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3. Genome-wide significant risk factors for Alzheimerʼs disease: role in progression to dementia due to Alzheimerʼs disease among subjects with mild cognitive impairment

Author

Lacour, A, Espinosa, A, Louwersheimer, E, Heilmann, S, Hernández, I, Wolfsgruber, S, Fernández, V, Wagner, H, Rosende-Roca, M, Mauleón, A, Moreno-Grau, S, Vargas, L, Pijnenburg, Y AL, Koene, T, Rodríguez-Gómez, O, Ortega, G, Ruiz, S, Holstege, H, Sotolongo-Grau, O, Kornhuber, J, Peters, O, Frölich, L, Hüll, M, Rüther, E, Wiltfang, J, Scherer, M, Riedel-Heller, S, Alegret, M, Nöthen, M M, Scheltens, P, Wagner, M, Tárraga, L, Jessen, F, Boada, M, Maier, W, van der Flier, W M, Becker, T, Ramirez, A, and Ruiz, A

Published
2017
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12. Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Author

Webb, T.R., Erdmann, J., Stirrups, K.E., Stitziel, N.O., Masca, N.G.D., Jansen, H., Kanoni, S., Nelson, C.P., Ferrario, P.G., Konig, I.R., Eicher, J.D., Johnson, A.D., Hamby, S.E., Betsholtz, C., Ruusalepp, A., Franzen, O., Schadt, E.E., Bjorkegren, J.L.M., Weeke, P.E., Auer, P.L., Schick, U.M., Lu, Y.C., Zhang, H., Dube, M.P., Goel, A., Farrall, M., Peloso, G.M., Won, H.H., R. do, Iperen, E. van, Kruppa, J., Mahajan, A., Scott, R.A., Willenborg, C., Braund, P.S., Capelleveen, J.C. van, Doney, A.S.F., Donnelly, L.A., Asselta, R., Merlini, P.A., Duga, S., Marziliano, N., Denny, J.C., Shaffer, C., El-Mokhtari, N.E., Franke, A., Heilmann, S., Hengstenberg, C., Hoffmann, P., Holmen, O.L., Hveem, K., Jansson, J.H., Jockel, K.H., Kessler, T., Kriebel, J., Laugwitz, K.L., Marouli, E., Martinelli, N., McCarthy, M.I., Zuydam, N.R. van, Meisinger, C., Esko, T., Mihailov, E., Escher, S.A., Alver, M., Moebus, S., Morris, A.D., Virtamo, J., Nikpay, M., Olivieri, O., Provost, S., AlQarawi, A., Robertson, N.R., Akinsansya, K.O., Reilly, D.F., Vogt, T.F., Yin, W., Asselbergs, F.W., Kooperberg, C., Jackson, R.D., Stahl, E., Muller-Nurasyid, M., Strauch, K., Varga, T.V., Waldenberger, M., Zeng, L.Y., Chowdhury, R., Salomaa, V., Ford, I., Jukema, J.W., Amouyel, P., Kontto, J., Nordestgaard, B.G., Ferrieres, J., Saleheen, D., Sattar, N., Surendran, P., Wagner, A., Young, R., Howson, J.M.M., Butterworth, A.S., Danesh, J., Ardissino, D., Bottinger, E.P., Erbel, R., Franks, P.W., Girelli, D., Hall, A.S., Hovingh, G.K., Kastrati, A., Lieb, W., Meitinger, T., Kraus, W.E., Shah, S.H., McPherson, R., Orho-Melander, M., Melander, O., Metspalu, A., Palmer, C.N.A., Peters, A., Rader, D.J., Reilly, M.P., Loos, R.J.F., Reiner, A.P., Roden, D.M., Tardif, J.C., Thompson, J.R., Wareham, N.J., Watkins, H., Willer, C.J., Samani, N.J., Schunkert, H., Deloukas, P., Kathiresan, S., Wellcome Trust Case Control, MORGAM Investigators, and Myocardial Infarction Genetics

Subjects
expression quantitative trait loci, single nucleotide polymorphism, cholesteryl ester transfer protein, genome-wide association, genetics
Abstract

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Published
2017

19. The effectiveness of the Inspiring Futures parenting programme in improving behavioural and emotional outcomes in primary school children with behavioural or emotional difficulties

Author

Axford, N. (Nick), Warner, G. (Georgina), Hobbs, T. (Tim), Heilmann, S. (Sarah), Raja, A. (Anam), Berry, V. (Vashti), Ukoumunne, O.C. (Obioha C.), Matthews, J. (Justin), Eames, T. (Tim), Kallitsoglou, A. (Angeliki), Blower, S. (Sarah), Wilkinson, T. (Tom), Timmons, L. (Luke), Bjornstad, G. (Gretchen), Axford, N. (Nick), Warner, G. (Georgina), Hobbs, T. (Tim), Heilmann, S. (Sarah), Raja, A. (Anam), Berry, V. (Vashti), Ukoumunne, O.C. (Obioha C.), Matthews, J. (Justin), Eames, T. (Tim), Kallitsoglou, A. (Angeliki), Blower, S. (Sarah), Wilkinson, T. (Tom), Timmons, L. (Luke), and Bjornstad, G. (Gretchen)

Abstract

Background: There is a need to build the evidence base of early interventions promoting children's health and development in the UK. Malachi Specialist Family Support Services ('Malachi') is a voluntary sector organisation based in the UK that delivers a therapeutic parenting group programme called Inspiring Futures to parents of children identified as having behavioural and emotional difficulties. The programme comprises two parts, delivered sequentially: (1) a group-based programme for all parents for 10-12 weeks, and (2) one-to-one sessions with selected parents from the group-based element for up to 12 weeks. Methods/design: A randomised controlled trial will be conducted to evaluate Malachi's Inspiring Futures parenting programme. Participants will be allocated to one of two possible arms, with follow-up measures at 16 weeks (post-parent group programme) and at 32 weeks (post-one-to-one sessions with selected parents). The sample size is 248 participants with a randomisation allocation ratio of 1:1. The intervention arm will be offered the Inspiring Futures programme. The control group will receive services as usual. The aim is to determine the effectiveness of the Inspiring Futures programme on the primary outcome of behavioural and emotional difficulties of primary school children identified as having behavioural or emotional difficulties. Discussion: This study will further enhance the evidence for early intervention parenting programmes for child behavioural and emotional problems in the UK.

Published
2018
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20. The effectiveness of the Inspiring Futures parenting programme in improving behavioural and emotional outcomes in primary school children with behavioural or emotional difficulties: study protocol for a randomised controlled trial.

Author

Axford, N, Warner, G, Hobbs, T, Heilmann, S, Raja, A, Berry, V, Ukoumunne, OC, Matthews, J, Eames, T, Kallitsoglou, A, Blower, S, Wilkinson, T, Timmons, L, Bjornstad, G, Axford, N, Warner, G, Hobbs, T, Heilmann, S, Raja, A, Berry, V, Ukoumunne, OC, Matthews, J, Eames, T, Kallitsoglou, A, Blower, S, Wilkinson, T, Timmons, L, and Bjornstad, G

Abstract

BACKGROUND: There is a need to build the evidence base of early interventions promoting children's health and development in the UK. Malachi Specialist Family Support Services ('Malachi') is a voluntary sector organisation based in the UK that delivers a therapeutic parenting group programme called Inspiring Futures to parents of children identified as having behavioural and emotional difficulties. The programme comprises two parts, delivered sequentially: (1) a group-based programme for all parents for 10-12 weeks, and (2) one-to-one sessions with selected parents from the group-based element for up to 12 weeks. METHODS/DESIGN: A randomised controlled trial will be conducted to evaluate Malachi's Inspiring Futures parenting programme. Participants will be allocated to one of two possible arms, with follow-up measures at 16 weeks (post-parent group programme) and at 32 weeks (post-one-to-one sessions with selected parents). The sample size is 248 participants with a randomisation allocation ratio of 1:1. The intervention arm will be offered the Inspiring Futures programme. The control group will receive services as usual. The aim is to determine the effectiveness of the Inspiring Futures programme on the primary outcome of behavioural and emotional difficulties of primary school children identified as having behavioural or emotional difficulties. DISCUSSION: This study will further enhance the evidence for early intervention parenting programmes for child behavioural and emotional problems in the UK. TRIAL REGISTRATION: Current Controlled Trials ISRCTN32083735 . Retrospectively registered 28 October 2014.

Published
2018

21. Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Author

Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, Sheth, K, Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, and Sheth, K

Abstract

OBJECTIVE: We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. METHODS: We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. RESULTS: We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10-4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10-48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1). CONCLUSIONS: Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

Published
2018

22. China’s core executive Leadership styles, structures and processes under Xi Jinping

Author

Heilmann, S., Stepan, M., Political Science and Public Administration, and Multi-layered governance in EUrope and beyond (MLG)

Subjects
SDG 16 - Peace, Justice and Strong Institutions
Abstract

Since Xi Jinping took the reins of the Chinese Communist Party and as President of the People’s Republic of China, the country’s domestic and foreign politics have undergone considerable changes. China has become more assertive as an international actor. It has launched new diplomatic initiatives centring on large infrastructure projects, while at the same time contributing to tense relations with many of its neighbouring countries. At home, several pieces of security-related legislation have further constrained the activities of both domestic as well as foreign civil actors. Participating scholars’ expertise covers a wide variety of issue areas, ranging from economic policy making to cyberspace politics, and from societal control to military modernization. MERICS Paper on China No. 1 - “China’s core executive: leadership styles, structures and processes under Xi Jinping” is an essay collection which offers the most comprehensive, authoritative and up-to-date account of the changes to China’s core executive under Xi Jinping through its analysis of developments in different policy areas. One observation is dominant – China has moved in further in the direction of top-down, autocratic policy making. The authors – among them renowned experts such as Roderick Mac Farquhar, Barry Naughton, Joseph Fewsmith, You Ji, Victor Shih, and Anthony Saich – discuss the effects of this on current policymaking and policy outcomes, as well as offering a thought-provoking look into the future. What happens if Xi Jinping fails with his overall reform agenda? What if he succeeds in strengthening the control of the party and in restructuring the Chinese economy? Will China’s IT-backed authoritarianism act as a model and spread to other countries, challenging Western democratic modes of governance? Whatever the future holds, such developments will have implications not only for China, but for all its close economic and political partners.

Published
2016

24. Top-level design and local-level paralysis: Local politics in times of political centralisation

Author

Stepan, M., Ahlers, A.L., Heilmann, S., Political Science and Public Administration, and Multi-layered governance in EUrope and beyond (MLG)

Subjects
SDG 16 - Peace, Justice and Strong Institutions
Abstract

China’s leadership under Xi has reinforced the party’s hierarchical command structures, demonstrated through its top-down campaigns, focusing on austerity, anti-corruption efforts and party discipline. It has reinvigorated sanctioning and incentive mechanisms for local cadres, with unknown effects on their long-term performance and loyalty to the CCP. Re-centralising the intergovernmental financial system strengthens the overall steering capacity of the central government temporarily, but does not alleviate the fiscal stress on local governments. The central government is pushing for greater market orientation at the local level, resulting, thus far, in short-sighted solutions that will end up reducing transparency concerning local debt. Local leaders are abstaining from bold policy moves out of fear of demotion, exclusion from the party, or legal repercussions. Consequently, subnational governments have ceased to act as independent actors of policy initiative and innovation. Policy piloting and experimentation will remain an important component of the policy process, but will be employed only very selectively and under the auspices of the central government. These reconfigurations of central-local relations give the central leadership more tools to enforce local compliance, and they appear to be effective in the short term. But they will suffocate subnational policy initiative, ultimately undermining the adaptive capacity of the Chinese state.

Published
2016

26. Genome-wide association study identifies multiple susceptibility loci for glioma

Author

Kinnersley, B, Labussière, M, Holroyd, A, Di Stefano, A-L, Broderick, P, Vijayakrishnan, J, Mokhtari, K, Delattre, J-Y, Gousias, K, Schramm, J, Schoemaker, MJ, Fleming, SJ, Herms, S, Heilmann, S, Schreiber, S, Wichmann, H-E, Nöthen, MM, Swerdlow, A, Lathrop, M, Simon, M, Bondy, M, Sanson, M, and Houlston, RS

Abstract

Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10−9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10−8), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10−11), 12q21.2 (rs12230172, P=7.53 × 10−11) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10−9). Our findings provide further insights into the genetic basis of the different glioma subtypes.

Published
2015

27. Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment

Author

Lacour, A., Espinosa, A., Louwersheimer, E., Heilmann, S., Hernandez, I., Wolfsgruber, S., Fernandez, V., Wagner, H., Rosende-Roca, M., Mauleon, A., Moreno-Grau, S., Vargas, L., Pijnenburg, Y. A. L., Koene, T., Rodriguez-Gomez, O., Ortega, G., Ruiz, S., Holstege, H., Sotolongo-Grau, O., Kornhuber, J., Peters, O., Froelich, L., Huell, M., Ruether, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Alegret, M., Noethen, M. M., Scheltens, P., Wagner, M., Tarraga, L., Jessen, F., Boada, M., Maier, W., van der Flier, W. M., Becker, T., Ramirez, A., Ruiz, A., Lacour, A., Espinosa, A., Louwersheimer, E., Heilmann, S., Hernandez, I., Wolfsgruber, S., Fernandez, V., Wagner, H., Rosende-Roca, M., Mauleon, A., Moreno-Grau, S., Vargas, L., Pijnenburg, Y. A. L., Koene, T., Rodriguez-Gomez, O., Ortega, G., Ruiz, S., Holstege, H., Sotolongo-Grau, O., Kornhuber, J., Peters, O., Froelich, L., Huell, M., Ruether, E., Wiltfang, J., Scherer, M., Riedel-Heller, S., Alegret, M., Noethen, M. M., Scheltens, P., Wagner, M., Tarraga, L., Jessen, F., Boada, M., Maier, W., van der Flier, W. M., Becker, T., Ramirez, A., and Ruiz, A.

Abstract

Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n = 853); (b) the German Dementia Competence Network (n = 812); (c) the Fundacio ACE from Barcelona, Spain (n = 1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n = 306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR) = 1.187 (1.054-1.32); P = 0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-e4 (apolipoprotein E-e4) carriers (HR = 1.746 (1.029-2.965); P = 0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression.

Published
2017

29. Prediction of male-pattern baldness from genotypes

Author

Liu, F. (Fan), Hamer, M.A. (Merel), Heilmann, S. (Sarah), Herold, C. (Christine), Moebus, S. (Susanne), Hofman, A. (Albert), Uitterlinden, A.G. (André), Nöthen, M.M. (Markus), Duijn, C.M. (Cornelia) van, Nijsten, T.E.C. (Tamar), Kayser, M.H. (Manfred), Liu, F. (Fan), Hamer, M.A. (Merel), Heilmann, S. (Sarah), Herold, C. (Christine), Moebus, S. (Susanne), Hofman, A. (Albert), Uitterlinden, A.G. (André), Nöthen, M.M. (Markus), Duijn, C.M. (Cornelia) van, Nijsten, T.E.C. (Tamar), and Kayser, M.H. (Manfred)

Abstract

The global demand for products that effectively prevent the development of male-pattern baldness (MPB) has drastically increased. However, there is currently no established genetic model for the estimation of MPB risk. We conducted a prediction analysis using single-nucleotide polymorphisms (SNPs) identified from previous GWASs of MPB in a total of 2725 German and Dutch males. A logistic regression model considering the genotypes of 25 SNPs from 12 genomic loci demonstrates that early-onset MPB risk is predictable at an accuracy level of 0.74 when 14 SNPs were included in the model, and measured using the area under the receiver-operating characteristic curves (AUC). Considering age as an additional predictor, the model can predict normal MPB status in middle-Aged and elderly individuals at a slightly lower accuracy (AUC 0.69-0.71) when 6-11 SNPs were used. A variance partitioning analysis suggests that 55.8% of early-onset MPB genetic liability can be explained by common autosomal SNPs and 23.3% by X-chromosome SNPs. For normal MPB status in elderly individuals, the proportion of explainable variance is lower (42.4% for autosomal and 9.8% for X-chromosome SNPs). The gap between GWAS findings and the variance partitioning results could be explained by a large body of common DNA variants with small effects that will likely be identified in GWAS of increased sample sizes. Although the accuracy obtained here has not reached a clinically desired level, our model was highly informative for up to 19% of Europeans, thus may assist decision making on early MPB intervention actions and in forensic investigations.

Published
2016
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30. Compelling evidence for FANCM as a breast cancer susceptibility gene

Author

Neidhardt, G., Hauke, J., Heilmann, S., Hellebrand, H., Surowy, H. M., Klaschik, K., Honisch, E., Gehrig, A., Sutter, C., Rump, A., Bogdanova-Markov, N., Bugert, P., Mangold, E., Steinemann, D., Ramirez, A., Ditsch, N., Arnold, N., Niederacher, D., Burwinkel, B., Thiele, H., Altmueller, I., Nuernberg, P., Engel, C., Wappenschmidt, B., Rhiem, K., Meindl, A., Schmutzler, R. K., Hahnen, E., Neidhardt, G., Hauke, J., Heilmann, S., Hellebrand, H., Surowy, H. M., Klaschik, K., Honisch, E., Gehrig, A., Sutter, C., Rump, A., Bogdanova-Markov, N., Bugert, P., Mangold, E., Steinemann, D., Ramirez, A., Ditsch, N., Arnold, N., Niederacher, D., Burwinkel, B., Thiele, H., Altmueller, I., Nuernberg, P., Engel, C., Wappenschmidt, B., Rhiem, K., Meindl, A., Schmutzler, R. K., and Hahnen, E.

Published
2016

33. Genome-wide significant risk factors for Alzheimer’s disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment

Author

Lacour, A, primary, Espinosa, A, additional, Louwersheimer, E, additional, Heilmann, S, additional, Hernández, I, additional, Wolfsgruber, S, additional, Fernández, V, additional, Wagner, H, additional, Rosende-Roca, M, additional, Mauleón, A, additional, Moreno-Grau, S, additional, Vargas, L, additional, Pijnenburg, Y A L, additional, Koene, T, additional, Rodríguez-Gómez, O, additional, Ortega, G, additional, Ruiz, S, additional, Holstege, H, additional, Sotolongo-Grau, O, additional, Kornhuber, J, additional, Peters, O, additional, Frölich, L, additional, Hüll, M, additional, Rüther, E, additional, Wiltfang, J, additional, Scherer, M, additional, Riedel-Heller, S, additional, Alegret, M, additional, Nöthen, M M, additional, Scheltens, P, additional, Wagner, M, additional, Tárraga, L, additional, Jessen, F, additional, Boada, M, additional, Maier, W, additional, van der Flier, W M, additional, Becker, T, additional, Ramirez, A, additional, and Ruiz, A, additional

Published
2016
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34. Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene

Author

Ruiz, A., Heilmann, S., Harold, D., Gerrish, A., Sims, R., Sotolongo-Grau, O., Espinosa, A., Alegret, M., Arrieta, J. L., Lacour, A., Leber, M., Becker, J., Becker, T., Lafuente, A., Ruiz, S., Vargas, L., Rodríguez, O., Ortega, G., Dominguez, M-A, IGAP, Mayeux, R., Haines, J. L., Pericak-Vance, M. A., Hernández, I., Farrer, L. A., Schellenberg, G. D., Chouraki, V., Launer, L. J., van Duijn, C., Seshadri, S., Antúnez, C., Breteler, Monique, Serrano-Ríos, M., Jessen, F., Wagner, H., Tárraga, L., Nöthen, M. M., Maier, W., Boada, M., Ramírez, A., Thelen, M., Mauleón, A., Rosende-Roca, M., Bellenguez, C., Bis, J. C., Breteler, M. M., and Epidemiology

Subjects
SNP, thyroid receptor, Genomics, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, genetics [Alzheimer Disease], TRIP4 protein, human, genetics [Genetic Loci], Biology, Polymorphism, Single Nucleotide, molecular epidemiology, Cellular and Molecular Neuroscience, Alzheimer Disease, dementia risk, medicine, GWAS, Humans, Genetic Predisposition to Disease, ddc:610, Biological Psychiatry, Genetics, Odds ratio, DNA, genetics [Transcription Factors], medicine.disease, R1, Psychiatry and Mental health, Genetic Loci, Spain, Multiple comparisons problem, genetics [Polymorphism, Single Nucleotide], Original Article, Alzheimer's disease, Follow-Up Studies, Genome-Wide Association Study, Transcription Factors
Abstract

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundacio ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P = 0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio = 1.31; confidence interval 95% (1.19-1.44); P = 9.74 x 10(-9)).

Published
2014
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39. Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene

Author

Ruiz, A. (A.), Heilmann, S. (Sarah), Becker, T. (Tim), Hernández, I. (Isabel), Wagner, H. (Hermann), Thelen, K.M. (Karin ), Mauleón, A. (A.), Rosende-Roca, M. (M.), Bellenguez, C. (Céline), Bis, J.C. (Joshua), Harold, D. (Denise), Gerrish, A. (Amy), Sims, R. (Rebecca), Sotolongo-Grau, O. (O.), Espinosa, L. (Lluis), Alegret, M. (M.), Arrieta, J.L. (J.), Lacour, A. (A.), Leber, I. (Isabelle), Becker, J. (Jessica), Lafuente, A. (A.), Ruiz, S. (S.), Vargas, L. (L.), Rodríguez, P.M., Ortega, G. (G.), Dominguez, M.A., Mayeux, R. (Richard), Haines, J.L. (Jonathan), Pericak-Vance, M.A. (Margaret), Farrer, L.A. (Lindsay), Schellenberg, G.D. (Gerard), Chouraki, V. (Vincent), Launer, L.J. (Lenore), Duijn, C.M. (Cornelia) van, Seshadri, S. (Sudha), Antúnez, C. (C.), Breteler, M.M.B. (Monique), Serrano-Ríos, M. (Manuel), Jessen, F., Tárraga, L. (L.), Nöthen, M.M. (Markus), Maier, W. (Wolfgang), Boada, M. (Mercè), Ramírez, M.J. (María), Ruiz, A. (A.), Heilmann, S. (Sarah), Becker, T. (Tim), Hernández, I. (Isabel), Wagner, H. (Hermann), Thelen, K.M. (Karin ), Mauleón, A. (A.), Rosende-Roca, M. (M.), Bellenguez, C. (Céline), Bis, J.C. (Joshua), Harold, D. (Denise), Gerrish, A. (Amy), Sims, R. (Rebecca), Sotolongo-Grau, O. (O.), Espinosa, L. (Lluis), Alegret, M. (M.), Arrieta, J.L. (J.), Lacour, A. (A.), Leber, I. (Isabelle), Becker, J. (Jessica), Lafuente, A. (A.), Ruiz, S. (S.), Vargas, L. (L.), Rodríguez, P.M., Ortega, G. (G.), Dominguez, M.A., Mayeux, R. (Richard), Haines, J.L. (Jonathan), Pericak-Vance, M.A. (Margaret), Farrer, L.A. (Lindsay), Schellenberg, G.D. (Gerard), Chouraki, V. (Vincent), Launer, L.J. (Lenore), Duijn, C.M. (Cornelia) van, Seshadri, S. (Sudha), Antúnez, C. (C.), Breteler, M.M.B. (Monique), Serrano-Ríos, M. (Manuel), Jessen, F., Tárraga, L. (L.), Nöthen, M.M. (Markus), Maier, W. (Wolfgang), Boada, M. (Mercè), and Ramírez, M.J. (María)

Abstract

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10 - 9).

Published
2014
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40. Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies

Author

Zink, A M, Wohlleber, E, Engels, H, Rødningen, O K, Ravn, K, Heilmann, S, Rehnitz, J, Katzorke, N, Kraus, C, Blichfeldt, S, Hoffmann, P, Reutter, H, Brockschmidt, F F, Kreiß-Nachtsheim, M, Vogt, P H, Prescott, T E, Tümer, Z, Lee, J A, Zink, A M, Wohlleber, E, Engels, H, Rødningen, O K, Ravn, K, Heilmann, S, Rehnitz, J, Katzorke, N, Kraus, C, Blichfeldt, S, Hoffmann, P, Reutter, H, Brockschmidt, F F, Kreiß-Nachtsheim, M, Vogt, P H, Prescott, T E, Tümer, Z, and Lee, J A

Abstract

Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.

Published
2014

41. Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene

Author

Ruiz, A, Heilmann, S, Becker, T, Hernandez, I, Wagner, H, Thelen, M, Mauleon, A, Rosende-Roca, M, Bellenguez, C, Bis, JC, Harold, D, Gerrish, A, Sims, R, Sotolongo-Grau, O, Espinosa, A, Alegret, M, Arrieta, JL, Lacour, A, Leber, M, Becker, J, Lafuente, A, Ruiz, S, Vargas, L, Rodriguez, O, Ortega, G, Dominguez, MA, Mayeux, R, Haines, JL, Pericak-Vance, MA, Farrer, LA, Schellenberg, GD, Chouraki, V, Launer, LJ (Lenore), Duijn, Cornelia, Seshadri, S, Antunez, C, Breteler, Monique, Serrano-Rios, M, Jessen, F, Tarraga, L, Nothen, MM, Maier, W, Boada, M, Ramirez, A, Ruiz, A, Heilmann, S, Becker, T, Hernandez, I, Wagner, H, Thelen, M, Mauleon, A, Rosende-Roca, M, Bellenguez, C, Bis, JC, Harold, D, Gerrish, A, Sims, R, Sotolongo-Grau, O, Espinosa, A, Alegret, M, Arrieta, JL, Lacour, A, Leber, M, Becker, J, Lafuente, A, Ruiz, S, Vargas, L, Rodriguez, O, Ortega, G, Dominguez, MA, Mayeux, R, Haines, JL, Pericak-Vance, MA, Farrer, LA, Schellenberg, GD, Chouraki, V, Launer, LJ (Lenore), Duijn, Cornelia, Seshadri, S, Antunez, C, Breteler, Monique, Serrano-Rios, M, Jessen, F, Tarraga, L, Nothen, MM, Maier, W, Boada, M, and Ramirez, A

Abstract

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundacio ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P = 0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio = 1.31; confidence interval 95% (1.19-1.44); P = 9.74 x 10(-9)).

Published
2014

42. Riechstörungen

Author

Hummel, T., primary, Landis, B.N., additional, Frasnelli, J.A., additional, Heilmann, S., additional, and Hüttenbrink, K.-B., additional

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44. Androgenetic Alopecia: Identification of Four Genetic Risk Loci and Evidence for the Contribution of WNT Signaling to Its Etiology

Author

Heilmann, S., Kiefer, A.K., Fricker, N., Drichel, D., Hillmer, A.M., Herold, C., Tung, J.Y., Eriksson, N., Redler, S., Betz, R.C., Li, R., Karason, A., Nyholt, D.R., Song, K., Vermeulen, S., Kanoni, S., Dedoussis, G., Martin, N.G., Kiemeney, L.A.L.M., Mooser, V., Stefansson, K., Richards, J.B., Becker, T., Brockschmidt, F.F., Hinds, D.A., Nothen, M.M., Heilmann, S., Kiefer, A.K., Fricker, N., Drichel, D., Hillmer, A.M., Herold, C., Tung, J.Y., Eriksson, N., Redler, S., Betz, R.C., Li, R., Karason, A., Nyholt, D.R., Song, K., Vermeulen, S., Kanoni, S., Dedoussis, G., Martin, N.G., Kiemeney, L.A.L.M., Mooser, V., Stefansson, K., Richards, J.B., Becker, T., Brockschmidt, F.F., Hinds, D.A., and Nothen, M.M.

Abstract

Item does not contain fulltext, The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 x 10(-8)

Published
2013

45. Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases

Author

Li, R., Brockschmidt, F.F., Kiefer, A.K., Stefansson, H., Nyholt, D.R., Song, K., Vermeulen, S., Kanoni, S., Glass, D., Medland, S.E., Dimitriou, M., Waterworth, D., Tung, J.Y., Geller, F., Heilmann, S., Hillmer, A.M., Bataille, V., Eigelshoven, S., Hanneken, S., Moebus, S., Herold, C., Heijer, M. den, Montgomery, G.W., Deloukas, P., Eriksson, N., Heath, A.C., Becker, T., Sulem, P., Mangino, M., Vollenweider, P., Spector, T.D., Dedoussis, G., Martin, N.G., Kiemeney, L.A., Mooser, V., Stefansson, K., Hinds, D.A., Nothen, Markus, Richards, J.B., Li, R., Brockschmidt, F.F., Kiefer, A.K., Stefansson, H., Nyholt, D.R., Song, K., Vermeulen, S., Kanoni, S., Glass, D., Medland, S.E., Dimitriou, M., Waterworth, D., Tung, J.Y., Geller, F., Heilmann, S., Hillmer, A.M., Bataille, V., Eigelshoven, S., Hanneken, S., Moebus, S., Herold, C., Heijer, M. den, Montgomery, G.W., Deloukas, P., Eriksson, N., Heath, A.C., Becker, T., Sulem, P., Mangino, M., Vollenweider, P., Spector, T.D., Dedoussis, G., Martin, N.G., Kiemeney, L.A., Mooser, V., Stefansson, K., Hinds, D.A., Nothen, Markus, and Richards, J.B.

Abstract

Contains fulltext : 109543.pdf (publisher's version ) (Open Access), Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62x10(-)(9)-1.01x10(-)(1)(2)). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9x10(-)(3)). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4x10(-)(8)(8)]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

Published
2012

46. Microdeletions Including FMR1 in Three Female Patients with Intellectual Disability - Further Delineation of the Phenotype and Expression Studies

Author

Zink, A.M., primary, Wohlleber, E., additional, Engels, H., additional, Rødningen, O.K., additional, Ravn, K., additional, Heilmann, S., additional, Rehnitz, J., additional, Katzorke, N., additional, Kraus, C., additional, Blichfeldt, S., additional, Hoffmann, P., additional, Reutter, H., additional, Brockschmidt, F.F., additional, Kreiß-Nachtsheim, M., additional, Vogt, P.H., additional, Prescott, T.E., additional, Tümer, Z., additional, and Lee, J.A., additional

Published
2014
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