Author: "Khor CC" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Khor CC"' showing total 382 results

Start Over Author "Khor CC"

382 results on '"Khor CC"'

1. Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis

Author: Seielstad, Mark, Ottenhoff, THM, Dass, RH, Yang, N, Zhang, MM, Wong, HEE, Sahiratmadja, E, Khor, CC, Alisjahbana, B, van, R, and Marzuki, S
Abstract: Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains the leading cause of mortality from a single infectious agent. Each year around 9 million individuals newly develop active TB disease, and over 2 billion individuals are latently infec
Published: 2012

2. Genetic variants on chromosome 1q41 influence ocular axial length and high myopia

Author: Seielstad, Mark, Fan, Q, Barathi, VA, Cheng, CY, Zhou, X, Meguro, A, Nakata, I, Khor, CC, Goh, LK, Li, YJ, and Lim, W
Abstract: As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide associ
Published: 2012

3. MUC5AC genetic variation is associated with tuberculous meningitis CSF cytokine responses and mortality

Author: Sabo, MC, Thuong, NTT, Chang, X, Ardiansyah, E, Tram, TTB, Hai, HT, Nghia, HDT, Bang, ND, Dian, S, Ganiem, AR, Shaporifar, S, Kumar, V, Li, Z, Hibberd, M, Khor, CC, Thwaites, G, Heemskerk, D, van Laarhoven, A, van Crevel, R, Dunstan, SJ, and Shah, JA
Abstract: BACKGROUND: The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. METHODS: Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with TNF concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. RESULTS: MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF(p = 1.8*10-8) and IFNγ(p = 2.3*10-6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.03, 1.49; p = 0.02), but not pulmonary tuberculosis (OR 1.11, 95% CI 0.98, 1.25; p = 0.10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank p = 0.005) in a Vietnam discovery cohort (N = 210), an independent Vietnam validation cohort (N = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank p = 0.02), and an Indonesia validation cohort (N = 468, 127/287, 44.3% vs 65/181, 35.9%, log-rank p = 0.06). CONCLUSIONS: MUC5AC variants may contribute to immune changes that influence TBM outcomes.
Published: 2023

4. 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, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, 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, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, 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, A-E, Faul, JD, Fernandez-Lopez, J-C, 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, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, 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, Mollehave, 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, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, 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, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, 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, Wei, WB, 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, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, 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, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, 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, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, 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, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, 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, Nothen, 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, J, 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, X-O, 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, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, 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, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, 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, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, Hirschhorn, JN, 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, S-H, Ferreira, T, Highland, HH, Ji, Y, Karaderi, T, Lin, K, Lull, K, Malden, DE, Medina-Gomez, C, Machado, M, Moore, A, Rueger, 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, Canadas-Garre, M, Catamo, E, Chai, J-F, Chai, X, Chang, L-C, Chang, Y-C, Chen, C-H, Chesi, A, Choi, SH, Chung, R-H, 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, A-E, Faul, JD, Fernandez-Lopez, J-C, 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, Y-LA, Hofer, E, Holliday, E, Horn, K, Hornsby, WE, Hottenga, J-J, Huang, H, Huang, J, Huerta-Chagoya, A, Huffman, JE, Hung, Y-J, Huo, S, Hwang, MY, Iha, H, Ikeda, DD, Isono, M, Jackson, AU, Jager, S, Jansen, IE, Johansson, I, Jonas, JB, Jonsson, A, Jorgensen, T, Kalafati, I-P, Kanai, M, Kanoni, S, Karhus, LL, Kasturiratne, A, Katsuya, T, Kawaguchi, T, Kember, RL, Kentistou, KA, Kim, H-N, Kim, YJ, Kleber, ME, Knol, MJ, Kurbasic, A, Lauzon, M, Le, P, Lea, R, Lee, J-Y, Leonard, HL, Li, SA, Li, X, Liang, J, Lin, H, Lin, S-Y, Liu, J, Liu, X, Lo, KS, Long, J, Lores-Motta, L, Luan, J, Lyssenko, V, Lyytikainen, L-P, 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, Mollehave, 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, Parna, K, Pauper, M, Petersen, ERB, Petersen, L, Pitkanen, N, Polasek, 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, RKC, Smit, RAJ, Smith, A, Smith, JA, Smyth, LJ, Southam, LE, Steinthorsdottir, V, Sun, L, Takeuchi, F, Tallapragada, D, 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, Wei, WB, 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, J-H, Zhao, W, Zhou, W, Zimmermann, ME, Zoledziewska, M, Adair, LS, Adams, HHH, Aguilar-Salinas, CA, Al-Mulla, F, Arnett, DK, Asselbergs, FW, Asvold, BO, Attia, J, Banas, B, Bandinelli, S, Bennett, DA, Bergler, T, Bharadwaj, D, Biino, G, Bisgaard, H, Boerwinkle, E, Boger, CA, Bonnelykke, K, Boomsma, D, Borglum, AD, Borja, JB, Bouchard, C, Bowden, DW, Brandslund, I, Brumpton, B, Buring, JE, Caulfield, MJ, Chambers, JC, Chandak, GR, Chanock, SJ, Chaturvedi, N, Chen, Y-DI, Chen, Z, Cheng, C-Y, 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, DP, de Silva, HJ, Dedoussis, G, den Hollander, A, Du, S, Easton, DF, Elders, PJM, Eliassen, AH, Ellinor, PT, Elmstahl, S, Erdmann, J, Evans, MK, Fatkin, D, Feenstra, B, Feitosa, MF, Ferrucci, L, Ford, I, Fornage, M, Franke, A, Franks, PW, Freedman, B, 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, C-K, Hengstenberg, C, Hewitt, AW, Hishigaki, H, Hoyng, CB, Huang, PL, Huang, W, Hunt, SC, Hveem, K, Hypponen, E, Iacono, WG, Ichihara, S, Ikram, MA, Isasi, CR, Jackson, RD, Jarvelin, M-R, Jin, Z-B, Jockel, K-H, Joshi, PK, Jousilahti, P, Jukema, JW, Kahonen, M, Kamatani, Y, Kang, KD, Kaprio, J, Kardia, SLR, Karpe, F, Kato, N, Kee, F, Kessler, T, Khera, A, Khor, CC, Kiemeney, LALM, Kim, B-J, Kim, EK, Kim, H-L, Kirchhof, P, Kivimaki, M, Koh, W-P, Koistinen, HA, Kolovou, GD, Kooner, JS, Kooperberg, C, Kottgen, 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, Lehtimaki, T, Li, H, Li, L, Lieb, W, Lin, X, Lind, L, Linneberg, A, Liu, C-T, Loeffler, M, London, B, Lubitz, SA, Lye, SJ, Mackey, DA, Magi, R, Magnusson, PKE, Marcus, GM, Vidal, PM, Martin, NG, Marz, W, Matsuda, F, McGarrah, RW, McGue, M, McKnight, AJ, Medland, SE, Mellstrom, 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, Nothen, 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, J, 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, X-O, 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, J-C, Thanaraj, TA, Timpson, NJ, Tonjes, A, Tremblay, A, Tuomi, T, Tuomilehto, J, Tusie-Luna, M-T, Uitterlinden, AG, van Dam, RM, van der Harst, P, Van der Velde, N, van Duijn, CM, van Schoor, NM, Vitart, V, Volker, U, Vollenweider, P, Volzke, 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, T-Y, Woo, J-T, Wright, AF, Wu, J-Y, Xu, H, Yajnik, CS, Yokota, M, Yuan, J-M, Zeggini, E, Zemel, BS, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Zwart, J-A, Chasman, D, Cho, YS, Heid, IM, McCarthy, M, Ng, MCY, O'Donnell, CJ, Rivadeneira, F, Thorsteinsdottir, U, Sun, Y, 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, P-R, Esko, T, Assimes, TL, Auton, A, Abecasis, GR, Willer, CJ, Locke, AE, Berndt, S, Lettre, G, Frayling, TM, Okada, Y, Wood, AR, Visscher, PM, and Hirschhorn, JN
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 sizes1. 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 panel2) 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.
Published: 2022

5. REL and BHLHE40 Variants Are Associated with IL-12 and IL-10 Responses and Tuberculosis Risk

Author: Shah, JA, Warr, AJ, Graustein, AD, Saha, A, Dunstan, SJ, Thuong, NTT, Thwaites, GE, Caws, M, Thai, PVK, Bang, ND, Chau, TTH, Khor, CC, Li, Z, Hibberd, M, Chang, X, Nguyen, FK, Hernandez, CA, Jones, MA, Sassetti, CM, Fitzgerald, KA, Musvosvi, M, Gela, A, Hanekom, WA, Hatherill, M, Scriba, TJ, Hawn, TR, Shah, JA, Warr, AJ, Graustein, AD, Saha, A, Dunstan, SJ, Thuong, NTT, Thwaites, GE, Caws, M, Thai, PVK, Bang, ND, Chau, TTH, Khor, CC, Li, Z, Hibberd, M, Chang, X, Nguyen, FK, Hernandez, CA, Jones, MA, Sassetti, CM, Fitzgerald, KA, Musvosvi, M, Gela, A, Hanekom, WA, Hatherill, M, Scriba, TJ, and Hawn, TR
Abstract: The major human genes regulating Mycobacterium tuberculosis-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette-Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.
Published: 2022

6. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author: Gorski, M, Jung, B, Li, Y, Matias-Garcia, PR, Wuttke, M, Coassin, S, Thio, CHL, Kleber, ME, Winkler, TW, Wanner, V, Chai, JF, Chu, AY, Cocca, M, Feitosa, MF, Ghasemi, S, Hoppmann, A, Horn, K, Li, M, Nutile, T, Scholz, M, Sieber, KB, Teumer, A, Tin, A, Wang, J, Tayo, BO, Ahluwalia, TS, Almgren, P, Bakker, SJL, Banas, B, Bansal, N, Biggs, ML, Boerwinkle, E, Bottinger, EP, Brenner, H, Carroll, RJ, Chalmers, J, Chee, ML, Cheng, CY, Coresh, J, de Borst, MH, Degenhardt, F, Eckardt, KU, Endlich, K, Franke, A, Freitag-Wolf, S, Gampawar, P, Gansevoort, RT, Ghanbari, M, Gieger, C, Hamet, P, Ho, K, Hofer, E, Holleczek, B, Xian Foo, VH, Hutri-Kähönen, N, Hwang, SJ, Ikram, MA, Josyula, NS, Kähönen, M, Khor, CC, Koenig, W, Kramer, H, Krämer, BK, Kühnel, B, Lange, LA, Lehtimäki, T, Lieb, W, Alizadeh, BZ, Boezen, HM, Franke, L, van der Harst, P, Navis, G, Rots, M, Snieder, H, Swertz, M, Wolffenbuttel, BHR, Wijmenga, C, Abecasis, G, Baras, A, Cantor, M, Coppola, G, Economides, A, Lotta, LA, Overton, JD, Reid, JG, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, ED, Gu, Z, Lattari, M, Lopez, A, Schleicher, TD, Padilla, MS, Toledo, K, Widom, L, Wolf, SE, Pradhan, M, Manoochehri, K, Gorski, M, Jung, B, Li, Y, Matias-Garcia, PR, Wuttke, M, Coassin, S, Thio, CHL, Kleber, ME, Winkler, TW, Wanner, V, Chai, JF, Chu, AY, Cocca, M, Feitosa, MF, Ghasemi, S, Hoppmann, A, Horn, K, Li, M, Nutile, T, Scholz, M, Sieber, KB, Teumer, A, Tin, A, Wang, J, Tayo, BO, Ahluwalia, TS, Almgren, P, Bakker, SJL, Banas, B, Bansal, N, Biggs, ML, Boerwinkle, E, Bottinger, EP, Brenner, H, Carroll, RJ, Chalmers, J, Chee, ML, Cheng, CY, Coresh, J, de Borst, MH, Degenhardt, F, Eckardt, KU, Endlich, K, Franke, A, Freitag-Wolf, S, Gampawar, P, Gansevoort, RT, Ghanbari, M, Gieger, C, Hamet, P, Ho, K, Hofer, E, Holleczek, B, Xian Foo, VH, Hutri-Kähönen, N, Hwang, SJ, Ikram, MA, Josyula, NS, Kähönen, M, Khor, CC, Koenig, W, Kramer, H, Krämer, BK, Kühnel, B, Lange, LA, Lehtimäki, T, Lieb, W, Alizadeh, BZ, Boezen, HM, Franke, L, van der Harst, P, Navis, G, Rots, M, Snieder, H, Swertz, M, Wolffenbuttel, BHR, Wijmenga, C, Abecasis, G, Baras, A, Cantor, M, Coppola, G, Economides, A, Lotta, LA, Overton, JD, Reid, JG, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, ED, Gu, Z, Lattari, M, Lopez, A, Schleicher, TD, Padilla, MS, Toledo, K, Widom, L, Wolf, SE, Pradhan, M, and Manoochehri, K
Abstract: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Published: 2021

7. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author: Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, Wiggs, JL, Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, and Wiggs, JL
Abstract: Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
Published: 2021

8. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.

Author: Chang, X, Gurung, RL, Wang, L, Jin, A, Li, Z, Wang, R, Beckman, KB, Adams-Haduch, J, Meah, WY, Sim, KS, Lim, WK, Davila, S, Tan, P, Teo, JX, Yeo, KK, M, Y, Liu, S, Lim, SC, Liu, J, van Dam, RM, Friedlander, Y, Koh, W-P, Yuan, J-M, Khor, CC, Heng, C-K, Dorajoo, R, Chang, X, Gurung, RL, Wang, L, Jin, A, Li, Z, Wang, R, Beckman, KB, Adams-Haduch, J, Meah, WY, Sim, KS, Lim, WK, Davila, S, Tan, P, Teo, JX, Yeo, KK, M, Y, Liu, S, Lim, SC, Liu, J, van Dam, RM, Friedlander, Y, Koh, W-P, Yuan, J-M, Khor, CC, Heng, C-K, and Dorajoo, R
Abstract: The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10-14-6.94×10-10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.
Published: 2021

9. Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk

Author: Huang, QQ, Tang, HHF, Teo, SM, Mok, D, Ritchie, SC, Nath, AP, Brozynska, M, Salim, A, Bakshi, A, Holt, BJ, Khor, CC, Sly, Peter, Holt, PG, Holt, KE, Inouye, M, Huang, QQ, Tang, HHF, Teo, SM, Mok, D, Ritchie, SC, Nath, AP, Brozynska, M, Salim, A, Bakshi, A, Holt, BJ, Khor, CC, Sly, Peter, Holt, PG, Holt, KE, and Inouye, M
Abstract: Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4+ T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.
Published: 2020

10. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract.

Author: Yonova-Doing, E, Zhao, W, Igo, RP, Wang, C, Sundaresan, P, Lee, KE, Jun, GR, Alves, AC, Chai, X, Chan, ASY, Lee, MC, Fong, A, Tan, AG, Khor, CC, Chew, EY, Hysi, PG, Fan, Q, Chua, J, Chung, J, Liao, J, Colijn, JM, Burdon, KP, Fritsche, LG, Swift, MK, Hilmy, MH, Chee, ML, Tedja, M, Bonnemaijer, PWM, Gupta, P, Tan, QS, Li, Z, Vithana, EN, Ravindran, RD, Chee, S-P, Shi, Y, Liu, W, Su, X, Sim, X, Shen, Y, Wang, YX, Li, H, Tham, Y-C, Teo, YY, Aung, T, Small, KS, Mitchell, P, Jonas, JB, Wong, TY, Fletcher, AE, Klaver, CCW, Klein, BEK, Wang, JJ, Iyengar, SK, Hammond, CJ, Cheng, C-Y, Yonova-Doing, E, Zhao, W, Igo, RP, Wang, C, Sundaresan, P, Lee, KE, Jun, GR, Alves, AC, Chai, X, Chan, ASY, Lee, MC, Fong, A, Tan, AG, Khor, CC, Chew, EY, Hysi, PG, Fan, Q, Chua, J, Chung, J, Liao, J, Colijn, JM, Burdon, KP, Fritsche, LG, Swift, MK, Hilmy, MH, Chee, ML, Tedja, M, Bonnemaijer, PWM, Gupta, P, Tan, QS, Li, Z, Vithana, EN, Ravindran, RD, Chee, S-P, Shi, Y, Liu, W, Su, X, Sim, X, Shen, Y, Wang, YX, Li, H, Tham, Y-C, Teo, YY, Aung, T, Small, KS, Mitchell, P, Jonas, JB, Wong, TY, Fletcher, AE, Klaver, CCW, Klein, BEK, Wang, JJ, Iyengar, SK, Hammond, CJ, and Cheng, C-Y
Abstract: Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10-16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10-19), TMPRSS5 (rs4936279, P = 2.5 × 10-10), LINC01412 (rs16823886, P = 1.3 × 10-9), GLTSCR1 (rs1005911, P = 9.8 × 10-9), and COMMD1 (rs62149908, P = 1.2 × 10-8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.
Published: 2020

11. Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population.

Author: Chang, X, Dorajoo, R, Sun, Y, Wang, L, Ong, CN, Liu, J, Khor, CC, Yuan, J-M, Koh, WP, Friedlander, Y, Heng, C-K, Chang, X, Dorajoo, R, Sun, Y, Wang, L, Ong, CN, Liu, J, Khor, CC, Yuan, J-M, Koh, WP, Friedlander, Y, and Heng, C-K
Abstract: BACKGROUND: Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established. METHODS: A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling. RESULTS: Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p < 5 × 10- 8). Mediation analysis showed t
Published: 2020

12. Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome

Author: Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, Bezzina CR., Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, and Bezzina CR.
Abstract: Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS c
Published: 2020

13. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Grp, BMES-G, Consortium, N, and Control, WTC
Subjects: Lumican, genetic structures, Fibrillin-1, General Physics and Astronomy, Gene Expression, Q1, Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, Myopia, Link (knot theory), lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Corneal Dystrophies, Hereditary, Multidisciplinary, Eye Diseases, Hereditary, symbols, NEIGHBORHOOD consortium, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Proteoglycans, Decorin, Glaucoma, Open-Angle, Science, Quantitative Trait Loci, Computational biology, Biology, Keratoconus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, symbols.namesake, Transforming Growth Factor beta2, Quantitative Trait, Heritable, Asian People, Genome-Wide Association Analysis, Humans, Author Correction, Eye Disease and Disorders of Vision, Loeys-Dietz Syndrome, Genome, Human, Wellcome Trust Case Control Consortium 2, Blue Mountains Eye Study - GWAS group, General Chemistry, Mendelian Randomization Analysis, R1, eye diseases, Mendelian inheritance, Ehlers-Danlos Syndrome, lcsh:Q, sense organs, Genome-Wide Association Study
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation., Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
Published: 2019

14. Genome-wide association analyses identify two susceptibility loci for pachychoroid disease central serous chorioretinopathy.

Author: Hosoda, Y, Miyake, M, Schellevis, RL, Boon, CJF, Hoyng, CB, Miki, A, Meguro, A, Sakurada, Y, Yoneyama, S, Takasago, Y, Hata, M, Muraoka, Y, Nakanishi, H, Oishi, A, Ooto, S, Tamura, H, Uji, A, Miyata, M, Takahashi, A, Ueda-Arakawa, N, Tajima, A, Sato, T, Mizuki, N, Shiragami, C, Iida, T, Khor, CC, Wong, TY, Yamada, R, Honda, S, de Jong, EK, Hollander, AID, Matsuda, F, Yamashiro, K, Tsujikawa, A, Hosoda, Y, Miyake, M, Schellevis, RL, Boon, CJF, Hoyng, CB, Miki, A, Meguro, A, Sakurada, Y, Yoneyama, S, Takasago, Y, Hata, M, Muraoka, Y, Nakanishi, H, Oishi, A, Ooto, S, Tamura, H, Uji, A, Miyata, M, Takahashi, A, Ueda-Arakawa, N, Tajima, A, Sato, T, Mizuki, N, Shiragami, C, Iida, T, Khor, CC, Wong, TY, Yamada, R, Honda, S, de Jong, EK, Hollander, AID, Matsuda, F, Yamashiro, K, and Tsujikawa, A
Abstract: The recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10-13; rs6061548, odds ratio = 1.63, P = 5.36 × 10-15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.
Published: 2019

15. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies.

Author: Dorajoo, R, Chang, X, Gurung, RL, Li, Z, Wang, L, Wang, R, Beckman, KB, Adams-Haduch, J, M, Y, Liu, S, Meah, WY, Sim, KS, Lim, SC, Friedlander, Y, Liu, J, van Dam, RM, Yuan, J-M, Koh, W-P, Khor, CC, Heng, C-K, Dorajoo, R, Chang, X, Gurung, RL, Li, Z, Wang, L, Wang, R, Beckman, KB, Adams-Haduch, J, M, Y, Liu, S, Meah, WY, Sim, KS, Lim, SC, Friedlander, Y, Liu, J, van Dam, RM, Yuan, J-M, Koh, W-P, Khor, CC, and Heng, C-K
Abstract: Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10-8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10-7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10-4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.
Published: 2019

16. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author: Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, van Duijn, CM, Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, and van Duijn, CM
Abstract: A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
Published: 2019

17. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, and Whittaker, P
Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019

18. Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study

Author: Universitat Rovira i Virgili, Huang T, Wang T, Zheng Y, Ellervik C, Li X, Gao M, Fang Z, Chai JF, Ahluwalia TVS, Wang Y, Voortman T, Noordam R, Frazier-Wood A, Scholz M, Sonestedt E, Akiyama M, Dorajoo R, Zhou A, Kilpeläinen TO, Kleber ME, Crozier SR, Godfrey KM, Lemaitre R, Felix JF, Shi Y, Gupta P, Khor CC, Lehtimäki T, Wang CA, Tiesler CMT, Thiering E, Standl M, Rzehak P, Marouli E, He M, Lecoeur C, Corella D, Lai CQ, Moreno LA, Pitkänen N, Boreham CA, Zhang T, Saw SM, Ridker PM, Graff M, van Rooij FJA, Uitterlinden AG, Hofman A, van Heemst D, Rosendaal FR, de Mutsert R, Burkhardt R, Schulz CA, Ericson U, Kamatani Y, Yuan JM, Power C, Hansen T, Sørensen TIA, Tjønneland A, Overvad K, Delgado G, Cooper C, Djousse L, Rivadeneira F, Jameson K, Zhao W, Liu J, Lee NR, Raitakari O, Kähönen M, Viikari J, Grote V, Langhendries JP, Koletzko B, Escribano J, Verduci E, Dedoussis G, Yu C, Tham YC, Lim B, Lim SH, Froguel P, Balkau B, Fink NR, Vinding RK, Sevelsted A, Bisgaard H, Coltell O, Dallongeville J, Gottrand F, Pahkala K, Niinikoski H, Hyppönen E, Pedersen O, März W, Inskip H, Jaddoe VWV, Dennison E, Wong TY, Sabanayagam C, Tai ES, Mohlke KL, Mackey DA, Gruszfeld D, Deloukas P, Tucker KL, Fumeron F, Bønnelykke K, Rossing P, Estruch R, Ordovas JM, Arnett DK, Meirhaeghe A, Amouyel P, Cheng CY, Sim X, Teo YY, van Dam RM, Koh WP, Orho-Melander M, Loeffler M, Kubo M, Thiery J, Mook-Kanamori DO, Mozaffarian D, Psaty BM, Franco OH, Wu T, North KE, Davey Smith G, Chavarro JE, Chasman DI, Qi L BIRTH-GENE (BIG) Study Working Group, Universitat Rovira i Virgili, and Huang T, Wang T, Zheng Y, Ellervik C, Li X, Gao M, Fang Z, Chai JF, Ahluwalia TVS, Wang Y, Voortman T, Noordam R, Frazier-Wood A, Scholz M, Sonestedt E, Akiyama M, Dorajoo R, Zhou A, Kilpeläinen TO, Kleber ME, Crozier SR, Godfrey KM, Lemaitre R, Felix JF, Shi Y, Gupta P, Khor CC, Lehtimäki T, Wang CA, Tiesler CMT, Thiering E, Standl M, Rzehak P, Marouli E, He M, Lecoeur C, Corella D, Lai CQ, Moreno LA, Pitkänen N, Boreham CA, Zhang T, Saw SM, Ridker PM, Graff M, van Rooij FJA, Uitterlinden AG, Hofman A, van Heemst D, Rosendaal FR, de Mutsert R, Burkhardt R, Schulz CA, Ericson U, Kamatani Y, Yuan JM, Power C, Hansen T, Sørensen TIA, Tjønneland A, Overvad K, Delgado G, Cooper C, Djousse L, Rivadeneira F, Jameson K, Zhao W, Liu J, Lee NR, Raitakari O, Kähönen M, Viikari J, Grote V, Langhendries JP, Koletzko B, Escribano J, Verduci E, Dedoussis G, Yu C, Tham YC, Lim B, Lim SH, Froguel P, Balkau B, Fink NR, Vinding RK, Sevelsted A, Bisgaard H, Coltell O, Dallongeville J, Gottrand F, Pahkala K, Niinikoski H, Hyppönen E, Pedersen O, März W, Inskip H, Jaddoe VWV, Dennison E, Wong TY, Sabanayagam C, Tai ES, Mohlke KL, Mackey DA, Gruszfeld D, Deloukas P, Tucker KL, Fumeron F, Bønnelykke K, Rossing P, Estruch R, Ordovas JM, Arnett DK, Meirhaeghe A, Amouyel P, Cheng CY, Sim X, Teo YY, van Dam RM, Koh WP, Orho-Melander M, Loeffler M, Kubo M, Thiery J, Mook-Kanamori DO, Mozaffarian D, Psaty BM, Franco OH, Wu T, North KE, Davey Smith G, Chavarro JE, Chasman DI, Qi L BIRTH-GENE (BIG) Study Working Group
Abstract: Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose
Published: 2019

19. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing

Author: CRyPTIC Consortium, 100000 Genomes Project, Allix-Beguec, C, Arandjelovic, I, Bi, L, Beckert, P, Bonnet, M, Bradley, P, Cabibbe, AM, Cancino-Munoz, I, Caulfield, MJ, Chaiprasert, A, Cirillo, DM, Clifton, D, Comas, I, Crook, DW, De Filippo, MR, de Neeling, H, Diel, R, Drobniewski, FA, Faksri, K, Farhat, MR, Fleming, J, Fowler, P, Fowler, TA, Gao, Q, Gardy, J, Gascoyne-Binzi, D, Gibertoni-Cruz, A-L, Gil-Brusola, A, Golubchik, T, Gonzalo, X, Grandjean, L, He, G, Guthrie, JL, Hoosdally, S, Hunt, M, Iqbal, Z, Ismail, N, Johnston, J, Khanzada, FM, Khor, CC, Kohl, TA, Kong, C, Lipworth, S, Liu, Q, Maphalala, G, Martinez, E, Mathys, V, Merker, M, Miotto, P, Mistry, N, Moore, DAJ, Murray, M, Niemann, S, Ong, RT-H, Peto, TEA, Posey, JE, Prammananan, T, Pym, A, Rodrigues, C, Rodrigues, M, Rodwell, T, Rossolini, GM, Padilla, ES, Schito, M, Shen, X, Shendure, J, Sintchenko, V, Sloutsky, A, Smith, EG, Snyder, M, Soetaert, K, Starks, AM, Supply, P, Suriyapol, P, Tahseen, S, Tang, P, Teo, Y-Y, Thuong, TNT, Thwaites, G, Tortoli, E, Omar, SV, van Soolingen, D, Walker, AS, Walker, TM, Wilcox, M, Wilson, DJ, Wyllie, D, Yang, Y, Zhang, H, Zhao, Y, and Zhu, B
Abstract: Background: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.\ud \ud \ud \ud Methods: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.\ud \ud \ud \ud Results: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted.\ud \ud \ud \ud Conclusions: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.)
Published: 2018

20. CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy

Author: Hosoda, Y, Yoshikawa, M, Miyake, M, Tabara, Y, Ahn, J, Woo, SJ, Honda, S, Sakurada, Y, Shiragami, C, Nakanishi, H, Oishi, A, Ooto, S, Miki, A, Iida, T, Iijima, H, Nakamura, M, Khor, CC, Wong, TY, Song, K, Park, KH, Yamada, R, Matsuda, F, Tsujikawa, A, Yamashiro, K, Hosoda, Y, Yoshikawa, M, Miyake, M, Tabara, Y, Ahn, J, Woo, SJ, Honda, S, Sakurada, Y, Shiragami, C, Nakanishi, H, Oishi, A, Ooto, S, Miki, A, Iida, T, Iijima, H, Nakamura, M, Khor, CC, Wong, TY, Song, K, Park, KH, Yamada, R, Matsuda, F, Tsujikawa, A, and Yamashiro, K
Abstract: Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10-10 and 6.75 × 10-8, respectively). Case-control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10-5 and 5.14 × 10-5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.
Published: 2018

21. Frequent transmission of the Mycobacterium tuberculosis Beijing lineage and positive selection for the EsxW Beijing variant in Vietnam

Author: Holt, KE, McAdam, P, Phan, VKT, Nguyen, TTT, Dang, TMH, Nguyen, NL, Nguyen, HL, Nguyen, TQN, Hoang, TH, Vu, TNH, Thwaites, G, Edwards, DJ, Nath, AP, Pham, K, Ascher, DB, Farrar, J, Khor, CC, Teo, YY, Inouye, M, Caws, M, Dunstan, SJ, Holt, KE, McAdam, P, Phan, VKT, Nguyen, TTT, Dang, TMH, Nguyen, NL, Nguyen, HL, Nguyen, TQN, Hoang, TH, Vu, TNH, Thwaites, G, Edwards, DJ, Nath, AP, Pham, K, Ascher, DB, Farrar, J, Khor, CC, Teo, YY, Inouye, M, Caws, M, and Dunstan, SJ
Abstract: To examine the transmission dynamics of Mycobacterium tuberculosis (Mtb) isolated from tuberculosis patients in Ho Chi Minh City, Vietnam, we sequenced the whole genomes of 1,635 isolates and compared these with 3,144 isolates from elsewhere. The data identify an underlying burden of disease caused by the endemic Mtb lineage 1 associated with the activation of long-term latent infection, and a threefold higher burden associated with the more recently introduced Beijing lineage and lineage 4 Mtb strains. We find that Beijing lineage Mtb is frequently transferred between Vietnam and other countries, and detect higher levels of transmission of Beijing lineage strains within this host population than the endemic lineage 1 Mtb. Screening for parallel evolution of Beijing lineage-associated SNPs in other Mtb lineages as a signal of positive selection, we identify an alteration in the ESX-5 type VII-secreted protein EsxW, which could potentially contribute to the enhanced transmission of Beijing lineage Mtb in Vietnamese and other host populations.
Published: 2018

22. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, and MacGregor, S
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018

23. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Author: Feitosa, MF, Kraja, AT, Chasman, DI, Sung, YJ, Winkler, TW, Ntalla, I, Guo, XQ, Franceschini, N, Cheng, CY (Ching-Yu), Sim, XL, Vojinovic, Dina, Marten, J, Musani, SK, Li, CW, Bentley, AR, Brown, MR, Schwander, K, Richard, MA, Noordam, R, Aschard, H, Bartz, TM, Bielak, LF, Dorajoo, R, Fisher, V, Hartwig, FP, Horimoto, A, Lohman, KK, Manning, AK, Rankinen, T, Smith, AV, Tajuddin, S M, Wojczynski, MK, Alver, M, Boissel, M, Cai, QY, Campbell, A (Archie), Chai, JF, Chen, X, Divers, J, Gao, C, Goel, A, Hagemeijer, Y, Harris, SE, He, MI, Hsu, FC, Jackson, AU, Kahonen, M, Kasturiratne, A, Komulainen, P, Kuhnel, B, Laguzzi, F, Luan, J, Matoba, N, Nolte, IM, Padmanabhan, S, Riaz, M, Rueedi, R, Robino, A, Said, MA, Scott, RA, Sofer, T, Stancakova, A, Takeuchi, F, Tayo, BO, van der Most, PJ, Varga, TV, Vitart, V, Wang, YJ, Ware, EB, Warren, HR, Weiss, S, Wen, WQ, Yanek, LR, Zhang, WH, Zhao, JH, Afaq, S, Amin, Najaf, Amini, M, Arking, DE, Aung, T, Boerwinkle, E, Borecki, I, Broeckel, U, Brown, M, Brumat, M, Burke, GL, Canouil, M, Chakravarti, A, Charumathi, S, Chen, YDI, Connell, JM, Correa, A, Fuentes, LDL, de Mutsert, R, de Silva, HJ, Deng, X, Ding, J, Duan, Q, Eaton, CB, Ehret, G, Eppinga, RN, Evangelou, E, Fau, JD, Felix, SB, Forouhi, NG, Forrester, T, Franco Duran, OH, Friedlander, Y, Gandin, I, Gao, H, Ghanbari, Mohsen, Gigante, B, Gu, CC, Gu, DF, Hagenaars, SP, Hallmans, G, Harris, TB, He, J, Heikkinen, S, Heng, CK, Hirata, M, Howard, BV, Ikram, Arfan, John, U, Katsuya, T, Khor, CC, Kilpelainen, TO, Koh, WP, Krieger, JE, Kritchevsky, SB, Kubo, M, Kuusisto, J, Lakka, TA, Langefeld, CD, Langenberg, C, Launer, LJ, Lehne, B, Lewis, CE, Li, YZ, Lin, S, Liu, JJ, Liu, JM, Loh, M, Louie, T, Magi, R, McKenzie, CA, Meitinger, T, Metspalu, A, Milaneschi, Y, Milani, L, Mohlke, KL, Momozawa, Y, Nalls, MA, Nelson, CP, Sotoodehnia, N, Norris, JM, O'Connell, JR, Palmer, ND, Perls, T, Pedersen, NL, Peters, A, Peyser, PA, Poulter, N, Raffel, LJ, Raitakari, OT, Roll, K, Rose, LM, Rosendaal, FR, Rotter, JI, Schmidt, CO, Schreiner, PJ, Schupf, N, Scott, WR, Sever, PS, Shi, Y, Sidney, S, Sims, M, Sitlani, CM, Smith, JA, Snieder, H, Starr, JM, Strauch, K, Stringham, HM, Tan, NYQ, Tang, H, Taylor, KD, Teo, YY, Tham, YC, Turner, ST, Uitterlinden, André, Vollenweider, P, Waldenberger, M, Wang, LH, Wang, YX, Wei, W, Williams, C, Yao, J, Yu, CZ, Yuan, JM, Zhao, W, Zonderman, AB, Becker, DM, Boehnke, M, Bowden, DW, Chambers, JC, Deary, IJ, Esko, T, Farrall, M, Franks, PW, Freedman, BI, Froguel, P, Gasparini, P, Gieger, C, Jonas, JB, Kamatani, Y, Kato, N, Kooner, JS, Kutalik, Z, Laakso, M, Laurie, CC, Leander, K, Lehtimaki, T, Study, LC, Magnusson, PKE, Oldehinkel, AJ, Penninx, B, Poiasek, O, Porteous, DJ, Rauramaa, R, Samani, NJ, Scott, J, Shu, XO, van der Harst, P, Wagenknecht, LE, Wareham, NJ, Watkins, H, Weir, DR, Wickremasinghe, AR, Wu, TC, Zheng, W, Bouchard, C, Christensen, K, Evans, MK, Gudnason, V, Horta, BL, Kardia, SLR, Liu, YM, Pereira, AC, Psaty, BM, Ridker, PM, van Dam, RM, Gauderman, WJ, Zhu, XF, Mook, Dennis, Fornage, M, Rotimi, CN, Cupples, LA, Kelly, TN, Fox, ER, Hayward, C, Duijn, Cornelia, Tai, ES, Wong, TY, Kooperberg, C, Palmas, W, Rice, K, Morrison, AC, Elliott, P, Caulfield, MJ, Munroe, PB, Rao, DC, Province, MA, Levy, D, Feitosa, MF, Kraja, AT, Chasman, DI, Sung, YJ, Winkler, TW, Ntalla, I, Guo, XQ, Franceschini, N, Cheng, CY (Ching-Yu), Sim, XL, Vojinovic, Dina, Marten, J, Musani, SK, Li, CW, Bentley, AR, Brown, MR, Schwander, K, Richard, MA, Noordam, R, Aschard, H, Bartz, TM, Bielak, LF, Dorajoo, R, Fisher, V, Hartwig, FP, Horimoto, A, Lohman, KK, Manning, AK, Rankinen, T, Smith, AV, Tajuddin, S M, Wojczynski, MK, Alver, M, Boissel, M, Cai, QY, Campbell, A (Archie), Chai, JF, Chen, X, Divers, J, Gao, C, Goel, A, Hagemeijer, Y, Harris, SE, He, MI, Hsu, FC, Jackson, AU, Kahonen, M, Kasturiratne, A, Komulainen, P, Kuhnel, B, Laguzzi, F, Luan, J, Matoba, N, Nolte, IM, Padmanabhan, S, Riaz, M, Rueedi, R, Robino, A, Said, MA, Scott, RA, Sofer, T, Stancakova, A, Takeuchi, F, Tayo, BO, van der Most, PJ, Varga, TV, Vitart, V, Wang, YJ, Ware, EB, Warren, HR, Weiss, S, Wen, WQ, Yanek, LR, Zhang, WH, Zhao, JH, Afaq, S, Amin, Najaf, Amini, M, Arking, DE, Aung, T, Boerwinkle, E, Borecki, I, Broeckel, U, Brown, M, Brumat, M, Burke, GL, Canouil, M, Chakravarti, A, Charumathi, S, Chen, YDI, Connell, JM, Correa, A, Fuentes, LDL, de Mutsert, R, de Silva, HJ, Deng, X, Ding, J, Duan, Q, Eaton, CB, Ehret, G, Eppinga, RN, Evangelou, E, Fau, JD, Felix, SB, Forouhi, NG, Forrester, T, Franco Duran, OH, Friedlander, Y, Gandin, I, Gao, H, Ghanbari, Mohsen, Gigante, B, Gu, CC, Gu, DF, Hagenaars, SP, Hallmans, G, Harris, TB, He, J, Heikkinen, S, Heng, CK, Hirata, M, Howard, BV, Ikram, Arfan, John, U, Katsuya, T, Khor, CC, Kilpelainen, TO, Koh, WP, Krieger, JE, Kritchevsky, SB, Kubo, M, Kuusisto, J, Lakka, TA, Langefeld, CD, Langenberg, C, Launer, LJ, Lehne, B, Lewis, CE, Li, YZ, Lin, S, Liu, JJ, Liu, JM, Loh, M, Louie, T, Magi, R, McKenzie, CA, Meitinger, T, Metspalu, A, Milaneschi, Y, Milani, L, Mohlke, KL, Momozawa, Y, Nalls, MA, Nelson, CP, Sotoodehnia, N, Norris, JM, O'Connell, JR, Palmer, ND, Perls, T, Pedersen, NL, Peters, A, Peyser, PA, Poulter, N, Raffel, LJ, Raitakari, OT, Roll, K, Rose, LM, Rosendaal, FR, Rotter, JI, Schmidt, CO, Schreiner, PJ, Schupf, N, Scott, WR, Sever, PS, Shi, Y, Sidney, S, Sims, M, Sitlani, CM, Smith, JA, Snieder, H, Starr, JM, Strauch, K, Stringham, HM, Tan, NYQ, Tang, H, Taylor, KD, Teo, YY, Tham, YC, Turner, ST, Uitterlinden, André, Vollenweider, P, Waldenberger, M, Wang, LH, Wang, YX, Wei, W, Williams, C, Yao, J, Yu, CZ, Yuan, JM, Zhao, W, Zonderman, AB, Becker, DM, Boehnke, M, Bowden, DW, Chambers, JC, Deary, IJ, Esko, T, Farrall, M, Franks, PW, Freedman, BI, Froguel, P, Gasparini, P, Gieger, C, Jonas, JB, Kamatani, Y, Kato, N, Kooner, JS, Kutalik, Z, Laakso, M, Laurie, CC, Leander, K, Lehtimaki, T, Study, LC, Magnusson, PKE, Oldehinkel, AJ, Penninx, B, Poiasek, O, Porteous, DJ, Rauramaa, R, Samani, NJ, Scott, J, Shu, XO, van der Harst, P, Wagenknecht, LE, Wareham, NJ, Watkins, H, Weir, DR, Wickremasinghe, AR, Wu, TC, Zheng, W, Bouchard, C, Christensen, K, Evans, MK, Gudnason, V, Horta, BL, Kardia, SLR, Liu, YM, Pereira, AC, Psaty, BM, Ridker, PM, van Dam, RM, Gauderman, WJ, Zhu, XF, Mook, Dennis, Fornage, M, Rotimi, CN, Cupples, LA, Kelly, TN, Fox, ER, Hayward, C, Duijn, Cornelia, Tai, ES, Wong, TY, Kooperberg, C, Palmas, W, Rice, K, Morrison, AC, Elliott, P, Caulfield, MJ, Munroe, PB, Rao, DC, Province, MA, and Levy, D
Published: 2018

24. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, Macgregor, S, Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, and Macgregor, S
Published: 2018

25. Plasma lipoprotein subfraction concentrations are associated with lipid metabolism and age-related macular degeneration.

Author: Cheung, CMG, Gan, A, Fan, Q, Chee, ML, Apte, RS, Khor, CC, Yeo, I, Mathur, R, Cheng, C-Y, Wong, TY, Tai, ES, Cheung, CMG, Gan, A, Fan, Q, Chee, ML, Apte, RS, Khor, CC, Yeo, I, Mathur, R, Cheng, C-Y, Wong, TY, and Tai, ES
Abstract: Disturbance in lipid metabolism has been suggested as a major pathogenic factor for age-related macular degeneration (AMD). Conventional lipid measures have been inconsistently associated with AMD. Other factors that can alter lipid metabolism include lipoprotein phenotype and genetic mutations. We performed a case-control study to examine the association between lipoprotein profile and neovascular AMD (nAMD) and whether the cholesterylester transfer protein (CETP) D442G mutation modulates these associations. Patients with nAMD had significantly higher concentrations of HDL and IDL compared with controls. The increase in HDL particles in nAMD patients was driven by an excess of medium-sized particles. Concurrently, patients with nAMD also had lower Apo A-1, lower VLDL and chylomicron lipoprotein. Many of these associations showed a dose-dependent association between controls, early AMD cases, and nAMD cases. Adjustment for the presence of the D442G mutation at the CETP locus did not significantly alter the increased AMD risk associated with HDL particle concentration. AMD is associated with variation in many lipoprotein subclasses, including increased HDL and IDL particles and decreased Apo A-1, VLDL, and chylomicron particles. These data suggest widespread systemic disturbance in lipid metabolism in the pathogenesis of AMD, including possible alterations in lipoprotein carrier capacity.
Published: 2017

26. HDL-cholesterol levels and risk of age-related macular degeneration: a multiethnic genetic study using Mendelian randomization.

Author: Fan, Q, Maranville, JC, Fritsche, L, Sim, X, Cheung, CMG, Chen, LJ, Gorski, M, Yamashiro, K, Ahn, J, Laude, A, Dorajoo, R, Lim, TH, Teo, Y-Y, Blaustein, RO, Yoshimura, N, Park, K-H, Pang, CP, Tai, ES, Khor, CC, Wong, TY, Runz, H, Cheng, C-Y, Fan, Q, Maranville, JC, Fritsche, L, Sim, X, Cheung, CMG, Chen, LJ, Gorski, M, Yamashiro, K, Ahn, J, Laude, A, Dorajoo, R, Lim, TH, Teo, Y-Y, Blaustein, RO, Yoshimura, N, Park, K-H, Pang, CP, Tai, ES, Khor, CC, Wong, TY, Runz, H, and Cheng, C-Y
Abstract: BACKGROUND: Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results. METHODS: We investigated the causal role of plasma lipid levels in AMD in multiethnic populations comprising 16 144 advanced AMD cases and 17 832 controls of European descent, together with 2219 cases and 5275 controls of Asian descent, using Mendelian randomization in three models. Model 1 is a conventional meta-analysis which does not account for pleiotropy of instrumental variable (IV) effects. Model 2 is a univariate, inverse variance weighted regression analysis that accounts for potential unbalanced pleiotropy using MR-Egger method. Finally, Model 3 is a multivariate regression analysis that addresses pleiotropy by MR-Egger method and by adjusting for effects on other lipid traits. RESULTS: A 1 standard deviation (SD) higher HDL-cholesterol level was associated with an odds ratio (OR) for AMD of 1.17 (95% confidence interval: 1.07-1.29) in Europeans (P = 6.88 × 10-4) and of 1.58 (1.24-2.00) in Asians (P = 2.92 × 10-4) in Model 3. The corresponding OR estimates were 1.30 (1.09-1.55) in Europeans (P = 3.18 × 10-3) and 1.42 (1.11-1.80) in Asians (P = 4.42 × 10-3) in Model 1, and 1.21 (1.11-1.31) in Europeans (P = 3.12 × 10-5) and 1.51 (1.20-1.91) in Asians (P = 7.61 × 10-4) in Model 2. Conversely, neither LDL-C (Europeans: OR = 0.96, P = 0.272; Asians: OR = 1.02, P = 0.874; Model 3) nor triglyceride levels (Europeans: OR = 0.91, P = 0.102; Asians: OR = 1.06, P = 0.613) were associated with AMD. We also assessed the association between lipid levels and polypoidal choroidal vasculopathy (PCV) in Asians, a subtype of AMD, and found a similar trend for association of PCV with HDL-C levels. CONCLUSIONS: Our study shows that high levels of plasma HDL-C are causally associated with an increased ri
Published: 2017

27. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Author: Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, Macgregor, S, Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, and Macgregor, S
Published: 2017

28. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma

Author: Khor, CC, Do, T, Jia, H, Nakano, M, George, R, Abu-Amero, K, Duvesh, R, Chen, LJ, Li, Z, Nongpiur, ME, Perera, SA, Qiao, C, Wong, HT, Sakai, H, De Melo, MB, Lee, MC, SChan, A, Azhany, Y, Dao, TLH, Ikeda, Y, Perez-Grossmann, RA, Zarnowski, T, Day, AC, Jonas, JB, Tam, POS, Tran, TA, Ayub, H, Akhtar, F, Micheal, S, Chew, PTK, Aljasim, LA, Dada, T, Luu, TT, Awadalla, MS, Kitnarong, N, Wanichwecharungruang, B, Aung, YY, Mohamed-Noor, J, Vijayan, S, Sarangapani, S, Husain, R, Jap, A, Baskaran, M, Goh, D, Su, DH, Wang, H, Yong, VK, Yip, LW, Trinh, TB, Makornwattana, M, Nguyen, TT, Leuenberger, EU, Park, KH, Wiyogo, WA, SKumar, R, Tello, C, Kurimoto, Y, Thapa, SS, Pathanapitoon, K, Salmon, JF, Sohn, YH, Fea, A, Ozaki, M, Lai, JSM, Tantisevi, V, Khaing, CC, Mizoguchi, T, Nakano, S, Kim, CY, Tang, G, Fan, S, Wu, R, Meng, H, Nguyen, TTG, Tran, TD, Ueno, M, Martinez, JM, Ramli, N, Aung, YM, Reyes, RD, Vernon, SA, Fang, SK, Xie, Z, Chen, XY, and Foo, JN
Abstract: © 2016 Nature America, Inc.Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10 -5), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10 -6), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10 -4), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10 -1), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10 -2). We also confirmed significant association at three previously described loci (P < 5 × 10 â'8 for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.
Published: 2016

29. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Author: Bailey, JNC, Loomis, SJ, Kang, JH, Allingham, RR, Gharahkhani, P, Khor, CC, Burdon, KP, Aschard, H, Chasman, DI, Igo, RP, Hysi, PG, Glastonbury, CA, Ashley-Koch, A, Brilliant, M, Brown, AA, Budenz, DL, Buil, A, Cheng, CY, Choi, H, Christen, WG, Curhan, G, De Vivo, I, Fingert, JH, Foster, PJ, Fuchs, C, Gaasterland, D, Gaasterland, T, Hewitt, AW, Hu, F, Hunter, DJ, Khawaja, AP, Lee, RK, Li, Z, Lichter, PR, Mackey, DA, McGuffin, P, Mitchell, P, Moroi, SE, Perera, SA, Pepper, KW, Qi, Q, Realini, T, Richards, JE, Ridker, PM, Rimm, E, Ritch, R, Ritchie, M, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Song, YE, Tamimi, RM, Topouzis, F, Viswanathan, AC, Verma, SS, Vollrath, D, Wang, JJ, Weisschuh, N, Wissinger, B, Wollstein, G, Wong, TY, Yaspan, BL, Zack, DJ, Zhang, K, Weinreb, RN, Pericak-Vance, MA, Small, K, Hammond, CJ, Aung, T, Liu, Y, Vithana, EN, MacGregor, S, Craig, JE, Kraft, P, Howell, G, Hauser, MA, and Pasquale, LR
Subjects: ANZRAG Consortium
Abstract: © 2016 Nature America, Inc. Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10 -11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10 -10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10 -10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
Published: 2016

30. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author: Springelkamp, H, Mishra, A, Hysi, PG, Gharahkhani, P, Höhn, R, Khor, CC, Cooke Bailey, JN, Luo, X, Ramdas, WD, Vithana, E, Koh, V, Yazar, S, Xu, L, Forward, H, Kearns, LS, Amin, N, Iglesias, AI, Sim, KS, van Leeuwen, EM, Demirkan, A, van der Lee, S, Loon, SC, Rivadeneira, F, Nag, A, Sanfilippo, PG, Schillert, A, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Zhou, T, Burdon, KP, Spector, TD, Lackner, KJ, Saw, SM, Vingerling, JR, Teo, YY, Pasquale, LR, Wolfs, RCW, Lemij, HG, Tai, ES, Jonas, JB, Cheng, CY, Aung, T, Jansonius, NM, Klaver, CCW, Craig, JE, Young, TL, Haines, JL, Macgregor, S, Mackey, DA, Pfeiffer, N, Wong, TY, Wiggs, JL, Hewitt, AW, van Duijn, CM, Hammond, CJ, Allingham, RR, Brilliant, MH, Budenz, DL, Bailey, JNC, Christen, WG, and Fingert, J
Subjects: genetic structures, sense organs, eye diseases
Abstract: © 2015 Wiley Periodicals, Inc. Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.
Published: 2015

31. Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer.

Author: Ng, T, Teo, SM, Yeo, HL, Shwe, M, Gan, YX, Cheung, YT, Foo, KM, Cham, MT, Lee, JA, Tan, YP, Fan, G, Yong, WS, Preetha, M, Loh, W-JK, Koo, S-L, Jain, A, Lee, GE, Wong, M, Dent, R, Yap, YS, Ng, R, Khor, CC, Ho, HK, Chan, A, Ng, T, Teo, SM, Yeo, HL, Shwe, M, Gan, YX, Cheung, YT, Foo, KM, Cham, MT, Lee, JA, Tan, YP, Fan, G, Yong, WS, Preetha, M, Loh, W-JK, Koo, S-L, Jain, A, Lee, GE, Wong, M, Dent, R, Yap, YS, Ng, R, Khor, CC, Ho, HK, and Chan, A
Abstract: BACKGROUND: Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment. METHODS: Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates. RESULTS: Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08-0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12-0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15-0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism. CONCLUSIONS: This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.
Published: 2016

32. Complete human CD1a deficiency on Langerhans cells due to a rare point mutation in the coding sequence

Author: Cerny, D, Duyen, HTL, Trung, DT, Zuest, R, Srinivasan, KG, Velumani, S, Khor, CC, Mori, L, Simmons, CP, Poidinger, M, Zolezzi, F, Ginhoux, F, Haniffa, M, Wills, B, Fink, K, Cerny, D, Duyen, HTL, Trung, DT, Zuest, R, Srinivasan, KG, Velumani, S, Khor, CC, Mori, L, Simmons, CP, Poidinger, M, Zolezzi, F, Ginhoux, F, Haniffa, M, Wills, B, and Fink, K
Published: 2016

33. Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies

Author: Martinon-Torres, F, Png, E, Khor, CC, Davila, S, Wright, VJ, Sim, KS, Vega, A, Fachal, L, Inwald, D, Nadel, S, Carrol, ED, Martinon-Torres, N, Marcos Alonso, S, Carracedo, A, Morteruel, E, Lopez-Bayon, J, Concha Torre, A, Calvo Monge, C, Gonzalez de Aguilar, PA, Esteban Torne, E, del Carmen Martinez-Padilla, M, Maria Martinon-Sanchez, J, Levin, M, Hibberd, ML, Salas, A, Martinon-Torres, F, Png, E, Khor, CC, Davila, S, Wright, VJ, Sim, KS, Vega, A, Fachal, L, Inwald, D, Nadel, S, Carrol, ED, Martinon-Torres, N, Marcos Alonso, S, Carracedo, A, Morteruel, E, Lopez-Bayon, J, Concha Torre, A, Calvo Monge, C, Gonzalez de Aguilar, PA, Esteban Torne, E, del Carmen Martinez-Padilla, M, Maria Martinon-Sanchez, J, Levin, M, Hibberd, ML, and Salas, A
Abstract: Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10-8) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10-9). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10-8). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.
Published: 2016

34. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error

Author: Fan, Q, Verhoeven, Virginie, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hohn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y (Yi), Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, XB, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, TH, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, Leeuwen, Elisa, Amin, Najaf, Uitterlinden, André, Rivadeneira, Fernando, Hofman, Bert, Vingerling, Hans, Wang, YX, Wang, X, Boh, ETH, Ikram, Kamran, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, ES, Vithana, E, Mihailov, E, Khor, CC, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, HS, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, MG, Paerssinen, O, Duijn, Cornelia, Wang, JJ, Williams, C, Jonas, JB, Teo, YY, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, TY (Tien Yin), Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, CY (Ching-Yu), Hammond, CJ, Klaver, Caroline, Saw, SM, Rahi, JS, Korobelnik, JF, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, Macgregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, KT, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, MF, Li, XH, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, Willem, Tedja, M, DeAngelis, MM, Morrison, M, Farrer, L, Zhou, XT, Chen, W, Mizuki, N, Meguro, A, Makela, KM, Fan, Q, Verhoeven, Virginie, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hohn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y (Yi), Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, XB, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, TH, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, Leeuwen, Elisa, Amin, Najaf, Uitterlinden, André, Rivadeneira, Fernando, Hofman, Bert, Vingerling, Hans, Wang, YX, Wang, X, Boh, ETH, Ikram, Kamran, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, ES, Vithana, E, Mihailov, E, Khor, CC, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, HS, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, MG, Paerssinen, O, Duijn, Cornelia, Wang, JJ, Williams, C, Jonas, JB, Teo, YY, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, TY (Tien Yin), Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, CY (Ching-Yu), Hammond, CJ, Klaver, Caroline, Saw, SM, Rahi, JS, Korobelnik, JF, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, Macgregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, KT, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, MF, Li, XH, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, Willem, Tedja, M, DeAngelis, MM, Morrison, M, Farrer, L, Zhou, XT, Chen, W, Mizuki, N, Meguro, A, and Makela, KM
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP x education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P < 8.5 x 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Published: 2016

35. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Author: Springelkamp, H, Höhn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, X, Ramdas, WD, Vithana, E, Nongpiur, ME, Montgomery, GW, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y, Amin, N, Karssen, LC, Sim, KS, Van Leeuwen, EM, Iglesias, AI, Verhoeven, VJM, Hauser, MA, Loon, SC, Despriet, DDG, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Van Koolwijk, LME, Rivadeneira, F, Souzeau, E, Jonsson, V, Menon, G, Mitchell, P, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Weinreb, RN, De Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Haines, JL, Kraft, P, Lee, RK, Lichter, PR, and Liu, Y
Subjects: genetic structures, sense organs, eye diseases
Abstract: © 2014 Macmillan Publishers Limited. All rights reserved. Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Published: 2014

36. Lens status influences the association between CFH polymorphisms and age-related macular degeneration: findings from two population-based studies in Singapore.

Author: Wong, CW, Liao, J, Cheung, GC, Khor, CC, Vithana, EN, Wang, JJ, Mitchell, P, Aung, T, Wong, TY, Cheng, C-Y, Wong, CW, Liao, J, Cheung, GC, Khor, CC, Vithana, EN, Wang, JJ, Mitchell, P, Aung, T, Wong, TY, and Cheng, C-Y
Abstract: AIMS: To determine the differential effects of genetic polymorphism in CFH and ARMS2 on risk of age-related macular degeneration (AMD) between phakic vs. pseudophakic/aphakic eyes. METHODS: 9,529 eyes of 4,918 participants from the Singapore Malay Eye Study and Singapore Indian Eye Study were analyzed. Participants had detailed eye examinations, including slit-lamp examinations and dilated fundus photography. AMD grading was performed according to the Wisconsin age-related maculopathy grading system. Lens status was defined. Single nucleotide polymorphisms (SNPs) rs10801555 (Y402H) within CFH and rs3750847 in ARMS2 were assessed. The main outcome measure was early AMD or any AMD. RESULTS: No significant associations between the CFH Y402H genotypes and early AMD were found in phakic individuals. In contrast, among pseudophakic/aphakic individuals, the CFH Y402H risk genotypes were significantly associated with higher odds of early AMD, with an OR of 1.57 (95% CI: 1.07-2.29) for GA genotype and 2.40 (95% CI: 1.25-4.61) for AA genotype, compared to those with GG genotype. There was significant interaction between pseudophakic/aphakic status and CFH Y402H variant on risk of early AMD (p = 0.037), adjusting for age, gender, and the first 5 genetic principal components. No significant interaction was found between lens status and ARMS2 rs3750847. CONCLUSIONS: CFH genetic polymorphism and pseudophakic/aphakic status may have a potential synergistic effect on early AMD, suggesting roles for the complement system and related pathways in the pathogenesis of AMD in eyes after cataract surgery.
Published: 2015

37. New loci and coding variants confer risk for age-related macular degeneration in East Asians.

Author: Cheng, C-Y, Yamashiro, K, Chen, LJ, Ahn, J, Huang, L, Cheung, CMG, Miyake, M, Cackett, PD, Yeo, IY, Laude, A, Mathur, R, Pang, J, Sim, KS, Koh, AH, Chen, P, Lee, SY, Wong, D, Chan, CM, Loh, BK, Sun, Y, Davila, S, Nakata, I, Nakanishi, H, Akagi-Kurashige, Y, Gotoh, N, Tsujikawa, A, Matsuda, F, Mori, K, Yoneya, S, Sakurada, Y, Iijima, H, Iida, T, Honda, S, Lai, TYY, Tam, POS, Chen, H, Tang, S, Ding, X, Wen, F, Lu, F, Zhang, X, Shi, Y, Zhao, P, Zhao, B, Sang, J, Gong, B, Dorajoo, R, Yuan, J-M, Koh, W-P, van Dam, RM, Friedlander, Y, Lin, Y, Hibberd, ML, Foo, JN, Wang, N, Wong, CH, Tan, GS, Park, SJ, Bhargava, M, Gopal, L, Naing, T, Liao, J, Ong, PG, Mitchell, P, Zhou, P, Xie, X, Liang, J, Mei, J, Jin, X, Saw, S-M, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Woo, SJ, Chung, H, Yu, H-G, Shin, JY, Park, DH, Kim, IT, Chang, W, Sagong, M, Lee, S-J, Kim, HW, Lee, JE, Li, Y, Liu, J, Teo, YY, Heng, CK, Lim, TH, Yang, S-K, Song, K, Vithana, EN, Aung, T, Bei, JX, Zeng, YX, Tai, ES, Li, XX, Yang, Z, Park, K-H, Pang, CP, Yoshimura, N, Wong, TY, Khor, CC, Cheng, C-Y, Yamashiro, K, Chen, LJ, Ahn, J, Huang, L, Cheung, CMG, Miyake, M, Cackett, PD, Yeo, IY, Laude, A, Mathur, R, Pang, J, Sim, KS, Koh, AH, Chen, P, Lee, SY, Wong, D, Chan, CM, Loh, BK, Sun, Y, Davila, S, Nakata, I, Nakanishi, H, Akagi-Kurashige, Y, Gotoh, N, Tsujikawa, A, Matsuda, F, Mori, K, Yoneya, S, Sakurada, Y, Iijima, H, Iida, T, Honda, S, Lai, TYY, Tam, POS, Chen, H, Tang, S, Ding, X, Wen, F, Lu, F, Zhang, X, Shi, Y, Zhao, P, Zhao, B, Sang, J, Gong, B, Dorajoo, R, Yuan, J-M, Koh, W-P, van Dam, RM, Friedlander, Y, Lin, Y, Hibberd, ML, Foo, JN, Wang, N, Wong, CH, Tan, GS, Park, SJ, Bhargava, M, Gopal, L, Naing, T, Liao, J, Ong, PG, Mitchell, P, Zhou, P, Xie, X, Liang, J, Mei, J, Jin, X, Saw, S-M, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Woo, SJ, Chung, H, Yu, H-G, Shin, JY, Park, DH, Kim, IT, Chang, W, Sagong, M, Lee, S-J, Kim, HW, Lee, JE, Li, Y, Liu, J, Teo, YY, Heng, CK, Lim, TH, Yang, S-K, Song, K, Vithana, EN, Aung, T, Bei, JX, Zeng, YX, Tai, ES, Li, XX, Yang, Z, Park, K-H, Pang, CP, Yoshimura, N, Wong, TY, and Khor, CC
Abstract: Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.
Published: 2015

38. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Author: Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, Virginie, Ikram, MK, Hohn, R, Vitart, V, Hewitt, AW, Oexle, K, Makela, KM, Macgregor, S, Pirastu, M, Fan, Q, Cheng, CY (Ching-Yu), St Pourcain, B, McMahon, G, Kemp, JP, Northstone, K, Rahi, JS, Cumberland, PM, Martin, NG, Sanfilippo, PG, Lu, Y (Yi), Wang, YX, Hayward, C, Polasek, O, Campbell, H, Bencic, G, Wright, AF, Wedenoja, J, Zeller, T, Schillert, A, Mirshahi, A, Lackner, K, Yip, SP, Yap, MKH, Ried, JS, Gieger, C, Murgia, F, Wilson, JF, Fleck, B, Yazar, S, Vingerling, Hans, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Amin, Najaf, Karssen, L, Oostra, Ben, Zhou, X, Teo, YY, Tai, ES, Vithana, E, Barathi, V, Zheng, YF, Siantar, RG, Neelam, K, Shin, YC, Lam, J (Jan), Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, HS, Lehtimaki, T, Kahonen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, CC, Aung, T, Young, TL, Mitchell, P, Klein, B, Duijn, Cornelia, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, SM, Parssinen, O, Stambolian, D, Hammond, CJ, Klaver, Caroline, Williams, C, Paterson, AD, Bailey-Wilson, JE, Guggenheim, JA, Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, Virginie, Ikram, MK, Hohn, R, Vitart, V, Hewitt, AW, Oexle, K, Makela, KM, Macgregor, S, Pirastu, M, Fan, Q, Cheng, CY (Ching-Yu), St Pourcain, B, McMahon, G, Kemp, JP, Northstone, K, Rahi, JS, Cumberland, PM, Martin, NG, Sanfilippo, PG, Lu, Y (Yi), Wang, YX, Hayward, C, Polasek, O, Campbell, H, Bencic, G, Wright, AF, Wedenoja, J, Zeller, T, Schillert, A, Mirshahi, A, Lackner, K, Yip, SP, Yap, MKH, Ried, JS, Gieger, C, Murgia, F, Wilson, JF, Fleck, B, Yazar, S, Vingerling, Hans, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Amin, Najaf, Karssen, L, Oostra, Ben, Zhou, X, Teo, YY, Tai, ES, Vithana, E, Barathi, V, Zheng, YF, Siantar, RG, Neelam, K, Shin, YC, Lam, J (Jan), Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, HS, Lehtimaki, T, Kahonen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, CC, Aung, T, Young, TL, Mitchell, P, Klein, B, Duijn, Cornelia, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, SM, Parssinen, O, Stambolian, D, Hammond, CJ, Klaver, Caroline, Williams, C, Paterson, AD, Bailey-Wilson, JE, and Guggenheim, JA
Abstract: To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged < 25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged < 25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
Published: 2015

39. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Author: Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, MF, Raghavan, S, Lipovich, L, Hidalgo, B, Fox, K, Huffman, JE, An, P, Lu, YC, Rasmussen-Torvik, LJ, Grarup, N, Ehm, MG, Li, Li, Baldridge, AS, Stancakova, A, Abrol, R, Besse, CL, Boland, A, Bork-Jensen, J, Fornage, M, Freitag, DF, Garcia, ME, Guo, XQ, Hara, K, Isaacs, Aaron, Jakobsdottir, J, Lange, LA, Layton, JC, Li, M, Zhao, JH, Meidtner, K, Morrison, AC, Nalls, MA, Peters, Marjolein, Sabater-Lleal, M, Schurmann, C, Silveira, A, Smith, AV, Southam, L, Stoiber, MH, Strawbridge, RJ, Taylor, KD, Varga, TV, Allin, KH, Amin, Najaf, Aponte, JL, Aung, T, Barbieri, C, Bihlmeyer, NA, Boehnke, M, Bombieri, C, Bowden, DW, Burns, SM, Chen, YN, Chen, YD, Cheng, CY (Ching-Yu), Correa, A, Czajkowski, J, Dehghan, Abbas, Ehret, GB, Eiriksdottir, G, Escher, SA, Farmaki, AE, Franberg, M, Gambaro, G, Giulianini, F, Goddard, WA, Goel, A, Gottesman, O, Grove, ML, Gustafsson, S, Hai, Y, Hallmans, G, Heo, J, Hoffmann, P, Ikram, MK, Jensen, RA, Jorgensen, ME, Jorgensen, T, Karaleftheri, M, Khor, CC, Kirkpatrick, A, Kraja, AT, Kuusisto, J, Lange, Edmee, Lee, IT, Lee, WJ, Leong, A, Liao, JM, Liu, CY, Liu, YM, Lindgren, CM, Linneberg, A, Malerba, G, Mamakou, V, Marouli, E, Maruthur, NM, Matchan, A, McKean-Cowdin, R, McLeod, O, Metcalf, GA, Mohlke, KL, Muzny, DM, Ntalla, I, Palmer, ND, Pasko, D, Peter, A, Rayner, NW, Renstrom, F, Rice, K, Sala, CF, Sennblad, B, Serafetinidis, I, Smith, JA, Soranzo, N, Speliotes, EK, Stahl, EA, Stirrups, K, Tentolouris, N, Thanopoulou, A, Torres, M, Traglia, M, Tsafantakis, E, Javad, S, Yanek, LR, Zengini, E, Becker, DM, Bis, JC, Brown, JB, Cupples, LA, Hansen, T, Ingelsson, E, Karter, AJ, Lorenzo, C, Mathias, RA, Norris, JM, Peloso, GM, Sheu, WHH, Toniolo, D, Vaidya, D, Varma, R, Wagenknecht, LE, Boeing, H, Bottinger, EP, Dedoussis, G, Deloukas, P, Ferrannini, E, Franco Duran, OH, Franks, PW, Gibbs, RA, Gudnason, V, Hamsten, A, Harris, TB, Hattersley, AT, Hayward, C, Hofman, Bert, Jansson, JH, Langenberg, C, Launer, LJ (Lenore), Levy, D, Oostra, Ben, O'Donnell, CJ, O'Rahilly, S, Padmanabhan, S, Pankow, JS, Polasek, O, Province, MA, Rich, SS, Ridker, PM, Rudan, I, Schulze, MB, Smith, BH, Uitterlinden, André, Walker, M, Watkins, H, Wong, TY (Tien Yin), Zeggini, E, Laakso, M, Borecki, IB, Chasman, DI, Pedersen, O, Psaty, BM, Tai, ES, Duijn, Cornelia, Wareham, NJ, Waterworth, DM, Boerwinkle, E, Kao, WHL, Florez, JC, Loos, RJF, Wilson, JG, Frayling, TM, Siscovick, DS, Dupuis, J, Rotter, JI, Meigs, JB, Scott, RA, Goodarzi, MO, Sharp, SJ, Forouhi, NG, Kerrison, ND, Lucarelli, DM, Sims, M, Barroso, I, McCarthy, MI, Arriola, L, Balkau, B, Barricarte, A, Gonzalez, C, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quiros, JR, Rolandsson, O, Sacerdote, C, Sanchez, MJ (Maria-Jose), Slimani, N, Tjonneland, A, Tumino, R, van der A, DL, van der Schouw, YT, Riboli, E, Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, MF, Raghavan, S, Lipovich, L, Hidalgo, B, Fox, K, Huffman, JE, An, P, Lu, YC, Rasmussen-Torvik, LJ, Grarup, N, Ehm, MG, Li, Li, Baldridge, AS, Stancakova, A, Abrol, R, Besse, CL, Boland, A, Bork-Jensen, J, Fornage, M, Freitag, DF, Garcia, ME, Guo, XQ, Hara, K, Isaacs, Aaron, Jakobsdottir, J, Lange, LA, Layton, JC, Li, M, Zhao, JH, Meidtner, K, Morrison, AC, Nalls, MA, Peters, Marjolein, Sabater-Lleal, M, Schurmann, C, Silveira, A, Smith, AV, Southam, L, Stoiber, MH, Strawbridge, RJ, Taylor, KD, Varga, TV, Allin, KH, Amin, Najaf, Aponte, JL, Aung, T, Barbieri, C, Bihlmeyer, NA, Boehnke, M, Bombieri, C, Bowden, DW, Burns, SM, Chen, YN, Chen, YD, Cheng, CY (Ching-Yu), Correa, A, Czajkowski, J, Dehghan, Abbas, Ehret, GB, Eiriksdottir, G, Escher, SA, Farmaki, AE, Franberg, M, Gambaro, G, Giulianini, F, Goddard, WA, Goel, A, Gottesman, O, Grove, ML, Gustafsson, S, Hai, Y, Hallmans, G, Heo, J, Hoffmann, P, Ikram, MK, Jensen, RA, Jorgensen, ME, Jorgensen, T, Karaleftheri, M, Khor, CC, Kirkpatrick, A, Kraja, AT, Kuusisto, J, Lange, Edmee, Lee, IT, Lee, WJ, Leong, A, Liao, JM, Liu, CY, Liu, YM, Lindgren, CM, Linneberg, A, Malerba, G, Mamakou, V, Marouli, E, Maruthur, NM, Matchan, A, McKean-Cowdin, R, McLeod, O, Metcalf, GA, Mohlke, KL, Muzny, DM, Ntalla, I, Palmer, ND, Pasko, D, Peter, A, Rayner, NW, Renstrom, F, Rice, K, Sala, CF, Sennblad, B, Serafetinidis, I, Smith, JA, Soranzo, N, Speliotes, EK, Stahl, EA, Stirrups, K, Tentolouris, N, Thanopoulou, A, Torres, M, Traglia, M, Tsafantakis, E, Javad, S, Yanek, LR, Zengini, E, Becker, DM, Bis, JC, Brown, JB, Cupples, LA, Hansen, T, Ingelsson, E, Karter, AJ, Lorenzo, C, Mathias, RA, Norris, JM, Peloso, GM, Sheu, WHH, Toniolo, D, Vaidya, D, Varma, R, Wagenknecht, LE, Boeing, H, Bottinger, EP, Dedoussis, G, Deloukas, P, Ferrannini, E, Franco Duran, OH, Franks, PW, Gibbs, RA, Gudnason, V, Hamsten, A, Harris, TB, Hattersley, AT, Hayward, C, Hofman, Bert, Jansson, JH, Langenberg, C, Launer, LJ (Lenore), Levy, D, Oostra, Ben, O'Donnell, CJ, O'Rahilly, S, Padmanabhan, S, Pankow, JS, Polasek, O, Province, MA, Rich, SS, Ridker, PM, Rudan, I, Schulze, MB, Smith, BH, Uitterlinden, André, Walker, M, Watkins, H, Wong, TY (Tien Yin), Zeggini, E, Laakso, M, Borecki, IB, Chasman, DI, Pedersen, O, Psaty, BM, Tai, ES, Duijn, Cornelia, Wareham, NJ, Waterworth, DM, Boerwinkle, E, Kao, WHL, Florez, JC, Loos, RJF, Wilson, JG, Frayling, TM, Siscovick, DS, Dupuis, J, Rotter, JI, Meigs, JB, Scott, RA, Goodarzi, MO, Sharp, SJ, Forouhi, NG, Kerrison, ND, Lucarelli, DM, Sims, M, Barroso, I, McCarthy, MI, Arriola, L, Balkau, B, Barricarte, A, Gonzalez, C, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quiros, JR, Rolandsson, O, Sacerdote, C, Sanchez, MJ (Maria-Jose), Slimani, N, Tjonneland, A, Tumino, R, van der A, DL, van der Schouw, YT, and Riboli, E
Abstract: Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Published: 2015

40. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia (vol 45, pg 314, 2013)

Author: Verhoeven, Virginie, Hysi, PG, Wojciechowski, R, Fan, Q, Guggenheim, JA, Hohn, R, Macgregor, S, Hewitt, AW, Nag, A, Cheng, CY (Ching-Yu), Yonova-Doing, E, Zhou, X, Ikram, Kamran, Buitendijk, Gabriëlle, McMahon, G, Kemp, JP, St Pourcain, B, Simpson, CL, Makela, KM, Lehtimaki, T, Kahonen, M, Paterson, AD, Hosseini, SM, Wong, HS, Xu, L, Jonas, JB, Parssinen, O, Wedenoja, J, Yip, SP, Ho, DWH, Pang, CP, Chen, LJ, Burdon, KP, Craig, JE, Klein, BEK, Klein, R, Haller, T, Metspalu, A, Khor, CC, Tai, ES, Aung, T, Vithana, E, Tay, WT, Barathi, VA, Chen, Peng, Li, RY, Liao, JM, Zheng, YF, Ong, RT, Doring, A, Evans, DM, Timpson, NJ, Verkerk, AJMH, Meitinger, T, Raitakari, O, Hawthorne, F, Spector, TD, Karssen, Lennart, Pirastu, M, Murgia, F, Ang, W, Mishra, A, Montgomery, GW, Pennell, CE, Cumberland, PM, Cotlarciuc, I, Mitchell, P, Wang, JJ, Schache, M, Janmahasathian, S, Igo, RP, Lass, JH, Chew, E, KIyengar, S, Gorgels, TGMF (Theo), Rudan, I, Hayward, C, Wright, AF, Polasek, O, Vatavuk, Z, Wilson, JF, Fleck, B, Zeller, T, Mirshahi, A, Müller, Caspar, Uitterlinden, André, Rivadeneira, Fernando, Vingerling, Hans, Hofman, Bert, Oostra, Ben, Amin, Najaf, Bergen, Arthur, Teo, YY, Rahi, JS, Vitart, V, Williams, C, Baird, PN, Wong, TY (Tien Yin), Oexle, K, Pfeiffer, N, Mackey, DA, Young, TL, Duijn, Cornelia, Saw, SM, Bailey-Wilson, JE, Stambolian, D, Klaver, Caroline, Hammond, CJ, Ophthalmology, Pathology, Epidemiology, Cell biology, Anesthesiology, Internal Medicine, Clinical Genetics, and Obstetrics & Gynecology
Published: 2013

41. Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Author: Vithana, EN, Khor, CC, Qiao, C, Nongpiur, ME, George, R, Chen, LJ, Do, T, Abu-Amero, K, Huang, CK, Low, S, Tajudin, LSA, Perera, SA, Cheng, CY, Xu, L, Jia, H, Ho, CL, Sim, KS, Wu, RY, Tham, CCY, Chew, PTK, Su, DH, Oen, FT, Sarangapani, S, Soumittra, N, Osman, EA, Wong, HT, Tang, G, Fan, S, Meng, H, Huong, DTL, Wang, H, Feng, B, Baskaran, M, Shantha, B, Ramprasad, VL, Kumaramanickavel, G, Iyengar, SK, How, AC, Lee, KY, Sivakumaran, TA, Yong, VHK, Ting, SML, Li, Y, Wang, YX, Tay, WT, Sim, X, Lavanya, R, Cornes, BK, Zheng, YF, Wong, TT, Loon, SC, Yong, VKY, Waseem, N, Yaakub, A, Chia, KS, Rand Allingham, R, Hauser, MA, Lam, DSC, Hibberd, ML, Bhattacharya, SS, Zhang, M, Teo, YY, Tan, DT, Jonas, JB, Tai, ES, Saw, SM, Hon, DN, Al-Obeidan, SA, Liu, J, Chau, TNB, Simmons, CP, Bei, JX, Zeng, YX, Foster, PJ, Vijaya, L, and Wong, TY
Subjects: medicine.medical_specialty, Population, Glaucoma, Genome-wide association study, Biology, Collagen Type XI, Polymorphism, Single Nucleotide, Article, Polymorphism (computer science), Epidemiology, Protein D-Aspartate-L-Isoaspartate Methyltransferase, Genetics, medicine, Humans, Stickler syndrome, Genetic Predisposition to Disease, education, education.field_of_study, Principal Component Analysis, Case-control study, Odds ratio, medicine.disease, Repressor Proteins, Logistic Models, Genetic Loci, Case-Control Studies, Carrier Proteins, Glaucoma, Angle-Closure, Genome-Wide Association Study
Abstract: Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10-12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10-10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10-9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

42. Impact of Measurement Error on Testing Genetic Association with Quantitative Traits

Author: Zaykin, D, Liao, J, Li, X, Wong, T-Y, Wang, JJ, Khor, CC, Tai, ES, Aung, T, Teo, Y-Y, Cheng, C-Y, Zaykin, D, Liao, J, Li, X, Wong, T-Y, Wang, JJ, Khor, CC, Tai, ES, Aung, T, Teo, Y-Y, and Cheng, C-Y
Abstract: Measurement error of a phenotypic trait reduces the power to detect genetic associations. We examined the impact of sample size, allele frequency and effect size in presence of measurement error for quantitative traits. The statistical power to detect genetic association with phenotype mean and variability was investigated analytically. The non-centrality parameter for a non-central F distribution was derived and verified using computer simulations. We obtained equivalent formulas for the cost of phenotype measurement error. Effects of differences in measurements were examined in a genome-wide association study (GWAS) of two grading scales for cataract and a replication study of genetic variants influencing blood pressure. The mean absolute difference between the analytic power and simulation power for comparison of phenotypic means and variances was less than 0.005, and the absolute difference did not exceed 0.02. To maintain the same power, a one standard deviation (SD) in measurement error of a standard normal distributed trait required a one-fold increase in sample size for comparison of means, and a three-fold increase in sample size for comparison of variances. GWAS results revealed almost no overlap in the significant SNPs (p<10(-5)) for the two cataract grading scales while replication results in genetic variants of blood pressure displayed no significant differences between averaged blood pressure measurements and single blood pressure measurements. We have developed a framework for researchers to quantify power in the presence of measurement error, which will be applicable to studies of phenotypes in which the measurement is highly variable.
Published: 2014

43. 2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy

Author: Li, J, Lindstroem, LS, Foo, JN, Rafiq, S, Schmidt, MK, Pharoah, PDP, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Van't Veer, LJ, Cornelissen, S, Rutgers, E, Southey, MC, Apicella, C, Dite, GS, Hopper, JL, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Blomqvist, C, Muranen, TA, Aittomaeki, K, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Hartikainen, JM, Kataja, V, Chenevix-Trench, G, Phillips, K-A, McLachlan, S-A, Lambrechts, D, Thienpont, B, Smeets, A, Wildiers, H, Chang-Claude, J, Flesch-Janys, D, Seibold, P, Rudolph, A, Giles, GG, Baglietto, L, Severi, G, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GIG, Borresen-Dale, A-L, Nord, S, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, R, Seynaeve, C, Hooning, M, Kriege, M, Hollestelle, A, Van den Ouweland, A, Li, Y, Hamann, U, Torres, D, Ulmer, HU, Rudiger, T, Shen, C-Y, Hsiung, C-N, Wu, P-E, Chen, S-T, Teo, SH, Taib, NAM, Yip, CH, Ho, GF, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Maishman, T, Tapper, WJ, Dunning, A, Shah, M, Luben, R, Brown, J, Khor, CC, Eccles, DM, Nevanlinna, H, Easton, D, Humphreys, K, Liu, J, Hall, P, Czene, K, Li, J, Lindstroem, LS, Foo, JN, Rafiq, S, Schmidt, MK, Pharoah, PDP, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Van't Veer, LJ, Cornelissen, S, Rutgers, E, Southey, MC, Apicella, C, Dite, GS, Hopper, JL, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Blomqvist, C, Muranen, TA, Aittomaeki, K, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Hartikainen, JM, Kataja, V, Chenevix-Trench, G, Phillips, K-A, McLachlan, S-A, Lambrechts, D, Thienpont, B, Smeets, A, Wildiers, H, Chang-Claude, J, Flesch-Janys, D, Seibold, P, Rudolph, A, Giles, GG, Baglietto, L, Severi, G, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GIG, Borresen-Dale, A-L, Nord, S, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, R, Seynaeve, C, Hooning, M, Kriege, M, Hollestelle, A, Van den Ouweland, A, Li, Y, Hamann, U, Torres, D, Ulmer, HU, Rudiger, T, Shen, C-Y, Hsiung, C-N, Wu, P-E, Chen, S-T, Teo, SH, Taib, NAM, Yip, CH, Ho, GF, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Maishman, T, Tapper, WJ, Dunning, A, Shah, M, Luben, R, Brown, J, Khor, CC, Eccles, DM, Nevanlinna, H, Easton, D, Humphreys, K, Liu, J, Hall, P, and Czene, K
Abstract: Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.
Published: 2014

44. ABCC5, a Gene That Influences the Anterior Chamber Depth, Is Associated with Primary Angle Closure Glaucoma

Author: Wiggs, JL, Nongpiur, ME, Khor, CC, Jia, H, Cornes, BK, Chen, L-J, Qiao, C, Nair, KS, Cheng, C-Y, Xu, L, George, R, Do, T, Abu-Amero, K, Perera, SA, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Low, S, Tajudin, L-SA, Ho, C-L, Tham, CCY, Soto, I, Chew, PTK, Wong, H-T, Shantha, B, Kuroda, M, Osman, EA, Tang, G, Fan, S, Meng, H, Wang, H, Feng, B, Yong, VHK, Ting, SML, Li, Y, Wang, Y-X, Li, Z, Lavanya, R, Wu, R-Y, Zheng, Y-F, Su, DH, Loon, S-C, Allingham, RR, Hauser, MA, Soumittra, N, Ramprasad, VL, Waseem, N, Yaakub, A, Chia, K-S, Kumaramanickavel, G, Wong, TT, How, AC, Tran, NBC, Simmons, CP, Bei, J-X, Zeng, Y-X, Bhattacharya, SS, Zhang, M, Tan, DT, Teo, Y-Y, Al-Obeidan, SA, Do, NH, Tai, E-S, Saw, S-M, Foster, PJ, Vijaya, L, Jonas, JB, Wong, T-Y, John, SWM, Pang, C-P, Vithana, EN, Wang, N, Aung, T, Wiggs, JL, Nongpiur, ME, Khor, CC, Jia, H, Cornes, BK, Chen, L-J, Qiao, C, Nair, KS, Cheng, C-Y, Xu, L, George, R, Do, T, Abu-Amero, K, Perera, SA, Ozaki, M, Mizoguchi, T, Kurimoto, Y, Low, S, Tajudin, L-SA, Ho, C-L, Tham, CCY, Soto, I, Chew, PTK, Wong, H-T, Shantha, B, Kuroda, M, Osman, EA, Tang, G, Fan, S, Meng, H, Wang, H, Feng, B, Yong, VHK, Ting, SML, Li, Y, Wang, Y-X, Li, Z, Lavanya, R, Wu, R-Y, Zheng, Y-F, Su, DH, Loon, S-C, Allingham, RR, Hauser, MA, Soumittra, N, Ramprasad, VL, Waseem, N, Yaakub, A, Chia, K-S, Kumaramanickavel, G, Wong, TT, How, AC, Tran, NBC, Simmons, CP, Bei, J-X, Zeng, Y-X, Bhattacharya, SS, Zhang, M, Tan, DT, Teo, Y-Y, Al-Obeidan, SA, Do, NH, Tai, E-S, Saw, S-M, Foster, PJ, Vijaya, L, Jonas, JB, Wong, T-Y, John, SWM, Pang, C-P, Vithana, EN, Wang, N, and Aung, T
Abstract: Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.
Published: 2014

45. Variation at HLA-DRB1 is associated with resistance to enteric fever

Author: Dunstan, SJ, Nguyen, TH, Buhm, H, Li, Z, Trinh, TBT, Sim, KS, Parry, CM, Nguyen, TC, Ha, V, Nguyen, PHL, Nga, TVT, Phat, VV, Koirala, S, Dongol, S, Arjyal, A, Karkey, A, Shilpakar, O, Dolecek, C, Foo, JN, Le, TP, Mai, NL, Tan, D, Aung, T, Do, NH, Teo, YY, Hibberd, ML, Anders, KL, Okada, Y, Raychaudhuri, S, Simmons, CP, Baker, S, de Bakker, PIW, Basnyat, B, Tran, TH, Farrar, JJ, Khor, CC, Dunstan, SJ, Nguyen, TH, Buhm, H, Li, Z, Trinh, TBT, Sim, KS, Parry, CM, Nguyen, TC, Ha, V, Nguyen, PHL, Nga, TVT, Phat, VV, Koirala, S, Dongol, S, Arjyal, A, Karkey, A, Shilpakar, O, Dolecek, C, Foo, JN, Le, TP, Mai, NL, Tan, D, Aung, T, Do, NH, Teo, YY, Hibberd, ML, Anders, KL, Okada, Y, Raychaudhuri, S, Simmons, CP, Baker, S, de Bakker, PIW, Basnyat, B, Tran, TH, Farrar, JJ, and Khor, CC
Abstract: Enteric fever affects more than 25 million people annually and results from systemic infection with Salmonella enterica serovar Typhi or Paratyphi pathovars A, B or C(1). We conducted a genome-wide association study of 432 individuals with blood culture-confirmed enteric fever and 2,011 controls from Vietnam. We observed strong association at rs7765379 (odds ratio (OR) for the minor allele = 0.18, P = 4.5 × 10(-10)), a marker mapping to the HLA class II region, in proximity to HLA-DQB1 and HLA-DRB1. We replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine-mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, P = 2.60 × 10(-11)) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.
Published: 2014

46. Patient-Based Transcriptome-Wide Analysis Identify Interferon and Ubiquination Pathways as Potential Predictors of Influenza A Disease Severity

Author: Fouchier, RAM, Long, TH, Tolfvenstam, T, Ooi, EE, Khor, CC, Naim, ANM, Ho, EXP, Ong, SH, Wertheim, HF, Fox, A, Chau, VVN, Ngoc, MN, Tuan, MH, Anh, TNT, Tambayah, P, Lin, R, Sangsajja, C, Manosuthi, W, Chuchottaworn, C, Sansayunh, P, Chotpitayasunondh, T, Suntarattiwong, P, Chokephaibulkit, K, Puthavathana, P, de Jong, MD, Farrar, J, van Doorn, HR, Hibberd, ML, Fouchier, RAM, Long, TH, Tolfvenstam, T, Ooi, EE, Khor, CC, Naim, ANM, Ho, EXP, Ong, SH, Wertheim, HF, Fox, A, Chau, VVN, Ngoc, MN, Tuan, MH, Anh, TNT, Tambayah, P, Lin, R, Sangsajja, C, Manosuthi, W, Chuchottaworn, C, Sansayunh, P, Chotpitayasunondh, T, Suntarattiwong, P, Chokephaibulkit, K, Puthavathana, P, de Jong, MD, Farrar, J, van Doorn, HR, and Hibberd, ML
Abstract: BACKGROUND: The influenza A virus is an RNA virus that is responsible for seasonal epidemics worldwide with up to five million cases of severe illness and 500,000 deaths annually according to the World Health Organization estimates. The factors associated with severe diseases are not well defined, but more severe disease is more often seen among persons aged >65 years, infants, pregnant women, and individuals of any age with underlying health conditions. METHODOLOGY/PRINCIPAL FINDINGS: Using gene expression microarrays, the transcriptomic profiles of influenza-infected patients with severe (N = 11), moderate (N = 40) and mild (N = 83) symptoms were compared with the febrile patients of unknown etiology (N = 73). We found that influenza-infected patients, regardless of their clinical outcomes, had a stronger induction of antiviral and cytokine responses and a stronger attenuation of NK and T cell responses in comparison with those with unknown etiology. More importantly, we found that both interferon and ubiquitination signaling were strongly attenuated in patients with the most severe outcomes in comparison with those with moderate and mild outcomes, suggesting the protective roles of these pathways in disease pathogenesis. CONCLUSION/SIGNIFICANCES: The attenuation of interferon and ubiquitination pathways may associate with the clinical outcomes of influenza patients.
Published: 2014

47. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Author: Springelkamp, Henriët, Hohn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, XY, Ramdas, Wishal, Vithana, E, Nongpiur, ME, Montgomery, G, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y (Yi), Amin, Najaf, Karssen, Lennart, Sim, KS, Leeuwen, Elisa, Iglesias, AI, Verhoeven, Virginie, Hauser, MA, Loon, SC, Despriet, Dominiek, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Koolwijk, Leonieke, Rivadeneira, Fernando, Souzeau, E, Jonsson, V, Menon, G, Weinreb, RN, Oostra, Ben, Uitterlinden, André, Hofman, Bert, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Spector, TD, Mirshahi, A, Saw, SM, Vingerling, Hans, Teo, YY, Haines, JL, Wolfs, R.C.W., Lemij, HG, Tai, ES, Jansonius, NM (Nomdo), Jonas, JB, Cheng, CY (Ching-Yu), Aung, T, Viswanathan, AC, Klaver, Caroline, Craig, JE, Macgregor, S, Mackey, DA, Lotery, AJ, Stefansson, K, Young, TL, Wiggs, JL, Pfeiffer, N, Wong, TY (Tien Yin), Pasquale, LR, Hewitt, AW, Duijn, Cornelia, Hammond, CJ, Bergen, AAB, Springelkamp, Henriët, Hohn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, XY, Ramdas, Wishal, Vithana, E, Nongpiur, ME, Montgomery, G, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y (Yi), Amin, Najaf, Karssen, Lennart, Sim, KS, Leeuwen, Elisa, Iglesias, AI, Verhoeven, Virginie, Hauser, MA, Loon, SC, Despriet, Dominiek, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Koolwijk, Leonieke, Rivadeneira, Fernando, Souzeau, E, Jonsson, V, Menon, G, Weinreb, RN, Oostra, Ben, Uitterlinden, André, Hofman, Bert, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Spector, TD, Mirshahi, A, Saw, SM, Vingerling, Hans, Teo, YY, Haines, JL, Wolfs, R.C.W., Lemij, HG, Tai, ES, Jansonius, NM (Nomdo), Jonas, JB, Cheng, CY (Ching-Yu), Aung, T, Viswanathan, AC, Klaver, Caroline, Craig, JE, Macgregor, S, Mackey, DA, Lotery, AJ, Stefansson, K, Young, TL, Wiggs, JL, Pfeiffer, N, Wong, TY (Tien Yin), Pasquale, LR, Hewitt, AW, Duijn, Cornelia, Hammond, CJ, and Bergen, AAB
Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Published: 2014

48. Polypoidal choroidal vasculopathy and systemic lupus erythematosus

Author: Chin, YC, primary, Bhargava, M, additional, Khor, CC, additional, Cheung, CMG, additional, and Wong, TY, additional
Published: 2014
Full Text: View/download PDF

49. Combined genotype and haplotype tests for region-based association studies

Author: Zakharov, S, Wong, TY, Aung, T, Vithana, EN, Khor, CC, Salim, A, Thalamuthu, A, Zakharov, S, Wong, TY, Aung, T, Vithana, EN, Khor, CC, Salim, A, and Thalamuthu, A
Abstract: BACKGROUND: Although single-SNP analysis has proven to be useful in identifying many disease-associated loci, region-based analysis has several advantages. Empirically, it has been shown that region-based genotype and haplotype approaches may possess much higher power than single-SNP statistical tests. Both high quality haplotypes and genotypes may be available for analysis given the development of next generation sequencing technologies and haplotype assembly algorithms. RESULTS: As generally it is unknown whether genotypes or haplotypes are more relevant for identifying an association, we propose to use both of them with the purpose of preserving high power under both genotype and haplotype disease scenarios. We suggest two approaches for a combined association test and investigate the performance of these two approaches based on a theoretical model, population genetics simulations and analysis of a real data set. CONCLUSIONS: Based on a theoretical model, population genetics simulations and analysis of a central corneal thickness (CCT) Genome Wide Association Study (GWAS) data set we have shown that combined genotype and haplotype approach has a high potential utility for applications in association studies.
Published: 2013

50. Replication and Meta-Analysis of GWAS Identified Susceptibility Loci in Kawasaki Disease Confirm the Importance of B Lymphoid Tyrosine Kinase (BLK) in Disease Susceptibility

Author: Huang, L-M, Chang, C-J, Kuo, H-C, Chang, J-S, Lee, J-K, Tsai, F-J, Khor, CC, Chang, L-C, Chen, S-P, Ko, T-M, Liu, Y-M, Chen, Y-J, Hong, YM, Jang, GY, Hibberd, ML, Kuijpers, T, Burgner, D, Levin, M, Burns, JC, Davila, S, Chen, Y-T, Chen, C-H, Wu, J-Y, Lee, Y-C, Huang, L-M, Chang, C-J, Kuo, H-C, Chang, J-S, Lee, J-K, Tsai, F-J, Khor, CC, Chang, L-C, Chen, S-P, Ko, T-M, Liu, Y-M, Chen, Y-J, Hong, YM, Jang, GY, Hibberd, ML, Kuijpers, T, Burgner, D, Levin, M, Burns, JC, Davila, S, Chen, Y-T, Chen, C-H, Wu, J-Y, and Lee, Y-C
Abstract: The BLK and CD40 loci have been associated with Kawasaki disease (KD) in two genome-wide association studies (GWAS) conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in populations of Korean and European descent. The BLK region was significantly associated with KD susceptibility in both populations. Within the BLK gene the rs2736340-located linkage disequilibrium (LD ) comprising the promoter and first intron was strongly associated with KD, with the combined results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls) providing very compelling evidence of association (rs2736340, OR = 1.498, 1.354-1.657; P = 4.74×10(-31)). We determined the percentage of B cells present in the peripheral blood mononuclear cell (PBMC) population and the expression of BLK in the peripheral blood leukocytes (leukocytes) of KD patients during the acute and convalescent stages. The percentage of B cells in the PBMC population and the expression of BLK in leukocytes were induced in patients in the acute stage of KD. In B cell lines derived from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role during the acute stage of KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD. These associative data suggest a role for B cells during acute KD. Understanding the functional implications may facilitate the development of B cell-mediated therapy for KD.
Published: 2013

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Region

Database

Publisher

382 results on '"Khor CC"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources