, Christa, Smit, Johannes H., Abecasis, Goncalo R., Adair, Linda S., Alexander, Myriam, Altshuler, David, Amin, Najaf, Arking, Dan E., Arora, Pankaj, Aulchenko, Yurii, Bakker, Stephan J. L., Bandinelli, Stefania, Barroso, Ines, Beckmann, Jacques S., Beilby, John P., Bergman, Richard N., Bergmann, Sven, Bis, Joshua C., Boehnke, Michael, Bonnycastle, Lori L., Bornstein, Stefan R., Bots, Michiel L., Bragg-Gresham, Jennifer L., Brand, Stefan-Martin, Brand, Eva, Braund, Peter S., Brown, Morris J., Burton, Paul R., Casas, Juan P., Caulfield, Mark J., Chakravarti, Aravinda, Chambers, John C., Chandak, Giriraj R., Chang, Yen-Pei C., Charchar, Fadi J., Chaturvedi, Nish, Shin Cho, Yoon, Clarke, Robert, Collins, Francis S., Collins, Rory, Connell, John M., Cooper, Jackie A., Cooper, Matthew N., Cooper, Richard S., Corsi, Anna Maria, Dörr, Marcus, Dahgam, Santosh, Danesh, John, Smith, George Davey, Day, Ian N. M., Deloukas, Panos, Denniff, Matthew, Dominiczak, Anna F., Dong, Yanbin, Doumatey, Ayo, Elliott, Paul, Elosua, Roberto, Erdmann, Jeanette, Eyheramendy, Susana, Farrall, Martin, Fava, Cristiano, Forrester, Terrence, Fowkes, F. Gerald R., Fox, Ervin R., Frayling, Timothy M., Galan, Pilar, Ganesh, Santhi K., Garcia, Melissa, Gaunt, Tom R., Glazer, Nicole L., Go, Min Jin, Goel, Anuj, Grässler, Jürgen, Grobbee, Diederick E., Groop, Leif, Guarrera, Simonetta, Guo, Xiuqing, Hadley, David, Hamsten, Anders, Han, Bok-Ghee, Hardy, Rebecca, Hartikainen, Anna-Liisa, Heath, Simon, Heckbert, Susan R., Hedblad, Bo, Hercberg, Serge, Hernandez, Dena, Hicks, Andrew A., Hilton, Gina, Hingorani, Aroon D., Bolton, Judith A Hoffman, Hopewell, Jemma C., Howard, Philip, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Ikram, M. Arfan, Islam, Muhammad, Iwai, Naoharu, Jarvelin, Marjo-Riitta, Jackson, Anne U., Jafar, Tazeen H., Janipalli, Charles S., Johnson, Toby, Kathiresan, Sekar, Khaw, Kay-Tee, Kim, Hyung-Lae, Kinra, Sanjay, Kita, Yoshikuni, Kivimaki, Mika, Kooner, Jaspal S., Kumar, M. J. Kranthi, Kuh, Diana, Kulkarni, Smita R., Kumari, Meena, Kuusisto, Johanna, Kuznetsova, Tatiana, Laakso, Markku, Laan, Maris, Laitinen, Jaana, Lakatta, Edward G., Langefeld, Carl D., Larson, Martin G., Lathrop, Mark, Lawlor, Debbie A., Lawrence, Robert W., Lee, Jong-Young, Lee, Nanette R., Levy, Daniel, Li, Yali, Longstreth, Will T., Luan, Jian'an, Lucas, Gavin, Ludwig, Barbara, Mangino, Massimo, Mani, K. Radha, Marmot, Michael G., Mattace-Raso, Francesco U. S., Matullo, Giuseppe, McArdle, Wendy L., McKenzie, Colin A., Meitinger, Thomas, Melander, Olle, Meneton, Pierre, Meschia, James F., Miki, Tetsuro, Milaneschi, Yuri, Mohlke, Karen L., Mooser, Vincent, Morken, Mario A., Morris, Richard W., Mosley, Thomas H., Najjar, Samer, Narisu, Narisu, Newton-Cheh, Christopher, Nguyen, Khanh-Dung Hoang, Nilsson, Peter, Nyberg, Fredrik, O'Donnell, Christopher J., Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ong, RickTwee-Hee, Ongen, Halit, Onland-Moret, N. Charlotte, O'Reilly, Paul F., Org, Elin, Orru, Marco, Palmas, Walter, Palmen, Jutta, Palmer, Lyle J., Palmer, Nicholette D., Parker, Alex N., Peden, John F., Peltonen, Leena, Perola, Markus, Pihur, Vasyl, Platou, Carl G. P., Plump, Andrew, Prabhakaran, Dorairajan, Psaty, Bruce M., Raffel, Leslie J., Rao, Dabeeru C., Rasheed, Asif, Ricceri, Fulvio, Rice, Kenneth M., Rosengren, Annika, Rotter, Jerome I., Rudock, Megan E., Sõber, Siim, Salako, Tunde, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schwartz, Steven M., Schwarz, Peter E. H., Scott, Laura J., Scott, James, Scuteri, Angelo, Sehmi, Joban S., Seielstad, Mark, Seshadri, Sudha, Sharma, Pankaj, Shaw-Hawkins, Sue, Shi, Gang, Shrine, Nick R. G., Sijbrands, Eric J. G., Sim, Xueling, Singleton, Andrew, Sjögren, Marketa, Smith, Nicholas L., Artigas, Maria Soler, Spector, Tim D., Staessen, Jan A., Stancakova, Alena, Steinle, Nanette I., Strachan, David P., Stringham, Heather M., Sun, Yan V., Swift, Amy J., Tabara, Yasuharu, Tai, E-Shyong, Talmud, Philippa J., Taylor, Andrew, Terzic, Janos, Thelle, Dag S., Tobin, Martin D., Tomaszewski, Maciej, Tripathy, Vikal, Tuomilehto, Jaakko, Tzoulaki, Ioanna, Uda, Manuela, Ueshima, Hirotsugu, Uiterwaal, Cuno S. P. M., Umemura, Satoshi, van der Harst, Pim, van der Schouw, Yvonne T., van Gilst, Wiek H., Vartiainen, Erkki, Vasan, Ramachandran S., Veldre, Gudrun, Verwoert, Germaine C., Viigimaa, Margus, Vinay, D. G., Vineis, Paolo, Voight, Benjamin F., Vollenweider, Peter, Wagenknecht, Lynne E., Wain, Louise V., Wang, Xiaoling, Wang, Thomas J., Wareham, Nicholas J., Watkins, Hugh, Weder, Alan B., Whincup, Peter H., Wiggins, Kerri L., Witteman, Jacqueline C. M., Wong, Andrew, Wu, Ying, Yajnik, Chittaranjan S., Yao, Jie, Young, J. H., Zelenika, Diana, Zhai, Guangju, Zhang, Weihua, Zhang, Feng, Zhao, Jing Hua, Zhu, Haidong, Zhu, Xiaofeng, Zitting, Paavo, Zukowska-Szczechowska, Ewa, Okada, Yukinori, Wu, Jer-Yuarn, Gu, Dongfeng, Takeuchi, Fumihiko, Takahashi, Atsushi, Maeda, Shiro, Tsunoda, Tatsuhiko, Chen, Peng, Lim, Su-Chi, Wong, Tien-Yin, Liu, Jianjun, Young, Terri L., Aung, Tin, Teo, Yik-Ying, Kim, Young Jin, Kang, Daehee, Chen, Chien-Hsiun, Tsai, Fuu-Jen, Chang, Li-Ching, Fann, S. -J. Cathy, Mei, Hao, Hixson, James E., Chen, Shufeng, Katsuya, Tomohiro, Isono, Masato, Albrecht, Eva, Yamamoto, Kazuhiko, Kubo, Michiaki, Nakamura, Yusuke, Kamatani, Naoyuki, Kato, Norihiro, He, Jiang, Chen, Yuan-Tsong, Tanaka, Toshihiro, Reilly, Muredach P, Schunkert, Heribert, Assimes, Themistocles L., Hall, Alistair, Hengstenberg, Christian, König, Inke R., Laaksonen, Reijo, McPherson, Ruth, Thompson, John R., Thorsteinsdottir, Unnur, Ziegler, Andreas, Absher, Devin, Chen, Li, Cupples13, L. Adrienne, Halperin, Eran, Li, Mingyao, Musunuru, Kiran, Preuss, Michael, Schillert, Arne, Thorleifsson, Gudmar, Wells, George A., Holm, Hilma, Roberts, Robert, Stewart, Alexandre F. R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlos, Knowles, Joshua, Myers, Richard, Quertermous, Thomas, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francois, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii-Der, Demissie-Banjaw, Serkalem, Folsom, Aaron, Lumley, Thomas, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcus, Grosshennig, Anika, Linsel-Nitschke, Patrick, Stark, Klaus, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andreas, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andreas, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lars, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johannes, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih-Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thomas, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei-Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, de Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, and Fox, Caroline S.

Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Published
2016
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13. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author

Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P, Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B, Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y, Bansal, Nisha, Feitosa, Mary F, Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, Van Der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan J L, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, De Borst, Martin H, De Grandi, Alessandro, De Mutsert, Renée, De Vries, Aiko P J, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent W V, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, Loeffler, Markus, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Maranville, Joseph C, Mascalzoni, Deborah, McMullen, Barbara, Meisinger, Christa, Meitinger, Thomas, Miliku, Kozeta, Mook-Kanamori, Dennis O, Müller-Nurasyid, Martina, Mychaleckyj, Josyf C, Nauck, Matthias, Nikus, Kjell, Ning, Boting, Noordam, Raymond, Connell, Jeffrey O', Olafsson, Isleifur, Palmer, Nicholette D, Peters, Annette, Podgornaia, Anna I, Ponte, Belen, Poulain, Tanja, Pramstaller, Peter P, Rabelink, Ton J, Raffield, Laura M, Reilly, Dermot F, Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M, Rivadeneira, Fernando, Runz, Heiko, Ryan, Kathleen A, Sabanayagam, Charumathi, Saum, Kai-Uwe, Schöttker, Ben, Shaffer, Christian M, Shi, Yuan, Smith, Albert V, Strauch, Konstantin, Stumvoll, Michael, Sun, Benjamin B, Szymczak, Silke, Tai, E-Shyong, Tan, Nicholas Y Q, Taylor, Kent D, Teren, Andrej, Tham, Yih-Chung, Thiery, Joachim, Thio, Chris H L, Thomsen, Hauke, Thorsteinsdottir, Unnur, Tönjes, Anke, Tremblay, Johanne, Uitterlinden, André G, Van Der Harst, Pim, Verweij, Niek, Vogelezang, Suzanne, Völker, Uwe, Waldenberger, Melanie, Wang, Chaolong, Wilson, Otis D, Wong, Charlene, Wong, Tien-Yin, Yang, Qiong, Yasuda, Masayuki, Akilesh, Shreeram, Bochud, Murielle, Böger, Carsten A, Devuyst, Olivier, Edwards, Todd L, Ho, Kevin, Morris, Andrew P, Parsa, Afshin, Pendergrass, Sarah A, Psaty, Bruce M, Rotter, Jerome I, Stefansson, Kari, Wilson, James G, Susztak, Katalin, Snieder, Harold, Heid, Iris M, Scholz, Markus, Butterworth, Adam S, Hung, Adriana M, Pattaro, Cristian, and Köttgen, Anna

Subjects
610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

14. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Franceschini, Nora, Giambartolomei, Claudia, De Vries, Paul S, Finan, Chris, Bis, Joshua C, Huntley, Rachael P, Lovering, Ruth C, Tajuddin, Salman M, Winkler, Thomas W, Graff, Misa, Kavousi, Maryam, Dale, Caroline, Smith, Albert V, Hofer, Edith, Van Leeuwen, Elisabeth M, Nolte, Ilja M, Lu, Lingyi, Scholz, Markus, Sargurupremraj, Muralidharan, Pitkänen, Niina, Franzén, Oscar, Joshi, Peter K, Noordam, Raymond, Marioni, Riccardo E, Hwang, Shih-Jen, Musani, Solomon K, Schminke, Ulf, Palmas, Walter, Isaacs, Aaron, Correa, Adolfo, Zonderman, Alan B, Hofman, Albert, Teumer, Alexander, Cox, Amanda J, Uitterlinden, André G, Wong, Andrew, Smit, Andries J, Newman, Anne B, Britton, Annie, Ruusalepp, Arno, Sennblad, Bengt, Hedblad, Bo, Pasaniuc, Bogdan, Penninx, Brenda W, Langefeld, Carl D, Wassel, Christina L, Tzourio, Christophe, Fava, Cristiano, Baldassarre, Damiano, O'Leary, Daniel H, Teupser, Daniel, Kuh, Diana, Tremoli, Elena, Mannarino, Elmo, Grossi, Enzo, Boerwinkle, Eric, Schadt, Eric E, Ingelsson, Erik, Veglia, Fabrizio, Rivadeneira, Fernando, Beutner, Frank, Chauhan, Ganesh, Heiss, Gerardo, Snieder, Harold, Campbell, Harry, Völzke, Henry, Markus, Hugh S, Deary, Ian J, Jukema, J Wouter, De Graaf, Jacqueline, Price, Jacqueline, Pott, Janne, Hopewell, Jemma C, Liang, Jingjing, Thiery, Joachim, Engmann, Jorgen, Gertow, Karl, Rice, Kenneth, Taylor, Kent D, Dhana, Klodian, Kiemeney, Lambertus A L M, Lind, Lars, Raffield, Laura M, Launer, Lenore J, Holdt, Lesca M, Dörr, Marcus, Dichgans, Martin, Traylor, Matthew, Sitzer, Matthias, Kumari, Meena, Kivimaki, Mika, Nalls, Mike A, Melander, Olle, Raitakari, Olli, Franco, Oscar H, Rueda-Ochoa, Oscar L, Roussos, Panos, Whincup, Peter H, Amouyel, Philippe, Giral, Philippe, Anugu, Pramod, Wong, Quenna, Malik, Rainer, Rauramaa, Rainer, Burkhardt, Ralph, Hardy, Rebecca, Schmidt, Reinhold, De Mutsert, Renée, Morris, Richard W, Strawbridge, Rona J, Wannamethee, S Goya, Hägg, Sara, Shah, Sonia, McLachlan, Stela, Trompet, Stella, Seshadri, Sudha, Kurl, Sudhir, Heckbert, Susan R, Ring, Susan, Harris, Tamara B, Lehtimäki, Terho, Galesloot, Tessel E, Shah, Tina, De Faire, Ulf, Plagnol, Vincent, Rosamond, Wayne D, Post, Wendy, Zhu, Xiaofeng, Zhang, Xiaoling, Guo, Xiuqing, Saba, Yasaman, Dehghan, Abbas, Seldenrijk, Adrie, Morrison, Alanna C, Hamsten, Anders, Psaty, Bruce M, Van Duijn, Cornelia M, Lawlor, Deborah A, Mook-Kanamori, Dennis O, Bowden, Donald W, Schmidt, Helena, Wilson, James F, Wilson, James G, Rotter, Jerome I, Wardlaw, Joanna M, Deanfield, John, Halcox, Julian, Lyytikäinen, Leo-Pekka, Loeffler, Markus, Evans, Michele K, Debette, Stéphanie, Humphries, Steve E, Völker, Uwe, Gudnason, Vilmundur, Hingorani, Aroon D, Björkegren, Johan L M, Casas, Juan P, and O'Donnell, Christopher J

Subjects
cardiovascular system, cardiovascular diseases, 610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

15. Sixteen new lung function signals identified through 1000 genomes project reference panel imputation

Author

Artigas, María Soler, Wain, Louise V., Miller, Suzanne, Kheirallah, Abdul Kader, Huffman, Jennifer E., Ntalla, Ioanna, Shrine, Nick, Obeidat, Ma'en, Trochet, Holly, McArdle, Wendy L., Alves, Alexessander Couto, Hui, Jennie, Zhao, Jing Hua, Joshi, Peter K., Teumer, Alexander, Albrecht, Eva, Imboden, Medea, Rawal, Rajesh, Lopez, Lorna M., Marten, Jonathan, Enroth, Stefan, Surakka, Ida, Polasek, Ozren, Lyytikäinen, Leo-Pekka, Granell, Raquel, Hysi, Pirro G., Flexeder, Claudia, Mahajan, Anubha, Beilby, John, Bossé, Yohan, Brandsma, Corry-Anke, Campbell, Harry, Gieger, Christian, Gläser, Sven, González, Juan R., Grallert, Harald, Hammond, Chris J., Harris, Sarah E., Hartikainen, Anna-Liisa, Heliövaara, Markku, Henderson, John, Hocking, Lynne, Horikoshi, Momoko, Hutri-Kähönen, Nina, Ingelsson, Erik, Johansson, Åsa, Kemp, John P., Kolcic, Ivana, Kumar, Ashish, Lind, Lars, Melén, Erik, Musk, Arthur W., Navarro, Pau, Nickle, David C., Padmanabhan, Sandosh, Raitakari, Olli T., Ried, Janina S., Ripatti, Samuli, Schulz, Holger, Scott, Robert A., Sin, Don D., Starr, John M., BiLeve, U. K., Viñuela, Ana, Völzke, Henry, Wild, Sarah H., Wright, Alan F., Zemunik, Tatijana, Jarvis, Deborah L., Spector, Tim D., Evans, David M., Lehtimäki, Terho, Vitart, Veronique, Kähönen, Mika, Gyllensten, Ulf, Rudan, Igor, Deary, Ian J., Karrasch, Stefan, Probst-Hensch, Nicole M., Heinrich, Joachim, Stubbe, Beate, Wilson, James F., Wareham, Nicholas J., James, Alan L., Morris, Andrew P., Jarvelin, Marjo-Riitta, Hayward, Caroline, Sayers, Ian, Strachan, David P., Hall, Ian P., and Tobin, Martin D.

Subjects
3. Good health

16. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

Published
2018

17. Author Correction: The power of genetic diversity in genome-wide association studies of lipids.

Author

Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW, Locke AE, Marouli E, Hwang MY, Han S, Narita A, Choudhury A, Bentley AR, Ekoru K, Verma A, Trivedi B, Martin HC, Hunt KA, Hui Q, Klarin D, Zhu X, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Ruotsalainen SE, Havulinna AS, Veturi Y, Feng Q, Rosenthal EA, Lingren T, Pacheco JA, Pendergrass SA, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Hindy G, Rasheed A, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Willemsen G, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Yao J, Manichaikul A, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Sidore C, Fiorillo E, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Thuesen BH, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Feitosa MF, Wojczynski MK, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Kember RL, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Leonard HL, Marten J, Schmidt B, Arendt M, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Ahmed M, Jackson AU, Yousri NA, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Chai X, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Hung YJ, Chen S, Liu F, Yang J, Kentistou KA, Gorski M, Brumat M, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Xue C, Zhang J, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, Lee J, van der Laan SW, Chitrala KN, Weiss S, Zimmermann ME, Lee JY, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hildalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Schwander K, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Highland HM, Young KL, Kawaguchi T, Thiery J, Bis JC, Nadkarni GN, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, Bhatti KF, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Chen YE, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Kato N, Schulze MB, Girotto G, Jung B, Böger CA, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Yajnik CS, Mercader JM, Tusié-Luna T, Aguilar-Salinas CA, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Lu F, Qu J, Hishigaki H, Lin X, März W, Parra EJ, Cruz M, Gudnason V, Tardif JC, Lettre G, 't Hart LM, Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Psaty BM, Brandslund I, Pramstaller PP, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Cucca F, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Justice AE, Baras A, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Thorsteinsdottir U, Stefansson K, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, O'Donnell CJ, Gaziano JM, Wilson P, Rotimi CN, Hazelhurst S, Ramsay M, Trembath RC, van Heel DA, Tamiya G, Yamamoto M, Kim BJ, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, Natarajan P, Peloso GM, Brown CD, Morris AP, Assimes TL, Deloukas P, Sun YV, and Willer CJ

Published
2023
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18. Uncovering the complex genetic architecture of human plasma lipidome using machine learning methods.

Author

Lehtimäki M, Mishra BH, Del-Val C, Lyytikäinen LP, Kähönen M, Cloninger CR, Raitakari OT, Laaksonen R, Zwir I, Lehtimäki T, and Mishra PP

Subjects
Humans, Genotype, Phenotype, Unsupervised Machine Learning, Polymorphism, Single Nucleotide, Lipidomics, Machine Learning
Abstract

Genetic architecture of plasma lipidome provides insights into regulation of lipid metabolism and related diseases. We applied an unsupervised machine learning method, PGMRA, to discover phenotype-genotype many-to-many relations between genotype and plasma lipidome (phenotype) in order to identify the genetic architecture of plasma lipidome profiled from 1,426 Finnish individuals aged 30-45 years. PGMRA involves biclustering genotype and lipidome data independently followed by their inter-domain integration based on hypergeometric tests of the number of shared individuals. Pathway enrichment analysis was performed on the SNP sets to identify their associated biological processes. We identified 93 statistically significant (hypergeometric p-value < 0.01) lipidome-genotype relations. Genotype biclusters in these 93 relations contained 5977 SNPs across 3164 genes. Twenty nine of the 93 relations contained genotype biclusters with more than 50% unique SNPs and participants, thus representing most distinct subgroups. We identified 30 significantly enriched biological processes among the SNPs involved in 21 of these 29 most distinct genotype-lipidome subgroups through which the identified genetic variants can influence and regulate plasma lipid related metabolism and profiles. This study identified 29 distinct genotype-lipidome subgroups in the studied Finnish population that may have distinct disease trajectories and therefore could be useful in precision medicine research., (© 2023. The Author(s).)

Published
2023
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19. A saturated map of common genetic variants associated with human height.

Author

Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, Graff M, Eliasen AU, Jiang Y, Raghavan S, Miao J, Arias JD, Graham SE, Mukamel RE, Spracklen CN, Yin X, Chen SH, Ferreira T, Highland HH, Ji Y, Karaderi T, Lin K, Lüll K, Malden DE, Medina-Gomez C, Machado M, Moore A, Rüeger S, Sim X, Vrieze S, Ahluwalia TS, Akiyama M, Allison MA, Alvarez M, Andersen MK, Ani A, Appadurai V, Arbeeva L, Bhaskar S, Bielak LF, Bollepalli S, Bonnycastle LL, Bork-Jensen J, Bradfield JP, Bradford Y, Braund PS, Brody JA, Burgdorf KS, Cade BE, Cai H, Cai Q, Campbell A, Cañadas-Garre M, Catamo E, Chai JF, Chai X, Chang LC, Chang YC, Chen CH, Chesi A, Choi SH, Chung RH, Cocca M, Concas MP, Couture C, Cuellar-Partida G, Danning R, Daw EW, Degenhard F, Delgado GE, Delitala A, Demirkan A, Deng X, Devineni P, Dietl A, Dimitriou M, Dimitrov L, Dorajoo R, Ekici AB, Engmann JE, Fairhurst-Hunter Z, Farmaki AE, Faul JD, Fernandez-Lopez JC, Forer L, Francescatto M, Freitag-Wolf S, Fuchsberger C, Galesloot TE, Gao Y, Gao Z, Geller F, Giannakopoulou O, Giulianini F, Gjesing AP, Goel A, Gordon SD, Gorski M, Grove J, Guo X, Gustafsson S, Haessler J, Hansen TF, Havulinna AS, Haworth SJ, He J, Heard-Costa N, Hebbar P, Hindy G, Ho YA, Hofer E, Holliday E, Horn K, Hornsby WE, Hottenga JJ, Huang H, Huang J, Huerta-Chagoya A, Huffman JE, Hung YJ, Huo S, Hwang MY, Iha H, Ikeda DD, Isono M, Jackson AU, Jäger S, Jansen IE, Johansson I, Jonas JB, Jonsson A, Jørgensen T, Kalafati IP, Kanai M, Kanoni S, Kårhus LL, Kasturiratne A, Katsuya T, Kawaguchi T, Kember RL, Kentistou KA, Kim HN, Kim YJ, Kleber ME, Knol MJ, Kurbasic A, Lauzon M, Le P, Lea R, Lee JY, Leonard HL, Li SA, Li X, Li X, Liang J, Lin H, Lin SY, Liu J, Liu X, Lo KS, Long J, Lores-Motta L, Luan J, Lyssenko V, Lyytikäinen LP, Mahajan A, Mamakou V, Mangino M, Manichaikul A, Marten J, Mattheisen M, Mavarani L, McDaid AF, Meidtner K, Melendez TL, Mercader JM, Milaneschi Y, Miller JE, Millwood IY, Mishra PP, Mitchell RE, Møllehave LT, Morgan A, Mucha S, Munz M, Nakatochi M, Nelson CP, Nethander M, Nho CW, Nielsen AA, Nolte IM, Nongmaithem SS, Noordam R, Ntalla I, Nutile T, Pandit A, Christofidou P, Pärna K, Pauper M, Petersen ERB, Petersen LV, Pitkänen N, Polašek O, Poveda A, Preuss MH, Pyarajan S, Raffield LM, Rakugi H, Ramirez J, Rasheed A, Raven D, Rayner NW, Riveros C, Rohde R, Ruggiero D, Ruotsalainen SE, Ryan KA, Sabater-Lleal M, Saxena R, Scholz M, Sendamarai A, Shen B, Shi J, Shin JH, Sidore C, Sitlani CM, Slieker RC, Smit RAJ, Smith AV, Smith JA, Smyth LJ, Southam L, Steinthorsdottir V, Sun L, Takeuchi F, Tallapragada DSP, Taylor KD, Tayo BO, Tcheandjieu C, Terzikhan N, Tesolin P, Teumer A, Theusch E, Thompson DJ, Thorleifsson G, Timmers PRHJ, Trompet S, Turman C, Vaccargiu S, van der Laan SW, van der Most PJ, van Klinken JB, van Setten J, Verma SS, Verweij N, Veturi Y, Wang CA, Wang C, Wang L, Wang Z, Warren HR, Bin Wei W, Wickremasinghe AR, Wielscher M, Wiggins KL, Winsvold BS, Wong A, Wu Y, Wuttke M, Xia R, Xie T, Yamamoto K, Yang J, Yao J, Young H, Yousri NA, Yu L, Zeng L, Zhang W, Zhang X, Zhao JH, Zhao W, Zhou W, Zimmermann ME, Zoledziewska M, Adair LS, Adams HHH, Aguilar-Salinas CA, Al-Mulla F, Arnett DK, Asselbergs FW, Åsvold BO, Attia J, Banas B, Bandinelli S, Bennett DA, Bergler T, Bharadwaj D, Biino G, Bisgaard H, Boerwinkle E, Böger CA, Bønnelykke K, Boomsma DI, Børglum AD, Borja JB, Bouchard C, Bowden DW, Brandslund I, Brumpton B, Buring JE, Caulfield MJ, Chambers JC, Chandak GR, Chanock SJ, Chaturvedi N, Chen YI, Chen Z, Cheng CY, Christophersen IE, Ciullo M, Cole JW, Collins FS, Cooper RS, Cruz M, Cucca F, Cupples LA, Cutler MJ, Damrauer SM, Dantoft TM, de Borst GJ, de Groot LCPGM, De Jager PL, de Kleijn DPV, Janaka de Silva H, Dedoussis GV, den Hollander AI, Du S, Easton DF, Elders PJM, Eliassen AH, Ellinor PT, Elmståhl S, Erdmann J, Evans MK, Fatkin D, Feenstra B, Feitosa MF, Ferrucci L, Ford I, Fornage M, Franke A, Franks PW, Freedman BI, Gasparini P, Gieger C, Girotto G, Goddard ME, Golightly YM, Gonzalez-Villalpando C, Gordon-Larsen P, Grallert H, Grant SFA, Grarup N, Griffiths L, Gudnason V, Haiman C, Hakonarson H, Hansen T, Hartman CA, Hattersley AT, Hayward C, Heckbert SR, Heng CK, Hengstenberg C, Hewitt AW, Hishigaki H, Hoyng CB, Huang PL, Huang W, Hunt SC, Hveem K, Hyppönen E, Iacono WG, Ichihara S, Ikram MA, Isasi CR, Jackson RD, Jarvelin MR, Jin ZB, Jöckel KH, Joshi PK, Jousilahti P, Jukema JW, Kähönen M, Kamatani Y, Kang KD, Kaprio J, Kardia SLR, Karpe F, Kato N, Kee F, Kessler T, Khera AV, Khor CC, Kiemeney LALM, Kim BJ, Kim EK, Kim HL, Kirchhof P, Kivimaki M, Koh WP, Koistinen HA, Kolovou GD, Kooner JS, Kooperberg C, Köttgen A, Kovacs P, Kraaijeveld A, Kraft P, Krauss RM, Kumari M, Kutalik Z, Laakso M, Lange LA, Langenberg C, Launer LJ, Le Marchand L, Lee H, Lee NR, Lehtimäki T, Li H, Li L, Lieb W, Lin X, Lind L, Linneberg A, Liu CT, Liu J, Loeffler M, London B, Lubitz SA, Lye SJ, Mackey DA, Mägi R, Magnusson PKE, Marcus GM, Vidal PM, Martin NG, März W, Matsuda F, McGarrah RW, McGue M, McKnight AJ, Medland SE, Mellström D, Metspalu A, Mitchell BD, Mitchell P, Mook-Kanamori DO, Morris AD, Mucci LA, Munroe PB, Nalls MA, Nazarian S, Nelson AE, Neville MJ, Newton-Cheh C, Nielsen CS, Nöthen MM, Ohlsson C, Oldehinkel AJ, Orozco L, Pahkala K, Pajukanta P, Palmer CNA, Parra EJ, Pattaro C, Pedersen O, Pennell CE, Penninx BWJH, Perusse L, Peters A, Peyser PA, Porteous DJ, Posthuma D, Power C, Pramstaller PP, Province MA, Qi Q, Qu J, Rader DJ, Raitakari OT, Ralhan S, Rallidis LS, Rao DC, Redline S, Reilly DF, Reiner AP, Rhee SY, Ridker PM, Rienstra M, Ripatti S, Ritchie MD, Roden DM, Rosendaal FR, Rotter JI, Rudan I, Rutters F, Sabanayagam C, Saleheen D, Salomaa V, Samani NJ, Sanghera DK, Sattar N, Schmidt B, Schmidt H, Schmidt R, Schulze MB, Schunkert H, Scott LJ, Scott RJ, Sever P, Shiroma EJ, Shoemaker MB, Shu XO, Simonsick EM, Sims M, Singh JR, Singleton AB, Sinner MF, Smith JG, Snieder H, Spector TD, Stampfer MJ, Stark KJ, Strachan DP, 't Hart LM, Tabara Y, Tang H, Tardif JC, Thanaraj TA, Timpson NJ, Tönjes A, Tremblay A, Tuomi T, Tuomilehto J, Tusié-Luna MT, Uitterlinden AG, van Dam RM, van der Harst P, Van der Velde N, van Duijn CM, van Schoor NM, Vitart V, Völker U, Vollenweider P, Völzke H, Wacher-Rodarte NH, Walker M, Wang YX, Wareham NJ, Watanabe RM, Watkins H, Weir DR, Werge TM, Widen E, Wilkens LR, Willemsen G, Willett WC, Wilson JF, Wong TY, Woo JT, Wright AF, Wu JY, Xu H, Yajnik CS, Yokota M, Yuan JM, Zeggini E, Zemel BS, Zheng W, Zhu X, Zmuda JM, Zonderman AB, Zwart JA, Chasman DI, Cho YS, Heid IM, McCarthy MI, Ng MCY, O'Donnell CJ, Rivadeneira F, Thorsteinsdottir U, Sun YV, Tai ES, Boehnke M, Deloukas P, Justice AE, Lindgren CM, Loos RJF, Mohlke KL, North KE, Stefansson K, Walters RG, Winkler TW, Young KL, Loh PR, Yang J, Esko T, Assimes TL, Auton A, Abecasis GR, Willer CJ, Locke AE, Berndt SI, Lettre G, Frayling TM, Okada Y, Wood AR, Visscher PM, and Hirschhorn JN

Subjects
Humans, Gene Frequency genetics, Genome, Human genetics, Genome-Wide Association Study, Haplotypes genetics, Linkage Disequilibrium genetics, Europe ethnology, Sample Size, Phenotype, Body Height genetics, Polymorphism, Single Nucleotide genetics, Chromosome Mapping
Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries., (© 2022. The Author(s).)

Published
2022
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20. The power of genetic diversity in genome-wide association studies of lipids.

Author

Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW, Locke AE, Marouli E, Hwang MY, Han S, Narita A, Choudhury A, Bentley AR, Ekoru K, Verma A, Trivedi B, Martin HC, Hunt KA, Hui Q, Klarin D, Zhu X, Thorleifsson G, Helgadottir A, Gudbjartsson DF, Holm H, Olafsson I, Akiyama M, Sakaue S, Terao C, Kanai M, Zhou W, Brumpton BM, Rasheed H, Ruotsalainen SE, Havulinna AS, Veturi Y, Feng Q, Rosenthal EA, Lingren T, Pacheco JA, Pendergrass SA, Haessler J, Giulianini F, Bradford Y, Miller JE, Campbell A, Lin K, Millwood IY, Hindy G, Rasheed A, Faul JD, Zhao W, Weir DR, Turman C, Huang H, Graff M, Mahajan A, Brown MR, Zhang W, Yu K, Schmidt EM, Pandit A, Gustafsson S, Yin X, Luan J, Zhao JH, Matsuda F, Jang HM, Yoon K, Medina-Gomez C, Pitsillides A, Hottenga JJ, Willemsen G, Wood AR, Ji Y, Gao Z, Haworth S, Mitchell RE, Chai JF, Aadahl M, Yao J, Manichaikul A, Warren HR, Ramirez J, Bork-Jensen J, Kårhus LL, Goel A, Sabater-Lleal M, Noordam R, Sidore C, Fiorillo E, McDaid AF, Marques-Vidal P, Wielscher M, Trompet S, Sattar N, Møllehave LT, Thuesen BH, Munz M, Zeng L, Huang J, Yang B, Poveda A, Kurbasic A, Lamina C, Forer L, Scholz M, Galesloot TE, Bradfield JP, Daw EW, Zmuda JM, Mitchell JS, Fuchsberger C, Christensen H, Brody JA, Feitosa MF, Wojczynski MK, Preuss M, Mangino M, Christofidou P, Verweij N, Benjamins JW, Engmann J, Kember RL, Slieker RC, Lo KS, Zilhao NR, Le P, Kleber ME, Delgado GE, Huo S, Ikeda DD, Iha H, Yang J, Liu J, Leonard HL, Marten J, Schmidt B, Arendt M, Smyth LJ, Cañadas-Garre M, Wang C, Nakatochi M, Wong A, Hutri-Kähönen N, Sim X, Xia R, Huerta-Chagoya A, Fernandez-Lopez JC, Lyssenko V, Ahmed M, Jackson AU, Yousri NA, Irvin MR, Oldmeadow C, Kim HN, Ryu S, Timmers PRHJ, Arbeeva L, Dorajoo R, Lange LA, Chai X, Prasad G, Lorés-Motta L, Pauper M, Long J, Li X, Theusch E, Takeuchi F, Spracklen CN, Loukola A, Bollepalli S, Warner SC, Wang YX, Wei WB, Nutile T, Ruggiero D, Sung YJ, Hung YJ, Chen S, Liu F, Yang J, Kentistou KA, Gorski M, Brumat M, Meidtner K, Bielak LF, Smith JA, Hebbar P, Farmaki AE, Hofer E, Lin M, Xue C, Zhang J, Concas MP, Vaccargiu S, van der Most PJ, Pitkänen N, Cade BE, Lee J, van der Laan SW, Chitrala KN, Weiss S, Zimmermann ME, Lee JY, Choi HS, Nethander M, Freitag-Wolf S, Southam L, Rayner NW, Wang CA, Lin SY, Wang JS, Couture C, Lyytikäinen LP, Nikus K, Cuellar-Partida G, Vestergaard H, Hildalgo B, Giannakopoulou O, Cai Q, Obura MO, van Setten J, Li X, Schwander K, Terzikhan N, Shin JH, Jackson RD, Reiner AP, Martin LW, Chen Z, Li L, Highland HM, Young KL, Kawaguchi T, Thiery J, Bis JC, Nadkarni GN, Launer LJ, Li H, Nalls MA, Raitakari OT, Ichihara S, Wild SH, Nelson CP, Campbell H, Jäger S, Nabika T, Al-Mulla F, Niinikoski H, Braund PS, Kolcic I, Kovacs P, Giardoglou T, Katsuya T, Bhatti KF, de Kleijn D, de Borst GJ, Kim EK, Adams HHH, Ikram MA, Zhu X, Asselbergs FW, Kraaijeveld AO, Beulens JWJ, Shu XO, Rallidis LS, Pedersen O, Hansen T, Mitchell P, Hewitt AW, Kähönen M, Pérusse L, Bouchard C, Tönjes A, Chen YI, Pennell CE, Mori TA, Lieb W, Franke A, Ohlsson C, Mellström D, Cho YS, Lee H, Yuan JM, Koh WP, Rhee SY, Woo JT, Heid IM, Stark KJ, Völzke H, Homuth G, Evans MK, Zonderman AB, Polasek O, Pasterkamp G, Hoefer IE, Redline S, Pahkala K, Oldehinkel AJ, Snieder H, Biino G, Schmidt R, Schmidt H, Chen YE, Bandinelli S, Dedoussis G, Thanaraj TA, Kardia SLR, Kato N, Schulze MB, Girotto G, Jung B, Böger CA, Joshi PK, Bennett DA, De Jager PL, Lu X, Mamakou V, Brown M, Caulfield MJ, Munroe PB, Guo X, Ciullo M, Jonas JB, Samani NJ, Kaprio J, Pajukanta P, Adair LS, Bechayda SA, de Silva HJ, Wickremasinghe AR, Krauss RM, Wu JY, Zheng W, den Hollander AI, Bharadwaj D, Correa A, Wilson JG, Lind L, Heng CK, Nelson AE, Golightly YM, Wilson JF, Penninx B, Kim HL, Attia J, Scott RJ, Rao DC, Arnett DK, Hunt SC, Walker M, Koistinen HA, Chandak GR, Yajnik CS, Mercader JM, Tusié-Luna T, Aguilar-Salinas CA, Villalpando CG, Orozco L, Fornage M, Tai ES, van Dam RM, Lehtimäki T, Chaturvedi N, Yokota M, Liu J, Reilly DF, McKnight AJ, Kee F, Jöckel KH, McCarthy MI, Palmer CNA, Vitart V, Hayward C, Simonsick E, van Duijn CM, Lu F, Qu J, Hishigaki H, Lin X, März W, Parra EJ, Cruz M, Gudnason V, Tardif JC, Lettre G, 't Hart LM, Elders PJM, Damrauer SM, Kumari M, Kivimaki M, van der Harst P, Spector TD, Loos RJF, Province MA, Psaty BM, Brandslund I, Pramstaller PP, Christensen K, Ripatti S, Widén E, Hakonarson H, Grant SFA, Kiemeney LALM, de Graaf J, Loeffler M, Kronenberg F, Gu D, Erdmann J, Schunkert H, Franks PW, Linneberg A, Jukema JW, Khera AV, Männikkö M, Jarvelin MR, Kutalik Z, Cucca F, Mook-Kanamori DO, van Dijk KW, Watkins H, Strachan DP, Grarup N, Sever P, Poulter N, Rotter JI, Dantoft TM, Karpe F, Neville MJ, Timpson NJ, Cheng CY, Wong TY, Khor CC, Sabanayagam C, Peters A, Gieger C, Hattersley AT, Pedersen NL, Magnusson PKE, Boomsma DI, de Geus EJC, Cupples LA, van Meurs JBJ, Ghanbari M, Gordon-Larsen P, Huang W, Kim YJ, Tabara Y, Wareham NJ, Langenberg C, Zeggini E, Kuusisto J, Laakso M, Ingelsson E, Abecasis G, Chambers JC, Kooner JS, de Vries PS, Morrison AC, North KE, Daviglus M, Kraft P, Martin NG, Whitfield JB, Abbas S, Saleheen D, Walters RG, Holmes MV, Black C, Smith BH, Justice AE, Baras A, Buring JE, Ridker PM, Chasman DI, Kooperberg C, Wei WQ, Jarvik GP, Namjou B, Hayes MG, Ritchie MD, Jousilahti P, Salomaa V, Hveem K, Åsvold BO, Kubo M, Kamatani Y, Okada Y, Murakami Y, Thorsteinsdottir U, Stefansson K, Ho YL, Lynch JA, Rader DJ, Tsao PS, Chang KM, Cho K, O'Donnell CJ, Gaziano JM, Wilson P, Rotimi CN, Hazelhurst S, Ramsay M, Trembath RC, van Heel DA, Tamiya G, Yamamoto M, Kim BJ, Mohlke KL, Frayling TM, Hirschhorn JN, Kathiresan S, Boehnke M, Natarajan P, Peloso GM, Brown CD, Morris AP, Assimes TL, Deloukas P, Sun YV, and Willer CJ

Subjects
Genetic Predisposition to Disease genetics, Humans, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide genetics, Population Groups, Cardiovascular Diseases genetics, Genome-Wide Association Study methods
Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use 1 . Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels 2 , heart disease remains the leading cause of death worldwide 3 . Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS 4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns 24 . Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine 25 , we anticipate that increased diversity of participants will lead to more accurate and equitable 26 application of polygenic scores in clinical practice., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2021
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21. Adulthood blood levels of hsa-miR-29b-3p associate with preterm birth and adult metabolic and cognitive health.

Author

Marttila S, Rovio S, Mishra PP, Seppälä I, Lyytikäinen LP, Juonala M, Waldenberger M, Oksala N, Ala-Korpela M, Harville E, Hutri-Kähönen N, Kähönen M, Raitakari O, Lehtimäki T, and Raitoharju E

Subjects
Adolescent, Adult, Child, Child, Preschool, Cognitive Dysfunction blood, Cognitive Dysfunction genetics, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 genetics, Female, Finland epidemiology, Follow-Up Studies, Gene Expression Profiling, Humans, Infant, Newborn, Male, Metabolic Diseases blood, Metabolic Diseases genetics, Middle Aged, Pregnancy, Prognosis, Signal Transduction, Biomarkers blood, Cognitive Dysfunction epidemiology, Diabetes Mellitus, Type 2 epidemiology, Metabolic Diseases epidemiology, MicroRNAs genetics, Premature Birth physiopathology
Abstract

Preterm birth (PTB) is associated with increased risk of type 2 diabetes and neurocognitive impairment later in life. We analyzed for the first time the associations of PTB with blood miRNA levels in adulthood. We also investigated the relationship of PTB associated miRNAs and adulthood phenotypes previously linked with premature birth. Blood MicroRNA profiling, genome-wide gene expression analysis, computer-based cognitive testing battery (CANTAB) and serum NMR metabolomics were performed for Young Finns Study subjects (aged 34-49 years, full-term n = 682, preterm n = 84). Preterm birth (vs. full-term) was associated with adulthood levels of hsa-miR-29b-3p in a fully adjusted regression model (p = 1.90 × 10 -4 , FDR = 0.046). The levels of hsa-miR-29b-3p were down-regulated in subjects with PTB with appropriate birthweight for gestational age (p = 0.002, fold change [FC] = - 1.20) and specifically in PTB subjects with small birthweight for gestational age (p = 0.095, FC = - 1.39) in comparison to individuals born full term. Hsa-miR-29b-3p levels correlated with the expressions of its target-mRNAs BCL11A and CS and the gene set analysis results indicated a target-mRNA driven association between hsa-miR-29b-3p levels and Alzheimer's disease, Parkinson's disease, Insulin signaling and Regulation of Actin Cytoskeleton pathway expression. The level of hsa-miR-29b-3p was directly associated with visual processing and sustained attention in CANTAB test and inversely associated with serum levels of VLDL subclass component and triglyceride levels. In conlcusion, adult blood levels of hsa-miR-29b-3p were lower in subjects born preterm. Hsa-miR-29b-3p associated with cognitive function and may be linked with adulthood morbidities in subjects born preterm, possibly through regulation of gene sets related to neurodegenerative diseases and insulin signaling as well as VLDL and triglyceride metabolism.

Published
2021
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22. Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts.

Author

Laaksonen J, Mishra PP, Seppälä I, Lyytikäinen LP, Raitoharju E, Mononen N, Lepistö M, Almusa H, Ellonen P, Hutri-Kähönen N, Juonala M, Raitakari O, Kähönen M, Salonen JT, and Lehtimäki T

Subjects
Adult, Blood Pressure, Cohort Studies, DNA, Mitochondrial analysis, Female, Finland epidemiology, Genome-Wide Association Study, Genotype, Humans, Hypertension genetics, Male, Middle Aged, Phenotype, Risk Factors, DNA, Mitochondrial genetics, Genome, Mitochondrial, Hypertension epidemiology, Mitochondria genetics, Polymorphism, Single Nucleotide
Abstract

High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

Published
2021
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23. Whole blood microRNA levels associate with glycemic status and correlate with target mRNAs in pathways important to type 2 diabetes.

Author

Mononen N, Lyytikäinen LP, Seppälä I, Mishra PP, Juonala M, Waldenberger M, Klopp N, Illig T, Leiviskä J, Loo BM, Laaksonen R, Oksala N, Kähönen M, Hutri-Kähönen N, Raitakari O, Lehtimäki T, and Raitoharju E

Subjects
Humans, Blood Glucose metabolism, Diabetes Mellitus, Type 2 blood, MicroRNAs blood, RNA, Messenger blood
Abstract

We analyzed the associations between whole blood microRNA profiles and the indices of glucose metabolism and impaired fasting glucose and examined whether the discovered microRNAs correlate with the expression of their mRNA targets. MicroRNA and gene expression profiling were performed for the Young Finns Study participants (n = 871). Glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured, the insulin resistance index (HOMA2-IR) was calculated, and the glycemic status (normoglycemic [n = 534]/impaired fasting glucose [IFG] [n = 252]/type 2 diabetes [T2D] [n = 24]) determined. Levels of hsa-miR-144-5p, -122-5p, -148a-3p, -589-5p, and hsa-let-7a-5p associated with glycemic status. hsa-miR-144-5p and -148a-3p associated with glucose levels, while hsa-miR-144-5p, -122-5p, -184, and -339-3p associated with insulin levels and HOMA2-IR, and hsa-miR-148a-3p, -15b-3p, -93-3p, -146b-5p, -221-3p, -18a-3p, -642a-5p, and -181-2-3p associated with HbA1c levels. The targets of hsa-miR-146b-5p that correlated with its levels were enriched in inflammatory pathways, and the targets of hsa-miR-221-3p were enriched in insulin signaling and T2D pathways. These pathways showed indications of co-regulation by HbA1c-associated miRNAs. There were significant differences in the microRNA profiles associated with glucose, insulin, or HOMA-IR compared to those associated with HbA1c. The HbA1c-associated miRNAs also correlated with the expression of target mRNAs in pathways important to the development of T2D.

Published
2019
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24. Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

Author

van Setten J, Verweij N, Mbarek H, Niemeijer MN, Trompet S, Arking DE, Brody JA, Gandin I, Grarup N, Hall LM, Hemerich D, Lyytikäinen LP, Mei H, Müller-Nurasyid M, Prins BP, Robino A, Smith AV, Warren HR, Asselbergs FW, Boomsma DI, Caulfield MJ, Eijgelsheim M, Ford I, Hansen T, Harris TB, Heckbert SR, Hottenga JJ, Iorio A, Kors JA, Linneberg A, MacFarlane PW, Meitinger T, Nelson CP, Raitakari OT, Silva Aldana CT, Sinagra G, Sinner M, Soliman EZ, Stoll M, Uitterlinden A, van Duijn CM, Waldenberger M, Alonso A, Gasparini P, Gudnason V, Jamshidi Y, Kääb S, Kanters JK, Lehtimäki T, Munroe PB, Peters A, Samani NJ, Sotoodehnia N, Ulivi S, Wilson JG, de Geus EJC, Jukema JW, Stricker B, van der Harst P, de Bakker PIW, and Isaacs A

Subjects
Female, Humans, Male, Genome-Wide Association Study, Netherlands, Electrocardiography, Genetic Loci, Polymorphism, Single Nucleotide
Abstract

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

Published
2019
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25. Pro-opiomelanocortin and its Processing Enzymes Associate with Plaque Stability in Human Atherosclerosis - Tampere Vascular Study.

Author

Rinne P, Lyytikäinen LP, Raitoharju E, Kadiri JJ, Kholova I, Kähönen M, Lehtimäki T, and Oksala N

Subjects
Animals, Atherosclerosis genetics, Biological Transport, Case-Control Studies, Cholesterol metabolism, Disease Models, Animal, Fluorescent Antibody Technique, Gene Expression, Gene Expression Profiling, Humans, Immunohistochemistry, Mice, Mice, Knockout, Plaque, Atherosclerotic genetics, Plaque, Atherosclerotic pathology, Proteolysis, alpha-MSH metabolism, Atherosclerosis metabolism, Atherosclerosis pathology, Plaque, Atherosclerotic metabolism, Pro-Opiomelanocortin metabolism
Abstract

α-melanocyte-stimulating hormone (α-MSH) is processed from pro-opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. α-MSH also promotes macrophage reverse cholesterol transport by inducing ATP-binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and α-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. α-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating α-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque α-MSH levels. Second, immunohistochemical analyses revealed the presence of α-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of α-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, α-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of α-MSH might protect against atherosclerosis.

Published
2018
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26. Fatty liver is associated with blood pathways of inflammatory response, immune system activation and prothrombotic state in Young Finns Study.

Author

Taipale T, Seppälä I, Raitoharju E, Mononen N, Lyytikäinen LP, Illig T, Waldenberger M, Juonala M, Hutri-Kähönen N, Oksala N, Kähönen M, Raitakari O, and Lehtimäki T

Subjects
Adult, Biomarkers blood, Biomarkers metabolism, CD40 Antigens genetics, CD40 Antigens metabolism, CD40 Ligand genetics, CD40 Ligand metabolism, Case-Control Studies, Extracellular Matrix metabolism, Fatty Liver genetics, Fatty Liver pathology, Female, Finland, Gene Expression Regulation, Humans, Integrin alpha4beta1 genetics, Integrin alpha4beta1 metabolism, Leukocytes cytology, Leukocytes physiology, Liver diagnostic imaging, Liver metabolism, Male, Middle Aged, Netrin-1 genetics, Netrin-1 metabolism, Risk Factors, Fatty Liver blood, Immune System metabolism, Signal Transduction genetics
Abstract

Fatty liver (FL) disease is the most common type of chronic liver disease. We hypothesized that liver's response to the process where large droplets of triglyceride fat accumulate in liver cells is reflected also in gene pathway expression in blood. Peripheral blood genome wide gene expression analysis and ultrasonic imaging of liver were performed for 1,650 participants (316 individuals with FL and 1,334 controls) of the Young Finns Study. Gene set enrichment analysis (GSEA) was performed for the expression data. Fourteen gene sets were upregulated (false discovery rate, FDR < 0.05) in subjects with FL. These pathways related to extracellular matrix (ECM) turnover, immune response regulation, prothrombotic state and neural tissues. After adjustment for known risk factors and biomarkers of FL, we found i) integrin A4B1 signaling, ii) leukocyte transendothelial migration, iii) CD40/CD40L and iv) netrin-1 signaling pathways to be upregulated in individuals with FL (nominal p < 0.05). From these all but not ii) remained significantly upregulated when analyzing only subjects without history of heavy alcohol use. In conclusion, FL was associated with blood gene sets of ECM turnover, inflammatory response, immune system activation and prothrombotic state. These may form a systemic link between FL and the development of cardiovascular diseases.

Published
2018
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27. Differentially expressed genes and canonical pathways in the ascending thoracic aortic aneurysm - The Tampere Vascular Study.

Author

Sulkava M, Raitoharju E, Mennander A, Levula M, Seppälä I, Lyytikäinen LP, Järvinen O, Illig T, Klopp N, Mononen N, Laaksonen R, Kähönen M, Oksala N, and Lehtimäki T

Subjects
Aged, Aorta, Thoracic metabolism, Aorta, Thoracic pathology, Aortic Aneurysm, Thoracic metabolism, Aortic Aneurysm, Thoracic pathology, Female, Gene Ontology, Humans, Male, Middle Aged, Aortic Aneurysm, Thoracic genetics, Signal Transduction, Transcriptome
Abstract

Ascending thoracic aortic aneurysm (ATAA) is a multifactorial disease with a strong inflammatory component. Surgery is often required to prevent aortic rupture and dissection. We performed gene expression analysis (Illumina HumanHT-12 version 3 Expression BeadChip) for 32 samples from ATAA (26 without/6 with dissection), and 28 left internal thoracic arteries (controls) collected in Tampere Vascular study. We compared expression profiles and conducted pathway analysis using Ingenuity Pathway Analysis (IPA) to reveal differences between ATAA and a healthy artery wall. Almost 5000 genes were differentially expressed in ATAA samples compared to controls. The most downregulated gene was homeobox (HOX) A5 (fold change, FC = -25.3) and upregulated cadherin-2 (FC = 12.6). Several other HOX genes were also found downregulated (FCs between -25.3 and -1.5, FDR < 0.05). 43, mostly inflammatory, canonical pathways in ATAA were found to be significantly (p < 0.05, FDR < 0.05) differentially expressed. The results remained essentially the same when the 6 dissected ATAA samples were excluded from the analysis. We show for the first time on genome level that ATAA is an inflammatory process, revealing a more detailed molecular pathway level pathogenesis. We propose HOX genes as potentially important players in maintaining aortic integrity, altered expression of which might be important in the pathobiology of ATAA.

Published
2017
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28. Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.

Author

Weng LC, Lunetta KL, Müller-Nurasyid M, Smith AV, Thériault S, Weeke PE, Barnard J, Bis JC, Lyytikäinen LP, Kleber ME, Martinsson A, Lin HJ, Rienstra M, Trompet S, Krijthe BP, Dörr M, Klarin D, Chasman DI, Sinner MF, Waldenberger M, Launer LJ, Harris TB, Soliman EZ, Alonso A, Paré G, Teixeira PL, Denny JC, Shoemaker MB, Van Wagoner DR, Smith JD, Psaty BM, Sotoodehnia N, Taylor KD, Kähönen M, Nikus K, Delgado GE, Melander O, Engström G, Yao J, Guo X, Christophersen IE, Ellinor PT, Geelhoed B, Verweij N, Macfarlane P, Ford I, Heeringa J, Franco OH, Uitterlinden AG, Völker U, Teumer A, Rose LM, Kääb S, Gudnason V, Arking DE, Conen D, Roden DM, Chung MK, Heckbert SR, Benjamin EJ, Lehtimäki T, März W, Smith JG, Rotter JI, van der Harst P, Jukema JW, Stricker BH, Felix SB, Albert CM, and Lubitz SA

Subjects
Age Factors, Aged, Chromosomes, Human, Pair 4 genetics, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide genetics, Reproducibility of Results, Risk Factors, Atrial Fibrillation genetics, Body Mass Index, Epistasis, Genetic, Genetic Predisposition to Disease, Hypertension genetics, Sex Characteristics
Abstract

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10 -5 ). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10 -8 ). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

Published
2017
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29. Corrigendum: 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

Author

Gorski M, Most PJV, Teumer A, Chu AY, Li M, Mijatovic V, Nolte IM, Cocca M, Taliun D, Gomez F, Li Y, Tayo B, Tin A, Feitosa MF, Aspelund T, Attia J, Biffar R, Bochud M, Boerwinkle E, Borecki I, Bottinger EP, Chen MH, Chouraki V, Ciullo M, Coresh J, Cornelis MC, Curhan GC, Adamo AP, Dehghan A, Dengler L, Ding J, Eiriksdottir G, Endlich K, Enroth S, Esko T, Franco OH, Gasparini P, Gieger C, Girotto G, Gottesman O, Gudnason V, Gyllensten U, Hancock SJ, Harris TB, Helmer C, Höllerer S, Hofer E, Hofman A, Holliday EG, Homuth G, Hu FB, Huth C, Hutri-Kähönen N, Hwang SJ, Imboden M, Johansson Å, Kähönen M, König W, Kramer H, Krämer BK, Kumar A, Kutalik Z, Lambert JC, Launer LJ, Lehtimäki T, de Borst MH, Navis G, Swertz M, Liu Y, Lohman K, Loos RJF, Lu Y, Lyytikäinen LP, McEvoy MA, Meisinger C, Meitinger T, Metspalu A, Metzger M, Mihailov E, Mitchell P, Nauck M, Oldehinkel AJ, Olden M, Wjh Penninx B, Pistis G, Pramstaller PP, Probst-Hensch N, Raitakari OT, Rettig R, Ridker PM, Rivadeneira F, Robino A, Rosas SE, Ruderfer D, Ruggiero D, Saba Y, Sala C, Schmidt H, Schmidt R, Scott RJ, Sedaghat S, Smith AV, Sorice R, Stengel B, Stracke S, Strauch K, Toniolo D, Uitterlinden AG, Ulivi S, Viikari JS, Völker U, Vollenweider P, Völzke H, Vuckovic D, Waldenberger M, Wang JJ, Yang Q, Chasman DI, Tromp G, Snieder H, Heid IM, Fox CS, Köttgen A, Pattaro C, Böger CA, and Fuchsberger C

Abstract

This corrects the article DOI: 10.1038/srep45040.

Published
2017
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30. Rare and low-frequency coding variants alter human adult height.

Author

Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu Y, Schurmann C, Highland HM, Rüeger S, Thorleifsson G, Justice AE, Lamparter D, Stirrups KE, Turcot V, Young KL, Winkler TW, Esko T, Karaderi T, Locke AE, Masca NG, Ng MC, Mudgal P, Rivas MA, Vedantam S, Mahajan A, Guo X, Abecasis G, Aben KK, Adair LS, Alam DS, Albrecht E, Allin KH, Allison M, Amouyel P, Appel EV, Arveiler D, Asselbergs FW, Auer PL, Balkau B, Banas B, Bang LE, Benn M, Bergmann S, Bielak LF, Blüher M, Boeing H, Boerwinkle E, Böger CA, Bonnycastle LL, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Burt AA, Butterworth AS, Carey DJ, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Galbany JC, Cox AJ, Cuellar-Partida G, Danesh J, Davies G, de Bakker PI, de Borst GJ, de Denus S, de Groot MC, de Mutsert R, Deary IJ, Dedoussis G, Demerath EW, den Hollander AI, Dennis JG, Di Angelantonio E, Drenos F, Du M, Dunning AM, Easton DF, Ebeling T, Edwards TL, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Faul JD, Feitosa MF, Feng S, Ferrannini E, Ferrario MM, Ferrieres J, Florez JC, Ford I, Fornage M, Franks PW, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Giedraitis V, Giri A, Girotto G, Gordon SD, Gordon-Larsen P, Gorski M, Grarup N, Grove ML, Gudnason V, Gustafsson S, Hansen T, Harris KM, Harris TB, Hattersley AT, Hayward C, He L, Heid IM, Heikkilä K, Helgeland Ø, Hernesniemi J, Hewitt AW, Hocking LJ, Hollensted M, Holmen OL, Hovingh GK, Howson JM, Hoyng CB, Huang PL, Hveem K, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jhun MA, Jia Y, Jiang X, Johansson S, Jørgensen ME, Jørgensen T, Jousilahti P, Jukema JW, Kahali B, Kahn RS, Kähönen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SL, Karpe F, Kee F, Keeman R, Kiemeney LA, Kitajima H, Kluivers KB, Kocher T, Komulainen P, Kontto J, Kooner JS, Kooperberg C, Kovacs P, Kriebel J, Kuivaniemi H, Küry S, Kuusisto J, La Bianca M, Laakso M, Lakka TA, Lange EM, Lange LA, Langefeld CD, Langenberg C, Larson EB, Lee IT, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu Y, Liu Y, Lophatananon A, Luan J, Lubitz SA, Lyytikäinen LP, Mackey DA, Madden PA, Manning AK, Männistö S, Marenne G, Marten J, Martin NG, Mazul AL, Meidtner K, Metspalu A, Mitchell P, Mohlke KL, Mook-Kanamori DO, Morgan A, Morris AD, Morris AP, Müller-Nurasyid M, Munroe PB, Nalls MA, Nauck M, Nelson CP, Neville M, Nielsen SF, Nikus K, Njølstad PR, Nordestgaard BG, Ntalla I, O'Connel JR, Oksa H, Loohuis LM, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CN, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JR, Person TN, Pirie A, Polasek O, Posthuma D, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Reiner AP, Renström F, Ridker PM, Rioux JD, Robertson N, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sandow K, Sapkota Y, Sattar N, Schmidt MK, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah S, Sim X, Sivapalaratnam S, Small KS, Smith AV, Smith JA, Southam L, Spector TD, Speliotes EK, Starr JM, Steinthorsdottir V, Stringham HM, Stumvoll M, Surendran P, 't Hart LM, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorsteinsdottir U, Thuesen BH, Tönjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Ulivi S, van der Laan SW, Van Der Leij AR, van Duijn CM, van Schoor NM, van Setten J, Varbo A, Varga TV, Varma R, Edwards DR, Vermeulen SH, Vestergaard H, Vitart V, Vogt TF, Vozzi D, Walker M, Wang F, Wang CA, Wang S, Wang Y, Wareham NJ, Warren HR, Wessel J, Willems SM, Wilson JG, Witte DR, Woods MO, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhao W, Zheng H, Zhou W, Rotter JI, Boehnke M, Kathiresan S, McCarthy MI, Willer CJ, Stefansson K, Borecki IB, Liu DJ, North KE, Heard-Costa NL, Pers TH, Lindgren CM, Oxvig C, Kutalik Z, Rivadeneira F, Loos RJ, Frayling TM, Hirschhorn JN, Deloukas P, and Lettre G

Subjects
ADAMTS Proteins genetics, Adult, Alleles, Cell Adhesion Molecules genetics, Female, Genome, Human genetics, Glycoproteins genetics, Glycoproteins metabolism, Glycosaminoglycans biosynthesis, Hedgehog Proteins genetics, Humans, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Interferon Regulatory Factors genetics, Interleukin-11 Receptor alpha Subunit genetics, Male, Multifactorial Inheritance genetics, NADPH Oxidase 4, NADPH Oxidases genetics, Phenotype, Pregnancy-Associated Plasma Protein-A metabolism, Procollagen N-Endopeptidase genetics, Proteoglycans biosynthesis, Proteolysis, Receptors, Androgen genetics, Somatomedins metabolism, Body Height genetics, Gene Frequency genetics, Genetic Variation genetics
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 0.1-4.8%) and effects of up to 2 centimetres 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 1-2 centimetres 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.

Published
2017
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31. Differentially expressed genes and canonical pathway expression in human atherosclerotic plaques - Tampere Vascular Study.

Author

Sulkava M, Raitoharju E, Levula M, Seppälä I, Lyytikäinen LP, Mennander A, Järvinen O, Zeitlin R, Salenius JP, Illig T, Klopp N, Mononen N, Laaksonen R, Kähönen M, Oksala N, and Lehtimäki T

Subjects
Atherosclerosis genetics, Case-Control Studies, Gene Expression Regulation, Humans, Thoracic Arteries pathology, Gene Expression Profiling, Plaque, Atherosclerotic genetics
Abstract

Cardiovascular diseases due to atherosclerosis are the leading cause of death globally. We aimed to investigate the potentially altered gene and pathway expression in advanced peripheral atherosclerotic plaques in comparison to healthy control arteries. Gene expression analysis was performed (Illumina HumanHT-12 version 3 Expression BeadChip) for 68 advanced atherosclerotic plaques (15 aortic, 29 carotid and 24 femoral plaques) and 28 controls (left internal thoracic artery (LITA)) from Tampere Vascular Study. Dysregulation of individual genes was compared to healthy controls and between plaques from different arterial beds and Ingenuity pathway analysis was conducted on genes with a fold change (FC) > ±1.5 and false discovery rate (FDR) < 0.05. 787 genes were significantly differentially expressed in atherosclerotic plaques. The most up-regulated genes were osteopontin and multiple MMPs, and the most down-regulated were cell death-inducing DFFA-like effector C and A (CIDEC, CIDEA) and apolipoprotein D (FC > 20). 156 pathways were differentially expressed in atherosclerotic plaques, mostly inflammation-related, especially related with leukocyte trafficking and signaling. In artery specific plaque analysis 50.4% of canonical pathways and 41.2% GO terms differentially expressed were in common for all three arterial beds. Our results confirm the inflammatory nature of advanced atherosclerosis and show novel pathway differences between different arterial beds., Competing Interests: The authors declare no competing financial interests.

Published
2017
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32. Blood hsa-miR-122-5p and hsa-miR-885-5p levels associate with fatty liver and related lipoprotein metabolism-The Young Finns Study.

Author

Raitoharju E, Seppälä I, Lyytikäinen LP, Viikari J, Ala-Korpela M, Soininen P, Kangas AJ, Waldenberger M, Klopp N, Illig T, Leiviskä J, Loo BM, Oksala N, Kähönen M, Hutri-Kähönen N, Laaksonen R, Raitakari O, and Lehtimäki T

Subjects
Adolescent, Adult, Child, Child, Preschool, Fatty Liver diagnostic imaging, Fatty Liver epidemiology, Female, Finland epidemiology, Follow-Up Studies, Genome-Wide Association Study, Humans, Male, Middle Aged, Ultrasonography, Fatty Liver blood, Lipoproteins blood, MicroRNAs blood
Abstract

MicroRNAs are involved in disease development and may be utilized as biomarkers. We investigated the association of blood miRNA levels and a) fatty liver (FL), b) lipoprotein and lipid pathways involved in liver lipid accumulation and c) levels of predicted mRNA targets in general population based cohort. Blood microRNA profiling (TaqMan OpenArray), genome-wide gene expression arrays and nuclear magnetic resonance metabolomics were performed for Young Finns Study participants aged 34-49 years (n = 871). Liver fat status was assessed ultrasonographically. Levels of hsa-miR-122-5p and -885-5p were up-regulated in individuals with FL (fold change (FC) = 1.55, p = 1.36 * 10 -14 and FC = 1.25, p = 4.86 * 10 -4 , respectively). In regression model adjusted with age, sex and BMI, hsa-miR-122-5p and -885-5p predicted FL (OR = 2.07, p = 1.29 * 10 -8 and OR = 1.41, p = 0.002, respectively). Together hsa-miR-122-5p and -885-5p slightly improved the detection of FL beyond established risk factors. These miRNAs may be associated with FL formation through the regulation of lipoprotein metabolism as hsa-miR-122-5p levels associated with small VLDL, IDL, and large LDL lipoprotein subclass components, while hsa-miR-885-5p levels associated inversely with XL HDL cholesterol levels. Hsa-miR-885-5p levels correlated inversely with oxysterol-binding protein 2 (OSBPL2) expression (r = -0.143, p = 1.00 * 10 -4 ) and suppressing the expression of this lipid receptor and sterol transporter could link hsa-miR-885-5p with HDL cholesterol levels., Competing Interests: MAK, PS, and AJK are shareholders in Brainshake Ltd., a company offering NMR-based metabolite profiling.

Published
2016
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33. Genome-wide associations for birth weight and correlations with adult disease.

Author

Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, Feenstra B, van Zuydam NR, Gaulton KJ, Grarup N, Bradfield JP, Strachan DP, Li-Gao R, Ahluwalia TS, Kreiner E, Rueedi R, Lyytikäinen LP, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Hottenga JJ, Vilor-Tejedor N, Joshi PK, Boh ETH, Ntalla I, Pitkänen N, Mahajan A, van Leeuwen EM, Joro R, Lagou V, Nodzenski M, Diver LA, Zondervan KT, Bustamante M, Marques-Vidal P, Mercader JM, Bennett AJ, Rahmioglu N, Nyholt DR, Ma RCW, Tam CHT, Tam WH, Ganesh SK, van Rooij FJ, Jones SE, Loh PR, Ruth KS, Tuke MA, Tyrrell J, Wood AR, Yaghootkar H, Scholtens DM, Paternoster L, Prokopenko I, Kovacs P, Atalay M, Willems SM, Panoutsopoulou K, Wang X, Carstensen L, Geller F, Schraut KE, Murcia M, van Beijsterveldt CE, Willemsen G, Appel EVR, Fonvig CE, Trier C, Tiesler CM, Standl M, Kutalik Z, Bonas-Guarch S, Hougaard DM, Sánchez F, Torrents D, Waage J, Hollegaard MV, de Haan HG, Rosendaal FR, Medina-Gomez C, Ring SM, Hemani G, McMahon G, Robertson NR, Groves CJ, Langenberg C, Luan J, Scott RA, Zhao JH, Mentch FD, MacKenzie SM, Reynolds RM, Lowe WL Jr, Tönjes A, Stumvoll M, Lindi V, Lakka TA, van Duijn CM, Kiess W, Körner A, Sørensen TI, Niinikoski H, Pahkala K, Raitakari OT, Zeggini E, Dedoussis GV, Teo YY, Saw SM, Melbye M, Campbell H, Wilson JF, Vrijheid M, de Geus EJ, Boomsma DI, Kadarmideen HN, Holm JC, Hansen T, Sebert S, Hattersley AT, Beilin LJ, Newnham JP, Pennell CE, Heinrich J, Adair LS, Borja JB, Mohlke KL, Eriksson JG, Widén EE, Kähönen M, Viikari JS, Lehtimäki T, Vollenweider P, Bønnelykke K, Bisgaard H, Mook-Kanamori DO, Hofman A, Rivadeneira F, Uitterlinden AG, Pisinger C, Pedersen O, Power C, Hyppönen E, Wareham NJ, Hakonarson H, Davies E, Walker BR, Jaddoe VW, Jarvelin MR, Grant SF, Vaag AA, Lawlor DA, Frayling TM, Davey Smith G, Morris AP, Ong KK, Felix JF, Timpson NJ, Perry JR, Evans DM, McCarthy MI, and Freathy RM

Subjects
Adult, Anthropometry, Blood Pressure genetics, Chromatin Assembly and Disassembly, Cohort Studies, Datasets as Topic, Female, Genetic Loci genetics, Genetic Variation genetics, Genomic Imprinting genetics, Genotype, Glucose metabolism, Glycogen biosynthesis, Humans, Insulin metabolism, Male, Phenotype, Signal Transduction, Aging genetics, Birth Weight genetics, Coronary Artery Disease genetics, Diabetes Mellitus, Type 2 genetics, Fetus metabolism, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10 -8 ). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R g  = -0.22, P = 5.5 × 10 -13 ), T2D (R g  = -0.27, P = 1.1 × 10 -6 ) and coronary artery disease (R g  = -0.30, P = 6.5 × 10 -9 ). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10 -4 ). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated., Competing Interests: One of the authors discloses competing financial interests: Krina Zondervan has a scientific collaboration with Bayer HealthCare Ltd. and Population Diagnostics Inc.

Published
2016
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34. Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke.

Author

Seppälä I, Kleber ME, Bevan S, Lyytikäinen LP, Oksala N, Hernesniemi JA, Mäkelä KM, Rothwell PM, Sudlow C, Dichgans M, Mononen N, Vlachopoulou E, Sinisalo J, Delgado GE, Laaksonen R, Koskinen T, Scharnagl H, Kähönen M, Markus HS, März W, and Lehtimäki T

Subjects
Aged, Alleles, Angiography, Atrial Fibrillation pathology, Case-Control Studies, Chronic Disease, Cohort Studies, Coronary Vessels diagnostic imaging, Female, Genotype, Humans, Logistic Models, Male, Middle Aged, Mutation, Missense, Odds Ratio, Polymorphism, Single Nucleotide, Stroke pathology, Transaminases metabolism, Atrial Fibrillation genetics, Stroke genetics, Transaminases genetics
Abstract

Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44-2.74) and chronic AF (OR = 2.03, 95% CI 1.35-3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.

Published
2016
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35. Genome-Wide Meta-Analysis of Cotinine Levels in Cigarette Smokers Identifies Locus at 4q13.2.

Author

Ware JJ, Chen X, Vink J, Loukola A, Minica C, Pool R, Milaneschi Y, Mangino M, Menni C, Chen J, Peterson RE, Auro K, Lyytikäinen LP, Wedenoja J, Stiby AI, Hemani G, Willemsen G, Hottenga JJ, Korhonen T, Heliövaara M, Perola M, Rose RJ, Paternoster L, Timpson N, Wassenaar CA, Zhu AZ, Davey Smith G, Raitakari OT, Lehtimäki T, Kähönen M, Koskinen S, Spector T, Penninx BW, Salomaa V, Boomsma DI, Tyndale RF, Kaprio J, and Munafò MR

Subjects
Female, Genome-Wide Association Study, Glucuronosyltransferase genetics, Humans, Male, Chromosomes, Human, Pair 4 genetics, Cotinine, Genetic Loci, Linkage Disequilibrium, Smoking genetics
Abstract

Genome-wide association studies (GWAS) of complex behavioural phenotypes such as cigarette smoking typically employ self-report phenotypes. However, precise biomarker phenotypes may afford greater statistical power and identify novel variants. Here we report the results of a GWAS meta-analysis of levels of cotinine, the primary metabolite of nicotine, in 4,548 daily smokers of European ancestry. We identified a locus close to UGT2B10 at 4q13.2 (minimum p = 5.89 × 10(-10) for rs114612145), which was consequently replicated. This variant is in high linkage disequilibrium with a known functional variant in the UGT2B10 gene which is associated with reduced nicotine and cotinine glucuronidation activity, but intriguingly is not associated with nicotine intake. Additionally, we observed association between multiple variants within the 15q25.1 region and cotinine levels, all located within the CHRNA5-A3-B4 gene cluster or adjacent genes, consistent with previous much larger GWAS using self-report measures of smoking quantity. These results clearly illustrate the increase in power afforded by using precise biomarker measures in GWAS. Perhaps more importantly however, they also highlight that biomarkers do not always mark the phenotype of interest. The use of metabolite data as a proxy for environmental exposures should be carefully considered in the context of individual differences in metabolic pathways.

Published
2016
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36. Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque.

Author

Fan YM, Hernesniemi J, Oksala N, Levula M, Raitoharju E, Collings A, Hutri-Kähönen N, Juonala M, Marniemi J, Lyytikäinen LP, Seppälä I, Mennander A, Tarkka M, Kangas AJ, Soininen P, Salenius JP, Klopp N, Illig T, Laitinen T, Ala-Korpela M, Laaksonen R, Viikari J, Kähönen M, Raitakari OT, and Lehtimäki T

Subjects
Adult, Alleles, Apolipoproteins B blood, Atherosclerosis pathology, Cholesterol, LDL blood, Female, Genotype, Haplotypes, Humans, Male, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Sex Factors, Atherosclerosis genetics, Lipid Metabolism physiology, Upstream Stimulatory Factors genetics
Abstract

Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.

Published
2014
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37. Seventy-five genetic loci influencing the human red blood cell.

Author

van der Harst P, Zhang W, Mateo Leach I, Rendon A, Verweij N, Sehmi J, Paul DS, Elling U, Allayee H, Li X, Radhakrishnan A, Tan ST, Voss K, Weichenberger CX, Albers CA, Al-Hussani A, Asselbergs FW, Ciullo M, Danjou F, Dina C, Esko T, Evans DM, Franke L, Gögele M, Hartiala J, Hersch M, Holm H, Hottenga JJ, Kanoni S, Kleber ME, Lagou V, Langenberg C, Lopez LM, Lyytikäinen LP, Melander O, Murgia F, Nolte IM, O'Reilly PF, Padmanabhan S, Parsa A, Pirastu N, Porcu E, Portas L, Prokopenko I, Ried JS, Shin SY, Tang CS, Teumer A, Traglia M, Ulivi S, Westra HJ, Yang J, Zhao JH, Anni F, Abdellaoui A, Attwood A, Balkau B, Bandinelli S, Bastardot F, Benyamin B, Boehm BO, Cookson WO, Das D, de Bakker PI, de Boer RA, de Geus EJ, de Moor MH, Dimitriou M, Domingues FS, Döring A, Engström G, Eyjolfsson GI, Ferrucci L, Fischer K, Galanello R, Garner SF, Genser B, Gibson QD, Girotto G, Gudbjartsson DF, Harris SE, Hartikainen AL, Hastie CE, Hedblad B, Illig T, Jolley J, Kähönen M, Kema IP, Kemp JP, Liang L, Lloyd-Jones H, Loos RJ, Meacham S, Medland SE, Meisinger C, Memari Y, Mihailov E, Miller K, Moffatt MF, Nauck M, Novatchkova M, Nutile T, Olafsson I, Onundarson PT, Parracciani D, Penninx BW, Perseu L, Piga A, Pistis G, Pouta A, Puc U, Raitakari O, Ring SM, Robino A, Ruggiero D, Ruokonen A, Saint-Pierre A, Sala C, Salumets A, Sambrook J, Schepers H, Schmidt CO, Silljé HH, Sladek R, Smit JH, Starr JM, Stephens J, Sulem P, Tanaka T, Thorsteinsdottir U, Tragante V, van Gilst WH, van Pelt LJ, van Veldhuisen DJ, Völker U, Whitfield JB, Willemsen G, Winkelmann BR, Wirnsberger G, Algra A, Cucca F, d'Adamo AP, Danesh J, Deary IJ, Dominiczak AF, Elliott P, Fortina P, Froguel P, Gasparini P, Greinacher A, Hazen SL, Jarvelin MR, Khaw KT, Lehtimäki T, Maerz W, Martin NG, Metspalu A, Mitchell BD, Montgomery GW, Moore C, Navis G, Pirastu M, Pramstaller PP, Ramirez-Solis R, Schadt E, Scott J, Shuldiner AR, Smith GD, Smith JG, Snieder H, Sorice R, Spector TD, Stefansson K, Stumvoll M, Tang WH, Toniolo D, Tönjes A, Visscher PM, Vollenweider P, Wareham NJ, Wolffenbuttel BH, Boomsma DI, Beckmann JS, Dedoussis GV, Deloukas P, Ferreira MA, Sanna S, Uda M, Hicks AA, Penninger JM, Gieger C, Kooner JS, Ouwehand WH, Soranzo N, and Chambers JC

Subjects
Animals, Cell Cycle genetics, Cytokines metabolism, Drosophila melanogaster genetics, Erythrocytes cytology, Female, Gene Expression Regulation genetics, Hematopoiesis genetics, Hemoglobins genetics, Humans, Male, Mice, Organ Specificity, Polymorphism, Single Nucleotide genetics, RNA Interference, Signal Transduction genetics, Erythrocytes metabolism, Genetic Loci, Genome-Wide Association Study, Phenotype
Abstract

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Published
2012
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38. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Author

Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ, Pihur V, Vollenweider P, O'Reilly PF, Amin N, Bragg-Gresham JL, Teumer A, Glazer NL, Launer L, Zhao JH, Aulchenko Y, Heath S, Sõber S, Parsa A, Luan J, Arora P, Dehghan A, Zhang F, Lucas G, Hicks AA, Jackson AU, Peden JF, Tanaka T, Wild SH, Rudan I, Igl W, Milaneschi Y, Parker AN, Fava C, Chambers JC, Fox ER, Kumari M, Go MJ, van der Harst P, Kao WH, Sjögren M, Vinay DG, Alexander M, Tabara Y, Shaw-Hawkins S, Whincup PH, Liu Y, Shi G, Kuusisto J, Tayo B, Seielstad M, Sim X, Nguyen KD, Lehtimäki T, Matullo G, Wu Y, Gaunt TR, Onland-Moret NC, Cooper MN, Platou CG, Org E, Hardy R, Dahgam S, Palmen J, Vitart V, Braund PS, Kuznetsova T, Uiterwaal CS, Adeyemo A, Palmas W, Campbell H, Ludwig B, Tomaszewski M, Tzoulaki I, Palmer ND, Aspelund T, Garcia M, Chang YP, O'Connell JR, Steinle NI, Grobbee DE, Arking DE, Kardia SL, Morrison AC, Hernandez D, Najjar S, McArdle WL, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Clarke R, Hopewell JC, Ongen H, Dreisbach AW, Li Y, Young JH, Bis JC, Kähönen M, Viikari J, Adair LS, Lee NR, Chen MH, Olden M, Pattaro C, Bolton JA, Köttgen A, Bergmann S, Mooser V, Chaturvedi N, Frayling TM, Islam M, Jafar TH, Erdmann J, Kulkarni SR, Bornstein SR, Grässler J, Groop L, Voight BF, Kettunen J, Howard P, Taylor A, Guarrera S, Ricceri F, Emilsson V, Plump A, Barroso I, Khaw KT, Weder AB, Hunt SC, Sun YV, Bergman RN, Collins FS, Bonnycastle LL, Scott LJ, Stringham HM, Peltonen L, Perola M, Vartiainen E, Brand SM, Staessen JA, Wang TJ, Burton PR, Soler Artigas M, Dong Y, Snieder H, Wang X, Zhu H, Lohman KK, Rudock ME, Heckbert SR, Smith NL, Wiggins KL, Doumatey A, Shriner D, Veldre G, Viigimaa M, Kinra S, Prabhakaran D, Tripathy V, Langefeld CD, Rosengren A, Thelle DS, Corsi AM, Singleton A, Forrester T, Hilton G, McKenzie CA, Salako T, Iwai N, Kita Y, Ogihara T, Ohkubo T, Okamura T, Ueshima H, Umemura S, Eyheramendy S, Meitinger T, Wichmann HE, Cho YS, Kim HL, Lee JY, Scott J, Sehmi JS, Zhang W, Hedblad B, Nilsson P, Smith GD, Wong A, Narisu N, Stančáková A, Raffel LJ, Yao J, Kathiresan S, O'Donnell CJ, Schwartz SM, Ikram MA, Longstreth WT Jr, Mosley TH, Seshadri S, Shrine NR, Wain LV, Morken MA, Swift AJ, Laitinen J, Prokopenko I, Zitting P, Cooper JA, Humphries SE, Danesh J, Rasheed A, Goel A, Hamsten A, Watkins H, Bakker SJ, van Gilst WH, Janipalli CS, Mani KR, Yajnik CS, Hofman A, Mattace-Raso FU, Oostra BA, Demirkan A, Isaacs A, Rivadeneira F, Lakatta EG, Orru M, Scuteri A, Ala-Korpela M, Kangas AJ, Lyytikäinen LP, Soininen P, Tukiainen T, Würtz P, Ong RT, Dörr M, Kroemer HK, Völker U, Völzke H, Galan P, Hercberg S, Lathrop M, Zelenika D, Deloukas P, Mangino M, Spector TD, Zhai G, Meschia JF, Nalls MA, Sharma P, Terzic J, Kumar MV, Denniff M, Zukowska-Szczechowska E, Wagenknecht LE, Fowkes FG, Charchar FJ, Schwarz PE, Hayward C, Guo X, Rotimi C, Bots ML, Brand E, Samani NJ, Polasek O, Talmud PJ, Nyberg F, Kuh D, Laan M, Hveem K, Palmer LJ, van der Schouw YT, Casas JP, Mohlke KL, Vineis P, Raitakari O, Ganesh SK, Wong TY, Tai ES, Cooper RS, Laakso M, Rao DC, Harris TB, Morris RW, Dominiczak AF, Kivimaki M, Marmot MG, Miki T, Saleheen D, Chandak GR, Coresh J, Navis G, Salomaa V, Han BG, Zhu X, Kooner JS, Melander O, Ridker PM, Bandinelli S, Gyllensten UB, Wright AF, Wilson JF, Ferrucci L, Farrall M, Tuomilehto J, Pramstaller PP, Elosua R, Soranzo N, Sijbrands EJ, Altshuler D, Loos RJ, Shuldiner AR, Gieger C, Meneton P, Uitterlinden AG, Wareham NJ, Gudnason V, Rotter JI, Rettig R, Uda M, Strachan DP, Witteman JC, Hartikainen AL, Beckmann JS, Boerwinkle E, Vasan RS, Boehnke M, Larson MG, Järvelin MR, Psaty BM, Abecasis GR, Chakravarti A, Elliott P, van Duijn CM, Newton-Cheh C, Levy D, Caulfield MJ, and Johnson T

Subjects
Africa ethnology, Asia ethnology, Blood Pressure physiology, Coronary Artery Disease genetics, Europe ethnology, Genome-Wide Association Study, Humans, Hypertension genetics, Kidney Diseases genetics, Stroke genetics, Blood Pressure genetics, Cardiovascular Diseases genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics
Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Published
2011
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