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36 results on '"Ring, Sm"'

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

Author: Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, Mendes de Oliveira, E, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santoni, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, RY, Terao, C, Riggan, MJ, Bolla, MK, Yazdanpanah, M, Yazdanpanah, N, Bradfield, JP, Broer, L, Campbell, A, Chasman, DI, Cousminer, DL, Franceschini, N, Franke, LH, Girotto, G, He, C, Järvelin, M-R, Joshi, PK, Kamatani, Y, Karlsson, R, Luan, J, Lunetta, KL, Mägi, R, Mangino, M, Medland, SE, Meisinger, C, Noordam, R, Nutile, T, Concas, MP, Polašek, O, Porcu, E, Ring, SM, Sala, C, Smith, AV, Tanaka, T, van der Most, PJ, Vitart, V, Wang, CA, Willemsen, G, Zygmunt, M, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Auer, PL, Barnes, CLK, Beckmann, MW, Berrington de Gonzalez, A, Bogdanova, NV, Bojesen, SE, Brenner, H, Buring, JE, Canzian, F, Chang-Claude, J, Couch, FJ, Cox, A, Crisponi, L, Czene, K, Daly, MB, Demerath, EW, Dennis, J, Devilee, P, De Vivo, I, Dörk, T, Dunning, AM, Dwek, M, Eriksson, JG, Fasching, PA, Fernandez-Rhodes, L, Ferreli, L, Fletcher, O, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, González-Neira, A, Grallert, H, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Hakonarson, H, Hart, RJ, Hickey, M, Hooning, MJ, Hoppe, R, Hopper, JL, Hottenga, J-J, Hu, FB, Huebner, H, Hunter, DJ, ABCTB Investigators, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PKE, Mannermaa, A, McCarthy, MI, Meitinger, T, Menni, C, Michailidou, K, Millwood, IY, Milne, RL, Montgomery, GW, Nevanlinna, H, Nolte, IM, Nyholt, DR, Obi, N, O'Brien, KM, Offit, K, Oldehinkel, AJ, Ostrowski, SR, Palotie, A, Pedersen, OB, Peters, A, Pianigiani, G, Plaseska-Karanfilska, D, Pouta, A, Pozarickij, A, Radice, P, Rennert, G, Rosendaal, FR, Ruggiero, D, Saloustros, E, Sandler, DP, Schipf, S, Schmidt, CO, Schmidt, MK, Small, K, Spedicati, B, Stampfer, M, Stone, J, Tamimi, RM, Teras, LR, Tikkanen, E, Turman, C, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Zemel, BS, Zheng, W, van Dijk, KW, Alizadeh, BZ, Bandinelli, S, Boerwinkle, E, Boomsma, DI, Ciullo, M, Chenevix-Trench, G, Cucca, F, Esko, T, Gieger, C, Grant, SFA, Gudnason, V, Hayward, C, Kolčić, I, Kraft, P, Lawlor, DA, Martin, NG, Nøhr, EA, Pedersen, NL, Pennell, CE, Ridker, PM, Robino, A, Snieder, H, Sovio, U, Spector, TD, Stöckl, D, Sudlow, C, Timpson, NJ, Toniolo, D, Uitterlinden, A, Ulivi, S, Völzke, H, Wareham, NJ, Widen, E, Wilson, JF, Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Pharoah, PDP, Li, L, Easton, DF, Njølstad, PR, Sulem, P, Murabito, JM, Murray, A, Manousaki, D, Juul, A, Erikstrup, C, Stefansson, K, Horikoshi, M, Chen, Z, Farooqi, IS, Pitteloud, N, Johansson, S, Day, FR, Perry, JRB, Ong, KK, Kentistou, KA, Kaisinger, LR, Stankovic, S, Vaudel, M, Mendes de Oliveira, E, Messina, A, Walters, RG, Liu, X, Busch, AS, Helgason, H, Thompson, DJ, Santoni, F, Petricek, KM, Zouaghi, Y, Huang-Doran, I, Gudbjartsson, DF, Bratland, E, Lin, K, Gardner, EJ, Zhao, Y, Jia, RY, Terao, C, Riggan, MJ, Bolla, MK, Yazdanpanah, M, Yazdanpanah, N, Bradfield, JP, Broer, L, Campbell, A, Chasman, DI, Cousminer, DL, Franceschini, N, Franke, LH, Girotto, G, He, C, Järvelin, M-R, Joshi, PK, Kamatani, Y, Karlsson, R, Luan, J, Lunetta, KL, Mägi, R, Mangino, M, Medland, SE, Meisinger, C, Noordam, R, Nutile, T, Concas, MP, Polašek, O, Porcu, E, Ring, SM, Sala, C, Smith, AV, Tanaka, T, van der Most, PJ, Vitart, V, Wang, CA, Willemsen, G, Zygmunt, M, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Auer, PL, Barnes, CLK, Beckmann, MW, Berrington de Gonzalez, A, Bogdanova, NV, Bojesen, SE, Brenner, H, Buring, JE, Canzian, F, Chang-Claude, J, Couch, FJ, Cox, A, Crisponi, L, Czene, K, Daly, MB, Demerath, EW, Dennis, J, Devilee, P, De Vivo, I, Dörk, T, Dunning, AM, Dwek, M, Eriksson, JG, Fasching, PA, Fernandez-Rhodes, L, Ferreli, L, Fletcher, O, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, González-Neira, A, Grallert, H, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Hakonarson, H, Hart, RJ, Hickey, M, Hooning, MJ, Hoppe, R, Hopper, JL, Hottenga, J-J, Hu, FB, Huebner, H, Hunter, DJ, ABCTB Investigators, Jernström, H, John, EM, Karasik, D, Khusnutdinova, EK, Kristensen, VN, Lacey, JV, Lambrechts, D, Launer, LJ, Lind, PA, Lindblom, A, Magnusson, PKE, Mannermaa, A, McCarthy, MI, Meitinger, T, Menni, C, Michailidou, K, Millwood, IY, Milne, RL, Montgomery, GW, Nevanlinna, H, Nolte, IM, Nyholt, DR, Obi, N, O'Brien, KM, Offit, K, Oldehinkel, AJ, Ostrowski, SR, Palotie, A, Pedersen, OB, Peters, A, Pianigiani, G, Plaseska-Karanfilska, D, Pouta, A, Pozarickij, A, Radice, P, Rennert, G, Rosendaal, FR, Ruggiero, D, Saloustros, E, Sandler, DP, Schipf, S, Schmidt, CO, Schmidt, MK, Small, K, Spedicati, B, Stampfer, M, Stone, J, Tamimi, RM, Teras, LR, Tikkanen, E, Turman, C, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Zemel, BS, Zheng, W, van Dijk, KW, Alizadeh, BZ, Bandinelli, S, Boerwinkle, E, Boomsma, DI, Ciullo, M, Chenevix-Trench, G, Cucca, F, Esko, T, Gieger, C, Grant, SFA, Gudnason, V, Hayward, C, Kolčić, I, Kraft, P, Lawlor, DA, Martin, NG, Nøhr, EA, Pedersen, NL, Pennell, CE, Ridker, PM, Robino, A, Snieder, H, Sovio, U, Spector, TD, Stöckl, D, Sudlow, C, Timpson, NJ, Toniolo, D, Uitterlinden, A, Ulivi, S, Völzke, H, Wareham, NJ, Widen, E, Wilson, JF, Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Pharoah, PDP, Li, L, Easton, DF, Njølstad, PR, Sulem, P, Murabito, JM, Murray, A, Manousaki, D, Juul, A, Erikstrup, C, Stefansson, K, Horikoshi, M, Chen, Z, Farooqi, IS, Pitteloud, N, Johansson, S, Day, FR, Perry, JRB, and Ong, KK
Abstract: Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.
Published: 2024

2. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, Perry, JRB, Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, and Perry, JRB
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021

3. Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color

Author: Simcoe, M, Valdes, A, Liu, F, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, W, Kraft, P, Hammond, CJ, Shi, Y, Chen, Y, Zeng, C, Klaver, CCW, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Han, J, Mackey, DA, Martin, NG, Cheng, C-Y, Hinds, DA, Spector, TD, Kayser, M, Hysi, PG, Simcoe, M, Valdes, A, Liu, F, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, W, Kraft, P, Hammond, CJ, Shi, Y, Chen, Y, Zeng, C, Klaver, CCW, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Han, J, Mackey, DA, Martin, NG, Cheng, C-Y, Hinds, DA, Spector, TD, Kayser, M, and Hysi, PG
Abstract: Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
Published: 2021

4. Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color

Author: Simcoe, M, Valdes, A, Liu, Fan, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, WT, Kraft, P, Hammond, CJ, Shi, Y, Chen, Yan, Zeng, CQ, Klaver, Caroline, Uitterlinden, André, Ikram, Arfan, Hamer, M, Duijn, Cornelia, Nijsten, T, Han, JL, Mackey, DA, Martin, NG, Cheng, CY (Ching-Yu), Hinds, DA, Spector, TD, Kayser, M, Hysi, PG, Simcoe, M, Valdes, A, Liu, Fan, Furlotte, NA, Evans, DM, Hemani, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Vuckovic, D, Girotto, G, Sala, C, Catamo, E, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, A, Wu, WT, Kraft, P, Hammond, CJ, Shi, Y, Chen, Yan, Zeng, CQ, Klaver, Caroline, Uitterlinden, André, Ikram, Arfan, Hamer, M, Duijn, Cornelia, Nijsten, T, Han, JL, Mackey, DA, Martin, NG, Cheng, CY (Ching-Yu), Hinds, DA, Spector, TD, Kayser, M, and Hysi, PG
Abstract: Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
Published: 2021

5. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author: Alves, AC, De Silva, NMG, Karhunen, V, Sovio, U, Das, S, Taal, HR, Warrington, NM, Lewin, AM, Kaakinen, M, Cousminer, DL, Thiering, E, Timpson, NJ, Bond, TA, Lowry, E, Brown, CD, Estivill, X, Lindi, V, Bradfield, JP, Geller, F, Speed, D, Coin, LJM, Loh, M, Barton, SJ, Beilin, LJ, Bisgaard, H, Bonnelykke, K, Alili, R, Hatoum, IJ, Schramm, K, Cartwright, R, Charles, M-A, Salerno, V, Clement, K, Claringbould, AAJ, van Duijn, CM, Moltchanova, E, Eriksson, JG, Elks, C, Feenstra, B, Flexeder, C, Franks, S, Frayling, TM, Freathy, RM, Elliott, P, Widen, E, Hakonarson, H, Hattersley, AT, Rodriguez, A, Banterle, M, Heinrich, J, Heude, B, Holloway, JW, Hofman, A, Hypponen, E, Inskip, H, Kaplan, LM, Hedman, AK, Laara, E, Prokisch, H, Grallert, H, Lakka, TA, Lawlor, DA, Melbye, M, Ahluwalia, TS, Marinelli, M, Millwood, IY, Palmer, LJ, Pennell, CE, Perry, JR, Ring, SM, Savolainen, MJ, Rivadeneira, F, Standl, M, Sunyer, J, Tiesler, CMT, Uitterlinden, AG, Schierding, W, O'Sullivan, JM, Prokopenko, I, Herzig, K-H, Smith, GD, O'Reilly, P, Felix, JF, Buxton, JL, Blakemore, AIF, Ong, KK, Jaddoe, VWV, Grant, SFA, Sebert, S, McCarthy, MI, Jarvelin, M-R, Alves, AC, De Silva, NMG, Karhunen, V, Sovio, U, Das, S, Taal, HR, Warrington, NM, Lewin, AM, Kaakinen, M, Cousminer, DL, Thiering, E, Timpson, NJ, Bond, TA, Lowry, E, Brown, CD, Estivill, X, Lindi, V, Bradfield, JP, Geller, F, Speed, D, Coin, LJM, Loh, M, Barton, SJ, Beilin, LJ, Bisgaard, H, Bonnelykke, K, Alili, R, Hatoum, IJ, Schramm, K, Cartwright, R, Charles, M-A, Salerno, V, Clement, K, Claringbould, AAJ, van Duijn, CM, Moltchanova, E, Eriksson, JG, Elks, C, Feenstra, B, Flexeder, C, Franks, S, Frayling, TM, Freathy, RM, Elliott, P, Widen, E, Hakonarson, H, Hattersley, AT, Rodriguez, A, Banterle, M, Heinrich, J, Heude, B, Holloway, JW, Hofman, A, Hypponen, E, Inskip, H, Kaplan, LM, Hedman, AK, Laara, E, Prokisch, H, Grallert, H, Lakka, TA, Lawlor, DA, Melbye, M, Ahluwalia, TS, Marinelli, M, Millwood, IY, Palmer, LJ, Pennell, CE, Perry, JR, Ring, SM, Savolainen, MJ, Rivadeneira, F, Standl, M, Sunyer, J, Tiesler, CMT, Uitterlinden, AG, Schierding, W, O'Sullivan, JM, Prokopenko, I, Herzig, K-H, Smith, GD, O'Reilly, P, Felix, JF, Buxton, JL, Blakemore, AIF, Ong, KK, Jaddoe, VWV, Grant, SFA, Sebert, S, McCarthy, MI, and Jarvelin, M-R
Abstract: Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
Published: 2019

6. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author: Hysi, PG, Valdes, AM, Liu, F, Furlotte, NA, Evans, DM, Bataille, V, Visconti, A, Hemani, G, McMahon, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Lin, BD, Willemsen, G, Hottenga, JJ, Vuckovic, D, Girotto, G, Gandin, I, Sala, C, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, AW, Chen, Y, Zeng, C, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Mackey, DA, Falchi, M, Boomsma, DI, Martin, NG, Hinds, DA, Kayser, M, Spector, TD, Hysi, PG, Valdes, AM, Liu, F, Furlotte, NA, Evans, DM, Bataille, V, Visconti, A, Hemani, G, McMahon, G, Ring, SM, Smith, GD, Duffy, DL, Zhu, G, Gordon, SD, Medland, SE, Lin, BD, Willemsen, G, Hottenga, JJ, Vuckovic, D, Girotto, G, Gandin, I, Sala, C, Concas, MP, Brumat, M, Gasparini, P, Toniolo, D, Cocca, M, Robino, A, Yazar, S, Hewitt, AW, Chen, Y, Zeng, C, Uitterlinden, AG, Ikram, MA, Hamer, MA, van Duijn, CM, Nijsten, T, Mackey, DA, Falchi, M, Boomsma, DI, Martin, NG, Hinds, DA, Kayser, M, and Spector, TD
Abstract: Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.
Published: 2018

7. Maternal and fetal genetic contribution to gestational weight gain

Author: Warrington, NM, Richmond, R, Fenstra, B, Myhre, R, Gaillard, Romy, Paternoster, L, Wang, CA, Beaumont, RN, Das, S, Murcia, M, Barton, SJ, Espinosa, A, Thiering, E, Atalay, M, Pitkanen, N, Ntalla, I, Jonsson, AE, Freathy, R, Karhunen, V, Tiesler, CMT, Allard, C, Crawford, A, Ring, SM, Melbye, M, Magnus, P, Rivadeneira, Fernando, Skotte, L, Hansen, T, Marsh, J, Guxens Junyent, Monica, Holloway, JW, Grallert, H, Jaddoe, Vincent, Lowe, WL, Roumeliotaki, T, Hattersley, AT, Lindi, V, Pahkala, K, Panoutsopoulou, K, Standl, M, Flexeder, C, Bouchard, L, Nohr, E, Marina, L, Kogevinas, M, Niinikoski, H, Dedoussis, G, Heinrich, J, Reynolds, RM, Lakka, T, Zeggini, E, Raitakari, OT, Chatzi, L, Inskip, HM, Bustamante, M, Hivert, MF, Jarvelin, MR, Sorensen, TIA, Pennell, C, Felix, Janine, Jacobsson, B, Geller, F, Evans, DM, Lawlor, DA, Warrington, NM, Richmond, R, Fenstra, B, Myhre, R, Gaillard, Romy, Paternoster, L, Wang, CA, Beaumont, RN, Das, S, Murcia, M, Barton, SJ, Espinosa, A, Thiering, E, Atalay, M, Pitkanen, N, Ntalla, I, Jonsson, AE, Freathy, R, Karhunen, V, Tiesler, CMT, Allard, C, Crawford, A, Ring, SM, Melbye, M, Magnus, P, Rivadeneira, Fernando, Skotte, L, Hansen, T, Marsh, J, Guxens Junyent, Monica, Holloway, JW, Grallert, H, Jaddoe, Vincent, Lowe, WL, Roumeliotaki, T, Hattersley, AT, Lindi, V, Pahkala, K, Panoutsopoulou, K, Standl, M, Flexeder, C, Bouchard, L, Nohr, E, Marina, L, Kogevinas, M, Niinikoski, H, Dedoussis, G, Heinrich, J, Reynolds, RM, Lakka, T, Zeggini, E, Raitakari, OT, Chatzi, L, Inskip, HM, Bustamante, M, Hivert, MF, Jarvelin, MR, Sorensen, TIA, Pennell, C, Felix, Janine, Jacobsson, B, Geller, F, Evans, DM, and Lawlor, DA
Published: 2018

8. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Author: Beaumont, RN, Warrington, NM, Cavadino, A, Tyrrell, J, Nodzenski, M, Horikoshi, M, Geller, F, Myhre, R, Richmond, Rebecca, Paternoster, L, Bradfield, JP, Kreiner-Moller, E, Huikari, V, Metrustry, S, Lunetta, KL, Painter, JN, Hottenga, JJ, Allard, C, Barton, SJ, Espinosa, A, Marsh, JA, Potter, C, Zhang, G, Ang, W, Berry, DJ, Bouchard, L, Das, S, Hakonarson, H, Heikkinen, J, Helgeland, O, Hocher, B, Hofman, Bert, Inskip, HM, Jones, SE, Kogevinas, M, Lind, PA, Marullo, L, Medland, SE, Murray, A, Murray, JC, Njolstad, PR, Nohr, EA, Reichetzeder, C, Ring, SM, Ruth, KS, Santa-Marina, L, Scholtens, DM, Sebert, S, Sengpiel, V, Tuke, MA, Vaudel, M, Weedon, MN, Willemsen, G, Wood, AR, Yaghootkar, H, Muglia, LJ, Bartels, M, Relton, CL, Pennell, CE, Chatzi, L, Estivill, X, Holloway, JW, Boomsma, DI, Montgomery, GW, Murabito, JM, Spector, TD, Power, C, Jarvelin, MR, Bisgaard, H, Grant, SFA, Sorensen, TIA, Jaddoe, Vincent, Jacobsson, B, Melbye, M, McCarthy, MI, Hattersley, AT, Hayes, MG, Frayling, TM, Hivert, MF, Felix, Janine, Hypponen, E, Lowe, WL, Evans, DM, Lawlor, DA, Feenstra, B, Freathy, RM, Beaumont, RN, Warrington, NM, Cavadino, A, Tyrrell, J, Nodzenski, M, Horikoshi, M, Geller, F, Myhre, R, Richmond, Rebecca, Paternoster, L, Bradfield, JP, Kreiner-Moller, E, Huikari, V, Metrustry, S, Lunetta, KL, Painter, JN, Hottenga, JJ, Allard, C, Barton, SJ, Espinosa, A, Marsh, JA, Potter, C, Zhang, G, Ang, W, Berry, DJ, Bouchard, L, Das, S, Hakonarson, H, Heikkinen, J, Helgeland, O, Hocher, B, Hofman, Bert, Inskip, HM, Jones, SE, Kogevinas, M, Lind, PA, Marullo, L, Medland, SE, Murray, A, Murray, JC, Njolstad, PR, Nohr, EA, Reichetzeder, C, Ring, SM, Ruth, KS, Santa-Marina, L, Scholtens, DM, Sebert, S, Sengpiel, V, Tuke, MA, Vaudel, M, Weedon, MN, Willemsen, G, Wood, AR, Yaghootkar, H, Muglia, LJ, Bartels, M, Relton, CL, Pennell, CE, Chatzi, L, Estivill, X, Holloway, JW, Boomsma, DI, Montgomery, GW, Murabito, JM, Spector, TD, Power, C, Jarvelin, MR, Bisgaard, H, Grant, SFA, Sorensen, TIA, Jaddoe, Vincent, Jacobsson, B, Melbye, M, McCarthy, MI, Hattersley, AT, Hayes, MG, Frayling, TM, Hivert, MF, Felix, Janine, Hypponen, E, Lowe, WL, Evans, DM, Lawlor, DA, Feenstra, B, and Freathy, RM
Published: 2018

9. TRPA1 gene polymorphisms and childhood asthma

Author: Gallo, V, Dijk, FN, Holloway, JW, Ring, SM, Koppelman, GH, Postma, DS, Strachan, DP, Granell, R, Jongste, Johan, Jaddoe, Vincent, den Dekker, Martijn, Duijts, Liesbeth, Henderson, AJ, Shaheen, SO, Gallo, V, Dijk, FN, Holloway, JW, Ring, SM, Koppelman, GH, Postma, DS, Strachan, DP, Granell, R, Jongste, Johan, Jaddoe, Vincent, den Dekker, Martijn, Duijts, Liesbeth, Henderson, AJ, and Shaheen, SO
Published: 2017

10. Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Author: Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, Zeggini, E, Tachmazidou, I, Suveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, AE, Gaunt, TR, Jousilahti, P, Kooijman, Marjolein, Lehne, B, Malerba, G, Mannisto, S, Matchan, A, Medina Gomez, Maria, Metrustry, SJ, Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, Katerina, Zaza, G, Zhang, WH, Artigas, MS, Bansal, N, Benn, M, Chen, ZS, Danecek, P, Lin, WY, Locke, A, Luan, JA, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, Janine, Franco Duran, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, Bert, Jaddoe, Vincent, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, Fernando, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, André, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, YL, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ, and Zeggini, E
Published: 2017

11. Genome-wide association study identifies 74 loci associated with educational attainment

Author: Okbay, Aysu, Beauchamp, JP, Fontana, MA, Lee, JJ, Pers, TH, Rietveld, Niels, Turley, P, Chen, GB, Emilsson, V, Meddens, SFW, Oskarsson, S, Pickrell, JK, Thom, K, Timshel, P, Vlaming, Ronald, Abdellaoui, A, Ahluwalia, TS, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Johan, Concas, MP, Derringer, J, Furlotte, NA, Galesloot, TE, Girotto, G, Gupta, R, Hall, LM, Harris, SE, Hofer, E, Horikoshi, M, Huffman, JE, Kaasik, K, Kalafati, IP, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sven, de Leeuw, C, Lind, PA, Lindgren, KO, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, MB, van der Most, PJ, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, WJ, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, KE, Shi, JX, Smith, AV, Poot, Raymond, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N (Niek), Vuckovic, D, Wellmann, J, Westra, HJ, Yang, JY, Zhao, W, Zhu, ZH, Alizadeh, BZ, Amin, Najaf, Bakshi, A, Baumeister, SE, Biino, G, Bonnelykke, K, Boyle, PA, Campbell, H, Cappuccio, FP, Davies, G, De Neve, JE, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, DM, Faul, JD, Feitosa, MF, Forstner, AJ, Gandin, I, Gunnarsson, B, Halldorsson, BV, Harris, TB, Heath, AC, Hocking, LJ, Holliday, EG, Homuth, G, Horan, MA, Hottenga, JJ, De Jager, PL, Joshi, PK, Jugessur, A, Kaakinen, MA, Kahonen, M, Kanoni, S, Keltigangas-Jarvinen, L, Kiemeney, LALM, Kolcic, I, Koskinen, S, Kraja, AT, Kroh, M, Kutalik, Z, Latvala, A, Launer, LJ, Lebreton, MP, Levinson, DF, Lichtenstein, P, Lichtner, P, Liewald, DCM, Loukola, A, Madden, PA, Magi, R, Maki-Opas, T, Marioni, RE, Marques-Vidal, P, Meddens, GA, McMahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, GW, Myhre, R, Nelson, CP, Nyholt, DR, Ollier, WER, Palotie, A, Paternoster, L, Pedersen, NL, Petrovic, KE, Porteous, DJ, Raikkonen, K, Ring, SM, Robino, A, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, AR, Sarin, AP, Schmidt, Heléna, Scott, RJ, Smith, BH, Smith, JA, Staessen, JA, Steinhagen-Thiessen, E, Strauch, K, Terracciano, A, Tobin, MD, Ulivi, S, Vaccargiu, S, Quaye, L, van Rooij, FJA, Venturini, C, Vinkhuyzen, AAE, Volker, U, Volzke, H, Vonk, JM, Vozzi, D, Waage, J, Ware, EB, Willemsen, G, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Bisgaard, H, Boomsma, DI, Borecki, IB, Bultmann, U, Chabris, CF, Cucca, F, Cusi, D, Deary, IJ, Dedoussis, GV, Duijn, Cornelia, Eriksson, JG, Franke, B, Franke, L, Gasparini, P, Gejman, PV, Gieger, C, Grabe, HJ, Gratten, J, Groenen, Patrick, Gudnason, V, van der Harst, P, Hayward, C, Hinds, DA, Hoffmann, W, Hyppnen, E, Iacono, WG, Jacobsson, B, Jarvelin, MR, Jockel, KH, Kaprio, J, Kardia, SLR, Lehtimaki, T, Lehrer, SF, Magnusson, PKE, Martin, NG, McGue, M, Metspalu, A, Pendleton, N, Penninx, BWJH, Perola, M, Pirastu, N, Pirastu, M, Polasek, O, Posthuma, Daniëlle, Power, C, Province, MA, Samani, NJ, Schlessinger, D, Schmidt, R, Sorensen, TIA, Spector, TD, Stefansson, K, Thorsteinsdottir, U, Thurik, Roy, Timpson, NJ, Tiemeier, Henning, Tung, JY, Uitterlinden, André, Vitart, V, Vollenweider, P, Weir, DR, Wilson, JF, Wright, AF, Conley, DC, Krueger, RF, Smith, GD, Hofman, Bert, Laibson, DI, Medland, SE, Meyer, MN, Yang, Jiaqi, Johannesson, M, Visscher, PM, Esko, T, Koellinger, PD, Cesarini, D, Benjamin, DJ, Okbay, Aysu, Beauchamp, JP, Fontana, MA, Lee, JJ, Pers, TH, Rietveld, Niels, Turley, P, Chen, GB, Emilsson, V, Meddens, SFW, Oskarsson, S, Pickrell, JK, Thom, K, Timshel, P, Vlaming, Ronald, Abdellaoui, A, Ahluwalia, TS, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Johan, Concas, MP, Derringer, J, Furlotte, NA, Galesloot, TE, Girotto, G, Gupta, R, Hall, LM, Harris, SE, Hofer, E, Horikoshi, M, Huffman, JE, Kaasik, K, Kalafati, IP, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sven, de Leeuw, C, Lind, PA, Lindgren, KO, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, MB, van der Most, PJ, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, WJ, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, KE, Shi, JX, Smith, AV, Poot, Raymond, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N (Niek), Vuckovic, D, Wellmann, J, Westra, HJ, Yang, JY, Zhao, W, Zhu, ZH, Alizadeh, BZ, Amin, Najaf, Bakshi, A, Baumeister, SE, Biino, G, Bonnelykke, K, Boyle, PA, Campbell, H, Cappuccio, FP, Davies, G, De Neve, JE, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, DM, Faul, JD, Feitosa, MF, Forstner, AJ, Gandin, I, Gunnarsson, B, Halldorsson, BV, Harris, TB, Heath, AC, Hocking, LJ, Holliday, EG, Homuth, G, Horan, MA, Hottenga, JJ, De Jager, PL, Joshi, PK, Jugessur, A, Kaakinen, MA, Kahonen, M, Kanoni, S, Keltigangas-Jarvinen, L, Kiemeney, LALM, Kolcic, I, Koskinen, S, Kraja, AT, Kroh, M, Kutalik, Z, Latvala, A, Launer, LJ, Lebreton, MP, Levinson, DF, Lichtenstein, P, Lichtner, P, Liewald, DCM, Loukola, A, Madden, PA, Magi, R, Maki-Opas, T, Marioni, RE, Marques-Vidal, P, Meddens, GA, McMahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, GW, Myhre, R, Nelson, CP, Nyholt, DR, Ollier, WER, Palotie, A, Paternoster, L, Pedersen, NL, Petrovic, KE, Porteous, DJ, Raikkonen, K, Ring, SM, Robino, A, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, AR, Sarin, AP, Schmidt, Heléna, Scott, RJ, Smith, BH, Smith, JA, Staessen, JA, Steinhagen-Thiessen, E, Strauch, K, Terracciano, A, Tobin, MD, Ulivi, S, Vaccargiu, S, Quaye, L, van Rooij, FJA, Venturini, C, Vinkhuyzen, AAE, Volker, U, Volzke, H, Vonk, JM, Vozzi, D, Waage, J, Ware, EB, Willemsen, G, Attia, JR, Bennett, DA, Berger, K, Bertram, L, Bisgaard, H, Boomsma, DI, Borecki, IB, Bultmann, U, Chabris, CF, Cucca, F, Cusi, D, Deary, IJ, Dedoussis, GV, Duijn, Cornelia, Eriksson, JG, Franke, B, Franke, L, Gasparini, P, Gejman, PV, Gieger, C, Grabe, HJ, Gratten, J, Groenen, Patrick, Gudnason, V, van der Harst, P, Hayward, C, Hinds, DA, Hoffmann, W, Hyppnen, E, Iacono, WG, Jacobsson, B, Jarvelin, MR, Jockel, KH, Kaprio, J, Kardia, SLR, Lehtimaki, T, Lehrer, SF, Magnusson, PKE, Martin, NG, McGue, M, Metspalu, A, Pendleton, N, Penninx, BWJH, Perola, M, Pirastu, N, Pirastu, M, Polasek, O, Posthuma, Daniëlle, Power, C, Province, MA, Samani, NJ, Schlessinger, D, Schmidt, R, Sorensen, TIA, Spector, TD, Stefansson, K, Thorsteinsdottir, U, Thurik, Roy, Timpson, NJ, Tiemeier, Henning, Tung, JY, Uitterlinden, André, Vitart, V, Vollenweider, P, Weir, DR, Wilson, JF, Wright, AF, Conley, DC, Krueger, RF, Smith, GD, Hofman, Bert, Laibson, DI, Medland, SE, Meyer, MN, Yang, Jiaqi, Johannesson, M, Visscher, PM, Esko, T, Koellinger, PD, Cesarini, D, and Benjamin, DJ
Abstract: Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample(1,2) of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
Published: 2016

12. New genetic loci link adipose and insulin biology to body fat distribution.

Author: ADIPOGen Consortium, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GEFOS Consortium, GENIE Consortium, International Endogene Consortium, LifeLines Cohort Study, MAGIC Investigators, MuTHER Consortium, PAGE Consortium, ReproGen Consortium, GLGC, ICBP, Dastani, Z., Hivert, MF., Timpson, N., Perry, JR., Yuan, X., Scott, RA., Henneman, P., Heid, IM., Kizer, JR., Lyytikainen, LP., Fuchsberger, C., Tanaka, T., Morris, AP., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, JS., Uh, HW., Wu, Y., Bidulescu, A., Rasmussen-Torvik, LJ., Greenwood, CM., Ladouceur, M., Grimsby, J., Manning, AK., Liu, CT., Kooner, J., Mooser, VE., Vollenweider, P., Kapur, KA., Chambers, J., Wareham, NJ., Langenberg, C., Frants, R., Willemsvan-vanDijk, K., Oostra, BA., Willems, SM., Lamina, C., Winkler, T., Psaty, BM., Tracy, RP., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, PP., Evans, DM., St Pourcain, B., Sattar, N., Wood, A., Bandinelli, S., Carlson, OD., Egan, JM., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, ML., Loo, BM., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, HE., Deloukas, P., Katsareli, E., Couper, DJ., Duncan, BB., Kloppenburg, M., Adair, LS., Borja, JB., Wilson, JG., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, TM., Allison, MA., Redline, S., Buxbaum, SG., Mohlke, KL., Meulenbelt, I., Ballantyne, CM., Dedoussis, GV., Hu, FB., Liu, Y., Paulweber, B., Spector, TD., Slagboom, P., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, JC., Salomaa, V., Eriksson, JG., Frayling, TM., Hicks, AA., Lehtimäki, T., Smith, GD., Siscovick, DS., Kronenberg, F., van Duijn, C., Loos, RJ., Waterworth, DM., Meigs, JB., Dupuis, J., Richards, JB., Willenborg, C., Farrall, M., Assimes, TL., Thompson, JR., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, BA., Stirrups, K., König, IR., Cazier, JB., Johansson£££Åsa£££ Å., Hall, AS., Lee, JY., Willer, CJ., 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K.L.
Abstract: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Published: 2015

13. New genetic loci link adipose and insulin biology to body fat distribution

Author: Shungin, D, Winkler, T, Croteau Chonka, D, Ferreira, T, Locke, A, Mägi, R, Strawbridge, R, Pers, T, Fischer, K, Justice, A, Workalemahu, T, Wu, J, Buchkovich, M, Heard Costa, N, Roman, T, Drong, A, Song, C, Gustafsson, S, Day, F, Esko, T, Fall, T, Kutalik, Z, Luan, J, Randall, J, Scherag, A, Vedantam, S, Wood, A, Chen, J, Fehrmann, R, Karjalainen, J, Kahali, B, Liu, C, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bragg Gresham, J, Buyske, S, Demirkan, A, Ehret, G, Feitosa, M, Goel, A, Jackson, A, Johnson, T, Kleber, M, Kristiansson, K, Mangino, M, Leach, I, Medina Gomez, C, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Stanca'Kova', A, Sung, Y, Tanaka, T, Teumer, A, Van Vliet Ostaptchouk, J, Yengo, L, Zhang, W, Albrecht, E, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Böhringer, S, Bonnet, F, Böttcher, Y, Bruinenberg, M, Carba, D, Caspersen, I, Clarke, R, Daw, E, Deelen, J, Deelman, E, Delgado, G, Doney, A, Eklund, N, Erdos, M, Estrada, K, Eury, E, Friedrich, N, Garcia, M, Giedraitis, V, Gigante, B, Go, A, Golay, A, Grallert, H, Grammer, T, Gräsler, J, Grewal, J, Groves, C, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heikkilä, K, Herzig, K, Helmer, Q, Hillege, H, Holmen, O, Hunt, S, Isaacs, A, Ittermann, T, James, A, Johansson, I, Juliusdottir, T, Kalafati, I, Kinnunen, L, Koenig, W, Kooner, I, Kratzer, W, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Menni, C, Merger, S, Mihailov, E, Milani, L, Mills, R, Moayyeri, A, Monda, K, Mooijaart, S, Mühleisen, T, Mulas, A, Müller, G, Müller Nurasyid, M, Nagaraja, R, Nalls, M, Narisu, N, Glorioso, N, Nolte, I, Olden, M, Rayner, N, Renstrom, F, Ried, J, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Sennblad, B, Seufferlein, T, Sitlani, C, Smith, A, Stirrups, K, Stringham, H, Sundström, J, Swertz, M, Swift, A, Syvänen, A, Tayo, B, Thorand, B, Thorleifsson, G, Tomaschitz, A, Troffa, C, Van Oort, F, Verweij, N, Vonk, J, Waite, L, Wennauer, R, Wilsgaard, T, Wojczynski, M, Wong, A, Zhang, Q, Zhao, J, Brennan, E, Choi, M, Eriksson, P, Folkersen, L, Franco Cereceda, A, Gharavi, A, Hedman, A, Hivert, M, Huang, J, Kanoni, S, Karpe, F, Keildson, S, Kiryluk, K, Liang, L, Lifton, R, Ma, B, Mcknight, A, Mcpherson, R, Metspalu, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Olsson, C, Perry, J, Reinmaa, E, Salem, R, Sandholm, N, Schadt, E, Scott, R, Stolk, L, Vallejo, E, Westra, H, Zondervan, K, Amouyel, P, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Brown, M, Burnier, M, Campbell, H, Chakravarti, A, Chines, P, Claudi Boehm, S, Collins, F, Crawford, D, Danesh, J, De Faire, U, De Geus, E, Dörr, M, Erbel, R, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gieger, C, Gudnason, V, Haiman, C, 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Moayyeri A, Vandenput L, Willner D, Xiao SM, Yerges Armstrong LM, Zheng HF, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Wilson SG, Aalto V, Alen M, Aragaki AK, Center JR, Dailiana Z, Duggan DJ, Garcia Giralt N, Giroux S, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Svensson O, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Cheng S, Christiansen C, Cooper C, Frost M, Goltzman D, González Macías J, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren Ö, Lorenc RS, Marc J, Mellström D, Obermayer Pietsch B, Olmos JM, Pettersson Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL, Urreizti R, Van Hul W, Zarrabeitia MT, Castano Betancourt M, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina Gómez C, Palsson ST, Reppe S, Sigurdsson G, van Meurs JB, Verlaan D, Williams FM, Wood AR, Zhou Y, Gautvik KM, Raychaudhuri S, Cauley JA, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Jackson RD, Jones G, Khaw KT, Lorentzon M, McCloskey E, Nandakumar K, Nicholson GC, Peacock M, Pols H, Prince RL, Reid IR, Robbins J, Sambrook PN, Sham PC, Tylavsky FA, Cupples LA, Econs MJ, Kung AW, Reeve J, Streeten EA, Zillikens MC, Ohlsson C, Karasik D, Brown MA, Ralston SH, Ioannidis JP, Kiel DP, Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, McKay GJ, Williams WW, Sadlier DM, Mäkinen VP, Swan EJ, Boright AP, Ahlqvist E, Deshmukh HA, Keller BJ, Huang H, Ahola A, Fagerholm E, Gordin D, Harjutsalo V, He B, Heikkilä O, Hietala K, Kytö J, Lahermo P, Lehto M, Österholm AM, Parkkonen M, Pitkäniemi J, Rosengård Bärlund M, Saraheimo M, Sarti C, Söderlund J, Soro Paavonen A, Syreeni A, Thorn LM, Tikkanen H, Tolonen N, Tryggvason K, Tuomilehto J, Wadén J, Gill GV, Prior S, Guiducci C, Mirel DB, Taylor A, Hosseini M, Parving HH, Rossing P, Tarnow L, Ladenvall C, Alhenc Gelas F, Lefebvre P, Rigalleau V, Roussel R, Tregouet DA, Maestroni A, Maestroni S, Falhammar H, Gu T, Möllsten A, Cimponeriu D, Mihai I, Mota M, Mota E, Serafinceanu C, Stavarachi M, Hanson RL, Nelson RG, Kretzler M, Colhoun HM, Panduru NM, Gu H, Brismar K, Zerbini G, Hadjadj S, Marre M, Lajer M, Waggott D, Savage DA, Bain SC, Martin F, Hirschhorn JN, Godson C, Groop PH, Maxwell AP, Schmidt EM, Sengupta S, Peloso GM, Ganna A, Chen J, Buchkovich ML, Mora S, Bragg Gresham JL, Chang HY, Den Hertog HM, Donnelly LA, Ehret GB, Feitosa MF, Ferreira T, Fraser RM, Freitag DF, Gurdasani D, Heikkilä K, Hyppönen E, Jackson AU, Kaakinen M, Kettunen J, Li X, Magnusson PK, Mangino M, Montasser ME, Nolte IM, Palmer CD, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Sidore C, Surakka I, Van den Herik EG, Volcik KA, Wong A, Asiki G, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, CESANA, GIANCARLO, Elliott P, Eyjolfsson GI, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hartikainen AL, Hung YJ, Jones MR, Kaleebu P, Kastelein JJ, Kim E, Komulainen P, Kumari M, Lin SY, Lindström J, Mach F, McArdle WL, Müller G, Nagaraja R, Narisu N, Nieminen TV, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stančáková A, Swift AJ, Tiret L, van Pelt L, Vedantam S, Wainwright N, Wijmenga C, Willemsen G, Wilsgaard T, Young EH, Bennett F, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Chakravarti A, Chen YD, Collins FS, Cooper RS, Feranil AB, Freimer NB, Gieger C, Groop LC, Hingorani A, Hovingh G, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Järvelin MR, Kaprio J, Kesäniemi A, Kivimaki M, Koudstaal PJ, Krauss RM, Kuh D, Kyvik KO, Lakka TA, Lindgren CM, Martin NG, McKenzie CA, Meneton P, Moilanen L, Munroe PB, Njølstad I, Power C, Price JF, Rauramaa R, Sanghera DK, Saramies J, Schwarz PE, Sheu WH, Strachan DP, Tayo BO, Tremoli E, Uusitupa M, Whitfield JB, Wolffenbuttel BH, Ordovas JM, Rich SS, Abecasis GR, Abecasis G, Caulfield M, Chasman D, Ehret G, Johnson A, Johnson L, Larson M, Levy D, Munroe P, Newton Cheh C, O'Reilly P, Palmas W, Psaty B, Rice K, Smith A, Snider H, Tobin M, Van Duijn C, Verwoert G, Rice KM, Tobin MD, Verwoert GC, Pihur V, O'Reilly PF, Launer L, Aulchenko Y, Heath S, Sõber S, Arora P, Zhang F, Lucas G, Milaneschi Y, Parker AN, Fava C, Fox ER, Go MJ, Sjögren M, Vinay D, Alexander M, Tabara Y, Shaw Hawkins S, Whincup PH, Shi G, Tayo B, Seielstad M, Sim X, Nguyen KD, Matullo G, Gaunt TR, Onland Moret NC, Cooper MN, Platou CG, Org E, Hardy R, Dahgam S, Palmen J, Kuznetsova T, Uiterwaal CS, Adeyemo A, Ludwig B, Tomaszewski M, Tzoulaki I, Palmer ND, Chang YP, Steinle NI, Grobbee DE, Morrison AC, Najjar S, Hadley D, Brown MJ, Connell JM, Hingorani AD, Day IN, Lawlor DA, Beilby JP, Lawrence RW, Ongen H, Li Y, Young JH, Bis JC, Lee NR, Bolton JA, Chaturvedi N, Islam M, Jafar TH, Kulkarni SR, Grässler J, Howard P, Guarrera S, Ricceri F, Emilsson V, Plump A, Weder AB, Sun YV, Bergman RN, Scott LJ, Stringham HM, Peltonen L, Vartiainen E, Brand SM, Staessen JA, Wang TJ, Burton PR, Artigas MS, Dong Y, Snieder H, Wang X, Zhu H, Lohman KK, Rudock ME, Heckbert SR, Smith NL, Wiggins KL, Doumatey A, Shriner D, Veldre G, Viigimaa M, Kinra S, Prabhakaran D, Tripathy V, Langefeld CD, Rosengren A, Thelle DS, Corsi AM, Singleton A, Forrester T, Hilton G, Salako T, Iwai N, Kita Y, Ogihara T, Ohkubo T, Okamura T, Ueshima H, Umemura S, Eyheramendy S, Meitinger T, Cho YS, Kim HL, Scott J, Sehmi JS, Hedblad B, Nilsson P, Stanèáková A, Raffel LJ, Yao J, Schwartz SM, Ikram M, Longstreth W. Jr, Mosley TH, Seshadri S, Shrine NR, Wain LV, Morken MA, Laitinen J, Zitting P, Cooper JA, van Gilst WH, Janipalli CS, Mani K, Yajnik CS, Mattace Raso FU, Lakatta EG, Orru M, Scuteri A, Ala Korpela M, Kangas AJ, Soininen P, Tukiainen T, Würtz P, Ong RT, Dörr M, Galan P, Hercberg S, Lathrop M, Zelenika D, Zhai G, Meschia JF, Nalls MA, Sharma P, Terzic J, Kumar M, Denniff M, Zukowska Szczechowska E, Wagenknecht LE, Fowkes F, Charchar FJ, Rotimi C, Bots ML, Brand E, Talmud PJ, Nyberg F, Laan M, Palmer LJ, van der Schouw YT, Casas JP, Vineis P, Ganesh SK, Wong TY, Tai ES, Rao DC, Morris RW, Dominiczak AF, Marmot MG, Miki T, Chandak GR, Zhu X, Gyllensten UB, Elosua R, Soranzo N, Sijbrands EJ, Uda M, Vasan RS, Larson MG, Caulfield MJ, Anderson CA, Gordon S, Guo Q, Henders A, Lambert A, Kraft P, Kennedy SH, Macgregor S, Missmer SA, Montgomery GW, Nyholt DR, Painter JN, Roseman F, Treloar SA, Visscher PM, Wallace L, Zondervan KT, Alizadeh B, de Boer RA, Boezen HM, Bruinenberg M, Franke L, Hillege HL, van der Klauw MM, Ormel J, Postma DS, Rosmalen JG, Slaets JP, Stolk RP, Lagou V, Welch RP, Wheeler E, Rehnberg E, Yengo L, Lecoeur C, Johnson PC, Mahajan A, Verweij N, Hottenga JJ, Sennblad B, Salo P, Timpson NJ, Hui J, Bielak LF, Zhao W, Horikoshi M, Navarro P, Fall T, Chen H, Robertson N, Rybin D, Chines PS, Song K, An P, Marullo L, Jansen H, Oldehinkel AJ, North KE, Forouhi NG, Edkins S, Varga TV, Oksa H, Antonella M, Kong A, Herder C, Antti J, Miljkovic I, Atalay M, Kiess W, James AL, Smit JH, Campbell S, Fowkes GR, Basart HV, Rathmann W, Maerz W, Province MA, Watanabe RM, de Geus EJ, Penninx BW, Oostra B, Toenjes A, Peyser PA, Körner A, Keinanen Kiukaanniemi SM, Saaristo TE, Boomsma D, Cucca F, Balkau B, Froguel P, Jarvelin MR, Bouatia Naji N, Ahmadi KR, Ainali C, Barrett A, Bataille V, Bell JT, Buil A, Dermitzakis ET, Dimas AS, Durbin R, Glass D, Hassanali N, Hedman ÅK, Ingle C, Keildson S, Knowles D, Krestyaninova M, Lowe CE, Meduri E, di Meglio P, Min JL, Montgomery SB, Nestle FO, Nica AC, Nisbet J, O'Rahilly S, Parts L, Potter S, Sekowska M, Shin SY, Small KS, Surdulescu G, Travers ME, Tsaprouni L, Tsoka S, Wilk A, Matise T, Buyske S, Higashio J, Williams R, Nato A, Ambite JL, Deelman E, Manolio T, Hindorff L, Heiss G, Taylor K, Avery C, Graff M, Lin D, Quibrera M, Cochran B, Kao L, Umans J, Cole S, MacCluer J, Person S, Pankow J, Gross M, Fornage M, Durda P, Jenny N, Patsy B, Arnold A, Buzkova P, Crawford D, Haines J, Murdock D, Glenn K, Brown Gentry K, Thornton Wells T, Dumitrescu L, Jeff J, Bush WS, Mitchell SL, Goodloe R, Wilson S, Boston J, Malinowski J, Restrepo N, Oetjens M, Fowke J, Zheng W, Spencer K, Ritchie M, Pendergrass S, Le Marchand L, Wilkens L, Park L, Tiirikainen M, Kolonel L, Lim U, Cheng I, Wang H, Shohet R, Haiman C, Stram D, Henderson B, Monroe K, Schumacher F, Peters U, Anderson G, Carlson C, Prentice R, LaCroix A, Wu C, Carty C, Gong J, Rosse S, Young A, Haessler J, Kocarnik J, Lin Y, Jackson R, Duggan D, Kuller L, Stolk L, He C, Sulem P, Barbalic M, Broer L, Byrne EM, Gudbjartsson DF, McArdle PF, Porcu E, van Wingerden S, Zhuang W, Albrecht E, Alizadeh BZ, Lauc LB, Broekmans FJ, Burri A, Chanock SJ, Chen C, Corre T, Coviello AD, d'Adamo P, Davies G, Deary IJ, Ebrahim S, Fauser BC, Ferreli L, Folsom AR, Garcia ME, Hall P, Haller T, Hankinson SE, Hass M, Heath AC, Janssens AC, Keyzer J, Lahti J, Lai S, Laisk T, Laven JS, Liu J, Lopez LM, Louwers YV, Marongiu M, Klaric IM, Masciullo C, McKnight B, Medland SE, Melzer D, Newman AB, Paré G, Peeters PH, Plump AS, Pop VJ, Räikkönen K, Salumets A, Smith JA, Stacey SN, Starr JM, Stathopoulou MG, Tenesa A, Thorand B, Tryggvadottir L, Tsui K, van Dam RM, van Gils CH, van Nierop P, Vink JM, Voorhuis M, Wallaschofski H, Widen E, Wijnands van Gent CJ, Zgaga L, Zygmunt M, Arnold AM, Buring JE, Crisponi L, Demerath EW, Hunter DJ, Schlessinger D, Murray A, Murabito JM, Visser JA, Lunetta KL, Elks CE, Cousminer DL, Feenstra B, Lin P, van Wingerden SW, Smith EN, Warrington NM, Alavere H, Berenson GS, Blackburn H, Busonero F, Chen W, Couper D, Easton DF, Foroud T, Geller F, Hernandez DG, Kilpeläinen TO, Li S, Melbye M, Murray JC, Murray SS, Nelis M, Ness AR, Northstone K, Pennell CE, Pharoah P, Rafnar T, Rice JP, Ring SM, Schork NJ, Segrè AV, Sovio U, Srinivasan SR, Tammesoo ML, Tyrer J, Weedon MN, Wichmann H, Young L, Zhuang WV, Bierut LJ, Boyd HA, and Murray A.
Abstract: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10-8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Published: 2015

14. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans.

Author: Timpson, NJ, Walter, K, Min, JL, Tachmazidou, I, Malerba, G, Shin, S-Y, Chen, L, Futema, M, Southam, L, Iotchkova, V, Cocca, M, Huang, J, Memari, Y, McCarthy, S, Danecek, P, Muddyman, D, Mangino, M, Menni, C, Perry, JRB, Ring, SM, Gaye, A, Dedoussis, G, Farmaki, A-E, Burton, P, Talmud, PJ, Gambaro, G, Spector, TD, Smith, GD, Durbin, R, Richards, JB, Humphries, SE, Zeggini, E, Soranzo, N, UK1OK Consortium Members, Timpson, NJ, Walter, K, Min, JL, Tachmazidou, I, Malerba, G, Shin, S-Y, Chen, L, Futema, M, Southam, L, Iotchkova, V, Cocca, M, Huang, J, Memari, Y, McCarthy, S, Danecek, P, Muddyman, D, Mangino, M, Menni, C, Perry, JRB, Ring, SM, Gaye, A, Dedoussis, G, Farmaki, A-E, Burton, P, Talmud, PJ, Gambaro, G, Spector, TD, Smith, GD, Durbin, R, Richards, JB, Humphries, SE, Zeggini, E, Soranzo, N, and UK1OK Consortium Members
Abstract: The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.
Published: 2014

15. Common variation near ROBO2 is associated with expressive vocabulary in infancy

Author: St Pourcain, B, Cents, RAM, Whitehouse, AJO, Haworth, CMA, Davis, OSP, O'Reilly, PF, Roulstone, S, Wren, Y, Ang, QW, Velders, FP, Evans, DM, Kemp, JP, Warrington, NM, Miller, L, Timpson, NJ, Ring, SM, Verhulst, Frank, Hofman, Bert, Rivadeneira, Fernando, Meaburn, EL, Price, TS, Dale, PS, Pillas, D, Yliherva, A, Rodriguez, A, Golding, J, Jaddoe, Vincent, Jarvelin, MR, Plomin, R, Pennell, CE, Tiemeier, Henning, Smith, GD, St Pourcain, B, Cents, RAM, Whitehouse, AJO, Haworth, CMA, Davis, OSP, O'Reilly, PF, Roulstone, S, Wren, Y, Ang, QW, Velders, FP, Evans, DM, Kemp, JP, Warrington, NM, Miller, L, Timpson, NJ, Ring, SM, Verhulst, Frank, Hofman, Bert, Rivadeneira, Fernando, Meaburn, EL, Price, TS, Dale, PS, Pillas, D, Yliherva, A, Rodriguez, A, Golding, J, Jaddoe, Vincent, Jarvelin, MR, Plomin, R, Pennell, CE, Tiemeier, Henning, and Smith, GD
Abstract: Twin studies suggest that expressive vocabulary at similar to 24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology consortium, analysing an early (15-18 months, 'one-word stage', N-Total = 8,889) and a later (24-30 months, 'two-word stage', N-Total = 10,819) phase of language acquisition. For the early phase, one single-nucleotide polymorphism (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon-binding receptor, reaches the genome-wide significance level (P = 1.3 x 10(-8)) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by genome-wide complex trait analysis (meta-GCTA h(5-18-months)(2) = 0.13, meta-GCTA h(24-30-months)(2) = 0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h(24-months)(2) = 0.20).
Published: 2014

16. Genome-Wide Association Study of Height-Adjusted BMI in Childhood Identifies Functional Variant in ADCY3

Author: Stergiakouli, E, Gaillard, Romy, Tavare, JM, Balthasar, N, Loos, RJ, Taal, Rob, Evans, DM, Rivadeneira, Fernando, St Pourcain, B, Uitterlinden, André, Kemp, JP, Hofman, Bert, Ring, SM, Cole, TJ, Jaddoe, Vincent, Smith, GD, Timpson, NJ, Stergiakouli, E, Gaillard, Romy, Tavare, JM, Balthasar, N, Loos, RJ, Taal, Rob, Evans, DM, Rivadeneira, Fernando, St Pourcain, B, Uitterlinden, André, Kemp, JP, Hofman, Bert, Ring, SM, Cole, TJ, Jaddoe, Vincent, Smith, GD, and Timpson, NJ
Abstract: ObjectiveGenome-wide association studies (GWAS) of BMI are mostly undertaken under the assumption that kg/m(2) is an index of weight fully adjusted for height, but in general this is not true. The aim here was to assess the contribution of common genetic variation to a adjusted version of that phenotype which appropriately accounts for covariation in height in children. MethodsA GWAS of height-adjusted BMI (BMI[x]=weight/height(x)), calculated to be uncorrelated with height, in 5809 participants (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was performed. ResultsGWAS based on BMI[x] yielded marked differences in genomewide results profile. SNPs in ADCY3 (adenylate cyclase 3) were associated at genome-wide significance level (rs11676272 (0.28 kg/m(3.1) change per allele G (0.19, 0.38), P=6 x 10(-9)). In contrast, they showed marginal evidence of association with conventional BMI [rs11676272 (0.25 kg/m(2) (0.15, 0.35), P=6 x 10(-7))]. Results were replicated in an independent sample, the Generation R study. ConclusionsAnalysis of BMI[x] showed differences to that of conventional BMI. The association signal at ADCY3 appeared to be driven by a missense variant and it was strongly correlated with expression of this gene. Our work highlights the importance of well understood phenotype use (and the danger of convention) in characterising genetic contributions to complex traits.
Published: 2014

17. Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment

Author: Kemp, JP, Medina-Gomez, C, Estrada Gil, Karol, St Pourcain, B, Heppe, Denise, Warrington, NM, Oei - Oei, Ling, Ring, SM, Kruithof, CJ (Claudia), Timpson, NJ, Wolber, LE, Reppe, S, Gautvik, K, Grundberg, E, Ge, B, van der Eerden, Bram, van de Peppel, Jeroen, Hibbs, MA, Ackert-Bicknell, CL, Choi, K, Koller, DL, Econs, MJ, Williams, FMK, Foroud, T, Zillikens, M.C., Ohlsson, C, Hofman, Bert, Uitterlinden, André, Smith, GD, Jaddoe, Vincent, Tobias, JH, Rivadeneira, Fernando, Evans, DM, Kemp, JP, Medina-Gomez, C, Estrada Gil, Karol, St Pourcain, B, Heppe, Denise, Warrington, NM, Oei - Oei, Ling, Ring, SM, Kruithof, CJ (Claudia), Timpson, NJ, Wolber, LE, Reppe, S, Gautvik, K, Grundberg, E, Ge, B, van der Eerden, Bram, van de Peppel, Jeroen, Hibbs, MA, Ackert-Bicknell, CL, Choi, K, Koller, DL, Econs, MJ, Williams, FMK, Foroud, T, Zillikens, M.C., Ohlsson, C, Hofman, Bert, Uitterlinden, André, Smith, GD, Jaddoe, Vincent, Tobias, JH, Rivadeneira, Fernando, and Evans, DM
Published: 2014

18. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

Author: Timpson, Nj, Walter, K, Min, Jl, Tachmazidou, I, Malerba, G, Shin, S, Chen, L, Futema, M, Southam, L, Iotchkova, V, Cocca, M, Huang, J, Memari, Y, Mccarthy, S, Danecek, P, Muddyman, D, Mangino, M, Menni, C, Perry, Jrb, Ring, Sm, Gaye, A, Dedoussis, G, Farmaki, A, Burton, P, Talmud, Pj, Gambaro, Giovanni, Spector, Td, Smith, Gd, Durbin, R, Richards, Jb, Humphries, Se, Zeggini, E, Soranzo, N., Gambaro, Giovanni (ORCID:0000-0001-5733-2370), Timpson, Nj, Walter, K, Min, Jl, Tachmazidou, I, Malerba, G, Shin, S, Chen, L, Futema, M, Southam, L, Iotchkova, V, Cocca, M, Huang, J, Memari, Y, Mccarthy, S, Danecek, P, Muddyman, D, Mangino, M, Menni, C, Perry, Jrb, Ring, Sm, Gaye, A, Dedoussis, G, Farmaki, A, Burton, P, Talmud, Pj, Gambaro, Giovanni, Spector, Td, Smith, Gd, Durbin, R, Richards, Jb, Humphries, Se, Zeggini, E, Soranzo, N., and Gambaro, Giovanni (ORCID:0000-0001-5733-2370)
Abstract: The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.
Published: 2014

19. Genome-wide association study of shared components of reading disability and language impairment.

Author: Eicher, JD, Eicher, JD, Powers, NR, Miller, LL, Akshoomoff, N, Amaral, DG, Bloss, CS, Libiger, O, Schork, NJ, Darst, BF, Casey, BJ, Chang, L, Ernst, T, Frazier, J, Kaufmann, WE, Keating, B, Kenet, T, Kennedy, D, Mostofsky, S, Murray, SS, Sowell, ER, Bartsch, H, Kuperman, JM, Brown, TT, Hagler, DJ, Dale, AM, Jernigan, TL, St Pourcain, B, Davey Smith, G, Ring, SM, Gruen, JR, Pediatric Imaging, Neurocognition, and Genetics Study, Eicher, JD, Eicher, JD, Powers, NR, Miller, LL, Akshoomoff, N, Amaral, DG, Bloss, CS, Libiger, O, Schork, NJ, Darst, BF, Casey, BJ, Chang, L, Ernst, T, Frazier, J, Kaufmann, WE, Keating, B, Kenet, T, Kennedy, D, Mostofsky, S, Murray, SS, Sowell, ER, Bartsch, H, Kuperman, JM, Brown, TT, Hagler, DJ, Dale, AM, Jernigan, TL, St Pourcain, B, Davey Smith, G, Ring, SM, Gruen, JR, and Pediatric Imaging, Neurocognition, and Genetics Study
Abstract: Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.
Published: 2013

20. Genome-wide association study of shared components of reading disability and language impairment.

Author: Eicher, JD, Eicher, JD, Powers, NR, Miller, LL, Akshoomoff, N, Amaral, DG, Bloss, CS, Libiger, O, Schork, NJ, Darst, BF, Casey, BJ, Chang, L, Ernst, T, Frazier, J, Kaufmann, WE, Keating, B, Kenet, T, Kennedy, D, Mostofsky, S, Murray, SS, Sowell, ER, Bartsch, H, Kuperman, JM, Brown, TT, Hagler, DJ, Dale, AM, Jernigan, TL, St Pourcain, B, Davey Smith, G, Ring, SM, Gruen, JR, Pediatric Imaging, Neurocognition, and Genetics Study, Eicher, JD, Eicher, JD, Powers, NR, Miller, LL, Akshoomoff, N, Amaral, DG, Bloss, CS, Libiger, O, Schork, NJ, Darst, BF, Casey, BJ, Chang, L, Ernst, T, Frazier, J, Kaufmann, WE, Keating, B, Kenet, T, Kennedy, D, Mostofsky, S, Murray, SS, Sowell, ER, Bartsch, H, Kuperman, JM, Brown, TT, Hagler, DJ, Dale, AM, Jernigan, TL, St Pourcain, B, Davey Smith, G, Ring, SM, Gruen, JR, and Pediatric Imaging, Neurocognition, and Genetics Study
Abstract: Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.
Published: 2013

21. Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances

Author: Fatemifar, G, Hoggart, CJ, Paternoster, L, Kemp, JP, Prokopenko, I, Horikoshi, M, Wright, VJ, Tobias, JH, Richmond, S, Zhurov, AI, Toma, AM, Pouta, A, Taanila, A, Sipila, K, Lähdesmäki, R, Pillas, D, Geller, F, Feenstra, B, Melbye, M, Nohr, EA, Ring, SM, St Pourcain, B, Timpson, NJ, Smith, GD, Jarvelin, MR, Evans, DM, Fatemifar, G, Hoggart, CJ, Paternoster, L, Kemp, JP, Prokopenko, I, Horikoshi, M, Wright, VJ, Tobias, JH, Richmond, S, Zhurov, AI, Toma, AM, Pouta, A, Taanila, A, Sipila, K, Lähdesmäki, R, Pillas, D, Geller, F, Feenstra, B, Melbye, M, Nohr, EA, Ring, SM, St Pourcain, B, Timpson, NJ, Smith, GD, Jarvelin, MR, and Evans, DM
Abstract: Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studieswere combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 3 1028) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P 5 9.080 3 10217). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development. © The Author 2013. Published by Oxford University Press. All rights reserved.
Published: 2013

22. Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances

Author: Fatemifar, G, Hoggart, CJ, Paternoster, L, Kemp, JP, Prokopenko, I, Horikoshi, M, Wright, VJ, Tobias, JH, Richmond, S, Zhurov, AI, Toma, AM, Pouta, A, Taanila, A, Sipila, K, Lähdesmäki, R, Pillas, D, Geller, F, Feenstra, B, Melbye, M, Nohr, EA, Ring, SM, St Pourcain, B, Timpson, NJ, Smith, GD, Jarvelin, MR, Evans, DM, Fatemifar, G, Hoggart, CJ, Paternoster, L, Kemp, JP, Prokopenko, I, Horikoshi, M, Wright, VJ, Tobias, JH, Richmond, S, Zhurov, AI, Toma, AM, Pouta, A, Taanila, A, Sipila, K, Lähdesmäki, R, Pillas, D, Geller, F, Feenstra, B, Melbye, M, Nohr, EA, Ring, SM, St Pourcain, B, Timpson, NJ, Smith, GD, Jarvelin, MR, and Evans, DM
Abstract: Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studieswere combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 3 1028) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P 5 9.080 3 10217). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development. © The Author 2013. Published by Oxford University Press. All rights reserved.
Published: 2013

23. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author: Paternoster, L, Standl, M, Chen, C-M, Ramasamy, A, Bonnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Saaf, A, Franke, A, Ellinghaus, D, Foelster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, A-L, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souef, P, St Pourcain, B, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, H-E, Mueller-Nurasyid, M, Novak, N, Klopp, N, Rodriguez, E, McArdle, W, Linneberg, A, Menne, T, Nohr, EA, Hofman, A, Uitterlinden, AG, van Duijin, CM, Rivadeneira, F, de Jongste, JC, van der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, J-J, Postma, D, Koppelman, GH, Smit, HA, Soderhall, C, Chawes, B, Kreiner-Moller, E, Bisgaard, H, Melen, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Jarvis, DL, Jaddoe, VWV, Gieger, C, Strachan, DP, Martin, NG, Jarvelin, M-R, Heinrich, J, Evans, DM, Weidinger, S, Paternoster, L, Standl, M, Chen, C-M, Ramasamy, A, Bonnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Saaf, A, Franke, A, Ellinghaus, D, Foelster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, A-L, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souef, P, St Pourcain, B, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, H-E, Mueller-Nurasyid, M, Novak, N, Klopp, N, Rodriguez, E, McArdle, W, Linneberg, A, Menne, T, Nohr, EA, Hofman, A, Uitterlinden, AG, van Duijin, CM, Rivadeneira, F, de Jongste, JC, van der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, J-J, Postma, D, Koppelman, GH, Smit, HA, Soderhall, C, Chawes, B, Kreiner-Moller, E, Bisgaard, H, Melen, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Jarvis, DL, Jaddoe, VWV, Gieger, C, Strachan, DP, Martin, NG, Jarvelin, M-R, Heinrich, J, Evans, DM, and Weidinger, S
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
Published: 2012

24. WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk

Author: Gibson, G, Zheng, H-F, Tobias, JH, Duncan, E, Evans, DM, Eriksson, J, Paternoster, L, Yerges-Armstrong, LM, Lehtimaki, T, Bergstrom, U, Kahonen, M, Leo, PJ, Raitakari, O, Laaksonen, M, Nicholson, GC, Viikari, J, Ladouceur, M, Lyytikainen, L-P, Medina-Gomez, C, Rivadeneira, F, Prince, RL, Sievanen, H, Leslie, WD, Mellstrom, D, Eisman, JA, Moverare-Skrtic, S, Goltzman, D, Hanley, DA, Jones, G, Pourcain, BS, Xiao, Y, Timpson, NJ, Smith, GD, Reid, IR, Ring, SM, Sambrook, PN, Karlsson, M, Dennison, EM, Kemp, JP, Danoy, P, Sayers, A, Wilson, SG, Nethander, M, McCloskey, E, Vandenput, L, Eastell, R, Liu, J, Spector, T, Mitchell, BD, Streeten, EA, Brommage, R, Pettersson-Kymmer, U, Brown, MA, Ohlsson, C, Richards, JB, Lorentzon, M, Gibson, G, Zheng, H-F, Tobias, JH, Duncan, E, Evans, DM, Eriksson, J, Paternoster, L, Yerges-Armstrong, LM, Lehtimaki, T, Bergstrom, U, Kahonen, M, Leo, PJ, Raitakari, O, Laaksonen, M, Nicholson, GC, Viikari, J, Ladouceur, M, Lyytikainen, L-P, Medina-Gomez, C, Rivadeneira, F, Prince, RL, Sievanen, H, Leslie, WD, Mellstrom, D, Eisman, JA, Moverare-Skrtic, S, Goltzman, D, Hanley, DA, Jones, G, Pourcain, BS, Xiao, Y, Timpson, NJ, Smith, GD, Reid, IR, Ring, SM, Sambrook, PN, Karlsson, M, Dennison, EM, Kemp, JP, Danoy, P, Sayers, A, Wilson, SG, Nethander, M, McCloskey, E, Vandenput, L, Eastell, R, Liu, J, Spector, T, Mitchell, BD, Streeten, EA, Brommage, R, Pettersson-Kymmer, U, Brown, MA, Ohlsson, C, Richards, JB, and Lorentzon, M
Abstract: We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)
Published: 2012

25. Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5CHRNA3CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight

Author: Tyrrell, J, Huikari, V, Christie, JT, Cavadino, A, Bakker, Rachel, Brion, MJA, Geller, F, Paternoster, L, Myhre, R, Potter, C, Johnson, PCD, Ebrahim, S, Feenstra, B, Hartikainen, AL, Hattersley, AT, Hofman, Bert, Kaakinen, M, Lowe, LP, Magnus, P, McConnachie, A, Melbye, M, Ng, JWY, Nohr, EA, Power, C, Ring, SM, Sebert, SP, Sengpiel, V, Taal, Rob, Watt, GCM, Sattar, N, Relton, CL, Jacobsson, B, Frayling, TM, Srensen, TIA, Murray, JC, Lawlor, DA, Pennell, CE, Jaddoe, Vincent, Hypponen, E, Lowe, WL, Jarvelin, MR, Smith, GD, Freathy, RM, Tyrrell, J, Huikari, V, Christie, JT, Cavadino, A, Bakker, Rachel, Brion, MJA, Geller, F, Paternoster, L, Myhre, R, Potter, C, Johnson, PCD, Ebrahim, S, Feenstra, B, Hartikainen, AL, Hattersley, AT, Hofman, Bert, Kaakinen, M, Lowe, LP, Magnus, P, McConnachie, A, Melbye, M, Ng, JWY, Nohr, EA, Power, C, Ring, SM, Sebert, SP, Sengpiel, V, Taal, Rob, Watt, GCM, Sattar, N, Relton, CL, Jacobsson, B, Frayling, TM, Srensen, TIA, Murray, JC, Lawlor, DA, Pennell, CE, Jaddoe, Vincent, Hypponen, E, Lowe, WL, Jarvelin, MR, Smith, GD, and Freathy, RM
Abstract: Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95 confidence interval (95 CI): 436 g] lower birth weight (P 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95 CI: 4to 14 g; P 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.
Published: 2012

26. Meta-Analysis of Genome-Wide Scans for Total Body BMD in Children and Adults Reveals Allelic Heterogeneity and Age-Specific Effects at the WNT16 Locus

Author: Medina-Gomez, C, Kemp, JP, Estrada Gil, Karol, Eriksson, J, Liu, J, Reppe, S, Evans, DM, Heppe, Denise, Vandenput, L, Herrera, L, Ring, SM, Kruithof, CJ (Claudia), Timpson, NJ, Zillikens, M.C., Olstad, OK, Zheng, HF, Richards, JB, Pourcain, BS, Hofman, Bert, Jaddoe, Vincent, Smith, GD, Lorentzon, M, Gautvik, KM, Uitterlinden, André, Brommage, R, Ohlsson, C, Tobias, JH, Rivadeneira, Fernando, Medina-Gomez, C, Kemp, JP, Estrada Gil, Karol, Eriksson, J, Liu, J, Reppe, S, Evans, DM, Heppe, Denise, Vandenput, L, Herrera, L, Ring, SM, Kruithof, CJ (Claudia), Timpson, NJ, Zillikens, M.C., Olstad, OK, Zheng, HF, Richards, JB, Pourcain, BS, Hofman, Bert, Jaddoe, Vincent, Smith, GD, Lorentzon, M, Gautvik, KM, Uitterlinden, André, Brommage, R, Ohlsson, C, Tobias, JH, and Rivadeneira, Fernando
Abstract: To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1 x 10(-11) observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located +/- 500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6x10(-31) and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42x10(-10)) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9x10(-16)) and rs7801723 (P = 8.9x10(-28)), also mapping to C7orf58 (r(2) = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later i
Published: 2012

27. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author: Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, and Melbye, M
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

28. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author: Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bøpnnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PMA, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AIF, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Pourcain, BS, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, Van Duijn, CM, Rivadeneira, F, De Jongste, JC, Van Der Valk, RJP, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CMT, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møpller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, and Melbye, M
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

29. Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5- CHRNA3-CHRNB4) interacts with maternal selfreported smoking status during pregnancy to influence birth weight

Author: Tyrrell, J, Huikari, V, Christie, JT, Cavadino, A, Bakker, R, Brion, MJA, Geller, F, Paternoster, L, Myhre, R, Potter, C, Johnson, PCD, Ebrahim, S, Feenstra, B, Hartikainen, AL, Hattersley, AT, Hofman, A, Kaakinen, M, Lowe, LP, Magnus, P, McConnachie, A, Melbye, M, Ng, JWY, Nohr, EA, Power, C, Ring, SM, Sebert, SP, Sengpiel, V, Taal, HR, Watt, GCM, Sattar, N, Relton, CL, Jacobsson, B, Frayling, TM, Sørensen, TIA, Murray, JC, Lawlor, DA, Pennell, CE, Jaddoe, VWV, Hypponen, E, Lowe, WL, Jarvelin, MR, Smith, GD, Freathy, RM, Tyrrell, J, Huikari, V, Christie, JT, Cavadino, A, Bakker, R, Brion, MJA, Geller, F, Paternoster, L, Myhre, R, Potter, C, Johnson, PCD, Ebrahim, S, Feenstra, B, Hartikainen, AL, Hattersley, AT, Hofman, A, Kaakinen, M, Lowe, LP, Magnus, P, McConnachie, A, Melbye, M, Ng, JWY, Nohr, EA, Power, C, Ring, SM, Sebert, SP, Sengpiel, V, Taal, HR, Watt, GCM, Sattar, N, Relton, CL, Jacobsson, B, Frayling, TM, Sørensen, TIA, Murray, JC, Lawlor, DA, Pennell, CE, Jaddoe, VWV, Hypponen, E, Lowe, WL, Jarvelin, MR, Smith, GD, and Freathy, RM
Abstract: Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P 5 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P 5 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: 24 to 14 g; P 5 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight. © The Author 2012. Published by Oxford University Press. All rights reserved.
Published: 2012

30. Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5- CHRNA3-CHRNB4) interacts with maternal selfreported smoking status during pregnancy to influence birth weight

Author: Tyrrell, J, Huikari, V, Christie, JT, Cavadino, A, Bakker, R, Brion, MJA, Geller, F, Paternoster, L, Myhre, R, Potter, C, Johnson, PCD, Ebrahim, S, Feenstra, B, Hartikainen, AL, Hattersley, AT, Hofman, A, Kaakinen, M, Lowe, LP, Magnus, P, McConnachie, A, Melbye, M, Ng, JWY, Nohr, EA, Power, C, Ring, SM, Sebert, SP, Sengpiel, V, Taal, HR, Watt, GCM, Sattar, N, Relton, CL, Jacobsson, B, Frayling, TM, Sørensen, TIA, Murray, JC, Lawlor, DA, Pennell, CE, Jaddoe, VWV, Hypponen, E, Lowe, WL, Jarvelin, MR, Smith, GD, Freathy, RM, Tyrrell, J, Huikari, V, Christie, JT, Cavadino, A, Bakker, R, Brion, MJA, Geller, F, Paternoster, L, Myhre, R, Potter, C, Johnson, PCD, Ebrahim, S, Feenstra, B, Hartikainen, AL, Hattersley, AT, Hofman, A, Kaakinen, M, Lowe, LP, Magnus, P, McConnachie, A, Melbye, M, Ng, JWY, Nohr, EA, Power, C, Ring, SM, Sebert, SP, Sengpiel, V, Taal, HR, Watt, GCM, Sattar, N, Relton, CL, Jacobsson, B, Frayling, TM, Sørensen, TIA, Murray, JC, Lawlor, DA, Pennell, CE, Jaddoe, VWV, Hypponen, E, Lowe, WL, Jarvelin, MR, Smith, GD, and Freathy, RM
Abstract: Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P 5 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P 5 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: 24 to 14 g; P 5 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight. © The Author 2012. Published by Oxford University Press. All rights reserved.
Published: 2012

31. ACTN3 genotype, athletic status, and life course physical capability: Meta-analysis of the published literature and findings from nine studies

Author: Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Moran, CN, Pitsiladis, YP, Ring, SM, Sayer, AA, Smith, GD, Starr, JM, Kuh, D, Day, IN, Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Moran, CN, Pitsiladis, YP, Ring, SM, Sayer, AA, Smith, GD, Starr, JM, Kuh, D, and Day, IN
Abstract: The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta‐analysis of the published literature on athletic status and investigate its associations with physical capability in several new population‐based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
Published: 2011

32. ACTN3 genotype, athletic status, and life course physical capability: Meta-analysis of the published literature and findings from nine studies

Author: Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Moran, CN, Pitsiladis, YP, Ring, SM, Sayer, AA, Smith, GD, Starr, JM, Kuh, D, Day, IN, Alfred, T, Ben-Shlomo, Y, Cooper, R, Hardy, R, Cooper, C, Deary, IJ, Gunnell, D, Harris, SE, Kumari, M, Martin, RM, Moran, CN, Pitsiladis, YP, Ring, SM, Sayer, AA, Smith, GD, Starr, JM, Kuh, D, and Day, IN
Abstract: The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta‐analysis of the published literature on athletic status and investigate its associations with physical capability in several new population‐based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
Published: 2011

33. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author: Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Donnelly, P, Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, and Donnelly, P
Abstract: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
Published: 2010

34. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight

Author: Freathy, RM, Mook-Kanamori, DO, Sovio, U, Prokopenko, I, Timpson, NJ, Berry, DJ, Warrington, NM, Widen, E, Hottenga, JJ, Kaakinen, M, Lange, LA, Bradfield, JP, Kerkhof, M, Marsh, JA, Maegi, R, Chen, C-M, Lyon, HN, Kirin, M, Adair, LS, Aulchenko, YS, Bennett, AJ, Borja, JB, Bouatia-Naji, N, Charoen, P, Coin, LJM, Cousminer, DL, de Geus, EJC, Deloukas, P, Elliott, P, Evans, DM, Froguel, P, Glaser, B, Groves, CJ, Hartikainen, A-L, Hassanali, N, Hirschhorn, JN, Hofman, A, Holly, JMP, Hyppoenen, E, Kanoni, S, Knight, BA, Laitinen, J, Lindgren, CM, McArdle, WL, O'Reilly, PF, Pennell, CE, Postma, DS, Pouta, A, Ramasamy, A, Rayner, NW, Ring, SM, Rivadeneira, F, Shields, BM, Strachan, DP, Surakka, I, Taanila, A, Tiesler, C, Uitterlinden, AG, van Duijn, CM, Wijga, AH, Willemsen, G, Zhang, H, Zhao, J, Wilson, JF, Steegers, EAP, Hattersley, AT, Eriksson, JG, Peltonen, L, Mohlke, KL, Grant, SFA, Hakonarson, H, Koppelman, GH, Dedoussis, GV, Heinrich, J, Gillman, MW, Palmer, LJ, Frayling, TM, Boomsma, DI, Smith, GD, Power, C, Jaddoe, VWV, Jarvelin, M-R, McCarthy, MI, Freathy, RM, Mook-Kanamori, DO, Sovio, U, Prokopenko, I, Timpson, NJ, Berry, DJ, Warrington, NM, Widen, E, Hottenga, JJ, Kaakinen, M, Lange, LA, Bradfield, JP, Kerkhof, M, Marsh, JA, Maegi, R, Chen, C-M, Lyon, HN, Kirin, M, Adair, LS, Aulchenko, YS, Bennett, AJ, Borja, JB, Bouatia-Naji, N, Charoen, P, Coin, LJM, Cousminer, DL, de Geus, EJC, Deloukas, P, Elliott, P, Evans, DM, Froguel, P, Glaser, B, Groves, CJ, Hartikainen, A-L, Hassanali, N, Hirschhorn, JN, Hofman, A, Holly, JMP, Hyppoenen, E, Kanoni, S, Knight, BA, Laitinen, J, Lindgren, CM, McArdle, WL, O'Reilly, PF, Pennell, CE, Postma, DS, Pouta, A, Ramasamy, A, Rayner, NW, Ring, SM, Rivadeneira, F, Shields, BM, Strachan, DP, Surakka, I, Taanila, A, Tiesler, C, Uitterlinden, AG, van Duijn, CM, Wijga, AH, Willemsen, G, Zhang, H, Zhao, J, Wilson, JF, Steegers, EAP, Hattersley, AT, Eriksson, JG, Peltonen, L, Mohlke, KL, Grant, SFA, Hakonarson, H, Koppelman, GH, Dedoussis, GV, Heinrich, J, Gillman, MW, Palmer, LJ, Frayling, TM, Boomsma, DI, Smith, GD, Power, C, Jaddoe, VWV, Jarvelin, M-R, and McCarthy, MI
Abstract: To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.
Published: 2010

35. Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy

Author: Gibson, G, Pillas, D, Hoggart, CJ, Evans, DM, O'Reilly, PF, Sipila, K, Lahdesmaki, R, Millwood, IY, Kaakinen, M, Netuveli, G, Blane, D, Charoen, P, Sovio, U, Pouta, A, Freimer, N, Hartikainen, A-L, Laitinen, J, Vaara, S, Glaser, B, Crawford, P, Timpson, NJ, Ring, SM, Deng, G, Zhang, W, McCarthy, MI, Deloukas, P, Peltonen, L, Elliott, P, Coin, LJM, Smith, GD, Jarvelin, M-R, Gibson, G, Pillas, D, Hoggart, CJ, Evans, DM, O'Reilly, PF, Sipila, K, Lahdesmaki, R, Millwood, IY, Kaakinen, M, Netuveli, G, Blane, D, Charoen, P, Sovio, U, Pouta, A, Freimer, N, Hartikainen, A-L, Laitinen, J, Vaara, S, Glaser, B, Crawford, P, Timpson, NJ, Ring, SM, Deng, G, Zhang, W, McCarthy, MI, Deloukas, P, Peltonen, L, Elliott, P, Coin, LJM, Smith, GD, and Jarvelin, M-R
Abstract: Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5x10(-8), and 5 with suggestive association (P<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.
Published: 2010

36. Genome-wide association study identifies eight loci associated with blood pressure

Author: Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, K, Nilsson, P, Van Der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliot, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, A, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, De Jong, PE, Snieder, H, Van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Altshuler, D, Jarvelin, M, Elliott, P, Lakatta, EG, Forouhi, N, Wareham, NJ, Loos, RJF, Deloukas, P, Lathrop, GM, Zelenika, D, Strachan, DP, Soranzo, N, Williams, FM, Zhai, G, Spector, TD, Peden, JF, Watkins, H, Ferrucci, L, Caulfield, M, Munroe, PB, Berglund, G, Melander, O, Matullo, G, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Ernst, F, Homuth, G, Völker, U, Elosua, R, Laakso, M, Connell, JM, Mooser, V, Salomaa, V, Tuomilehto, J, Laan, M, Navis, G, Seedorf, U, Syvänen, A, Tognoni, G, Sanna, S, Uda, M, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Felix, SB, Reffelmann, T, Lorbeer, R, Völzke, H, Rettig, R, Galan, P, Hercberg, S, Bingham, SA, Kooner, JS, Bandinelli, S, Meneton, P, Abecasis, G, Thompson, JR, Braga Marcano, CA, Barke, B, Dobson, R, Gungadoo, J, Lee, KL, Onipinla, A, Wallace, I, Xue, M, Clayton, DG, Leung, H, Nutland, S, Walker, NM, Todd, JA, Stevens, HE, Dunger, DB, Widmer, B, Downes, K, Cardon, LR, Kwiatkowski, DP, Barrett, JC, Evans, D, Morris, AP, Lindgren, CM, Rayner, NW, Timpson, NJ, Lyons, E, Vannberg, F, Hill, AVS, Teo, YY, Rockett, KA, Craddock, N, Attwood, AP, Bryan, C, Bumpstead, SJ, Chaney, A, Ghori, J, William, RG, Hunt, SE, Inouye, M, Keniry, E, King, E, McGinnis, R, Potter, S, Ravindrarajan, R, Whittaker, P, Withers, D, Bentley, D, Groves, CJ, Duncanson, A, Ouwehand, WH, Boorman, JP, Cant, B, Jolley, JD, Knight, AS, Koch, K, Taylor, NC, Watkins, NA, Winzer, T, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Donnely, P, Davidson, D, Marchini, JL, Spencer, ICA, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, IB, Howie, BN, Su, Z, Vukcevic, D, Easton, D, Everson, U, Hussey, JM, Meech, E, Prowse, CV, Walters, GR, Jones, RW, Ring, SM, Prembey, M, Breen, G, St Clair, D, Ceasar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskovina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGruffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, DT, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Lewis, CM, Onnie, CM, Prescott, NJ, Mathew, CG, Forbes, A, Sanderson, J, Mathew, C, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hider, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DPM, Thomson, W, Worthington, J, Frayling, TM, Freathy, RM, Lango, H, Perry, JRB, Weedon, MN, Hattersley, AT, Shields, BM, Hitman, GA, Walker, M, Newport, M, Sirugo, G, Conway, D, Jallow, M, Bradbury, LA, Pointon, JL, Brown, MA, Farrar, C, Wordsworth, P, Franklyn, JA, Heward, JM, Simmonds, MJ, Cough, SCL, Seal, S, Stratton, MR, Ban, M, Goris, A, Sawcer, SJ, Compston, A, Newton-Cheh, C, Johnson, T, Gateva, V, Tobin, MD, Bochud, M, Coin, L, Najjar, SS, Zhao, JH, Heath, SC, Eyheramendy, S, Papadakis, K, Voight, BF, Scott, LJ, Zhang, F, Farrall, M, Tanaka, T, Wallace, C, Chambers, JC, Khaw, K, Nilsson, P, Van Der Harst, P, Polidoro, S, Grobbee, DE, Onland-Moret, NC, Bots, ML, Wain, LV, Elliot, KS, Teumer, A, Luan, J, Lucas, G, Kuusisto, J, Burton, PR, Hadley, D, McArdle, WL, Brown, M, Dominiczak, A, Newhouse, SJ, Samani, NJ, Webster, J, Zeggini, E, Beckmann, JS, Bergmann, S, Lim, N, Song, K, Vollenweider, P, Waeber, G, Waterworth, DM, Yuan, X, Groop, L, Orho-Melander, M, Allione, A, Di Gregorio, A, Guarrera, S, Panico, S, Ricceri, F, Romanazzi, V, Sacerdote, C, Vineis, P, Barroso, I, Sandhu, MS, Luben, RN, Crawford, GJ, Jousilahti, P, Perola, M, Boehnke, M, Bonnycastle, LL, Collins, FS, Jackson, AU, Mohlke, KL, Stringham, HM, Valle, TT, Willer, CJ, Bergman, RN, Morken, MA, Döring, A, Gieger, C, Illig, T, Meitinger, T, Org, E, Pfeufer, A, Wichmann, HE, Kathiresan, S, Marrugat, J, O'Donnell, CJ, Schwartz, SM, Siscovick, DS, Subirana, I, Freimer, NB, Hartikainen, A, McCarthy, MI, O'Reilly, PF, Peltonen, L, Pouta, A, De Jong, PE, Snieder, H, Van Gilst, WH, Clarke, R, Goel, A, Hamsten, A, Altshuler, D, Jarvelin, M, Elliott, P, Lakatta, EG, Forouhi, N, Wareham, NJ, Loos, RJF, Deloukas, P, Lathrop, GM, Zelenika, D, Strachan, DP, Soranzo, N, Williams, FM, Zhai, G, Spector, TD, Peden, JF, Watkins, H, Ferrucci, L, Caulfield, M, Munroe, PB, Berglund, G, Melander, O, Matullo, G, Uiterwaal, CS, van der Schouw, YT, Numans, ME, Ernst, F, Homuth, G, Völker, U, Elosua, R, Laakso, M, Connell, JM, Mooser, V, Salomaa, V, Tuomilehto, J, Laan, M, Navis, G, Seedorf, U, Syvänen, A, Tognoni, G, Sanna, S, Uda, M, Scheet, P, Schlessinger, D, Scuteri, A, Dörr, M, Felix, SB, Reffelmann, T, Lorbeer, R, Völzke, H, Rettig, R, Galan, P, Hercberg, S, Bingham, SA, Kooner, JS, Bandinelli, S, Meneton, P, Abecasis, G, Thompson, JR, Braga Marcano, CA, Barke, B, Dobson, R, Gungadoo, J, Lee, KL, Onipinla, A, Wallace, I, Xue, M, Clayton, DG, Leung, H, Nutland, S, Walker, NM, Todd, JA, Stevens, HE, Dunger, DB, Widmer, B, Downes, K, Cardon, LR, Kwiatkowski, DP, Barrett, JC, Evans, D, Morris, AP, Lindgren, CM, Rayner, NW, Timpson, NJ, Lyons, E, Vannberg, F, Hill, AVS, Teo, YY, Rockett, KA, Craddock, N, Attwood, AP, Bryan, C, Bumpstead, SJ, Chaney, A, Ghori, J, William, RG, Hunt, SE, Inouye, M, Keniry, E, King, E, McGinnis, R, Potter, S, Ravindrarajan, R, Whittaker, P, Withers, D, Bentley, D, Groves, CJ, Duncanson, A, Ouwehand, WH, Boorman, JP, Cant, B, Jolley, JD, Knight, AS, Koch, K, Taylor, NC, Watkins, NA, Winzer, T, Braund, PS, Dixon, RJ, Mangino, M, Stevens, S, Donnely, P, Davidson, D, Marchini, JL, Spencer, ICA, Cardin, NJ, Ferreira, T, Pereira-Gale, J, Hallgrimsdottir, IB, Howie, BN, Su, Z, Vukcevic, D, Easton, D, Everson, U, Hussey, JM, Meech, E, Prowse, CV, Walters, GR, Jones, RW, Ring, SM, Prembey, M, Breen, G, St Clair, D, Ceasar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Holmans, PA, Jones, IR, Kirov, G, Moskovina, V, Nikolov, I, O'Donovan, MC, Owen, MJ, Collier, DA, Elkin, A, Farmer, A, Williamson, R, McGruffin, P, Young, AH, Ferrier, IN, Ball, SG, Balmforth, AJ, Barrett, JH, Bishop, DT, Iles, MM, Maqbool, A, Yuldasheva, N, Hall, AS, Bredin, F, Tremelling, M, Parkes, M, Drummond, H, Lees, CW, Nimmo, ER, Satsangi, J, Fisher, SA, Lewis, CM, Onnie, CM, Prescott, NJ, Mathew, CG, Forbes, A, Sanderson, J, Mathew, C, Barbour, J, Mohiuddin, MK, Todhunter, CE, Mansfield, JC, Ahmad, T, Cummings, FR, Jewell, DP, Barton, A, Bruce, IN, Donovan, H, Eyre, S, Gilbert, PD, Hider, SL, Hinks, AM, John, SL, Potter, C, Silman, AJ, Symmons, DPM, Thomson, W, Worthington, J, Frayling, TM, Freathy, RM, Lango, H, Perry, JRB, Weedon, MN, Hattersley, AT, Shields, BM, Hitman, GA, Walker, M, Newport, M, Sirugo, G, Conway, D, Jallow, M, Bradbury, LA, Pointon, JL, Brown, MA, Farrar, C, Wordsworth, P, Franklyn, JA, Heward, JM, Simmonds, MJ, Cough, SCL, Seal, S, Stratton, MR, Ban, M, Goris, A, Sawcer, SJ, and Compston, A
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10−24), CYP1A2 (P = 1 × 10−23), FGF5 (P = 1 × 10−21), SH2B3 (P = 3 × 10−18), MTHFR (P = 2 × 10−13), c10orf107 (P = 1 × 10−9), ZNF652 (P = 5 × 10−9) and PLCD3 (P = 1 × 10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

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