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1. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Author

Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, Ali, QZ, Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, and Ali, QZ

Abstract

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Published
2023

2. Rare and Common Variants Conferring Risk of Tooth Agenesis

Author

Jonsson, L., Magnusson, T.E., Thordarson, A., Jonsson, T., Geller, F., Feenstra, B., Melbye, M., Nohr, E.A., Vucic, S., Dhamo, B., Rivadeneira, F., Ongkosuwito, E.M., Wolvius, E.B., Leslie, E.J., Marazita, M.L., Howe, B.J., Uribe, L.M. Moreno, Alonso, I., Santos, M., Pinho, T., Jonsson, R., Audolfsson, G., Gudmundsson, L., Nawaz, M.S., Olafsson, S., Gustafsson, O., Ingason, A., Unnsteinsdottir, U., Bjornsdottir, G., Walters, G.B., Zervas, M., Oddsson, A., Gudbjartsson, D.F., Steinberg, S., Stefansson, H., Stefansson, K., Jonsson, L., Magnusson, T.E., Thordarson, A., Jonsson, T., Geller, F., Feenstra, B., Melbye, M., Nohr, E.A., Vucic, S., Dhamo, B., Rivadeneira, F., Ongkosuwito, E.M., Wolvius, E.B., Leslie, E.J., Marazita, M.L., Howe, B.J., Uribe, L.M. Moreno, Alonso, I., Santos, M., Pinho, T., Jonsson, R., Audolfsson, G., Gudmundsson, L., Nawaz, M.S., Olafsson, S., Gustafsson, O., Ingason, A., Unnsteinsdottir, U., Bjornsdottir, G., Walters, G.B., Zervas, M., Oddsson, A., Gudbjartsson, D.F., Steinberg, S., Stefansson, H., and Stefansson, K.

Abstract

Item does not contain fulltext, We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

Published
2018

3. Rare and Common Variants Conferring Risk of Tooth Agenesis

Author

Jonsson, L. (L.), Magnusson, T.E. (T. E.), Thordarson, A. (A.), Jonsson, T. (Thorvaldur), Geller, F. (Frank), Feenstra, B. (Bjarke), Melbye, M. (Mads), Nohr, C. (Christian), Vučić, S. (Strahinja), Dhamo, B. (Brunilda), Rivadeneira, F. (F.), Ongkosuwito, E.M. (Edwin), Wolvius, E.B. (Eppo), Leslie, E.J. (Elizabeth J.), Marazita, M.L. (Mary), Howe, B.J. (B. J.), Moreno Uribe, L.M. (L. M.), Alonso, I. (I.), Santos, M. (M.), Pinho, T. (T.), Jonsson, R. (R.), Audolfsson, G. (G.), Gudmundsson, L. (Larus), Nawaz, M.S. (M. S.), Olafsson, S. (S.), Gustafsson, O. (Omar), Ingason, A. (A.), Unnsteinsdottir, U. (U.), Bjornsdottir, G. (G.), Walters, G.B. (Bragi), Zervas, M. (M.), Oddsson, A. (A.), Gudbjartsson, D.F. (Daniel), Steinberg, S. (Stacy), Stefansson, H. (Hreinn), Stefansson, K. (K.), Jonsson, L. (L.), Magnusson, T.E. (T. E.), Thordarson, A. (A.), Jonsson, T. (Thorvaldur), Geller, F. (Frank), Feenstra, B. (Bjarke), Melbye, M. (Mads), Nohr, C. (Christian), Vučić, S. (Strahinja), Dhamo, B. (Brunilda), Rivadeneira, F. (F.), Ongkosuwito, E.M. (Edwin), Wolvius, E.B. (Eppo), Leslie, E.J. (Elizabeth J.), Marazita, M.L. (Mary), Howe, B.J. (B. J.), Moreno Uribe, L.M. (L. M.), Alonso, I. (I.), Santos, M. (M.), Pinho, T. (T.), Jonsson, R. (R.), Audolfsson, G. (G.), Gudmundsson, L. (Larus), Nawaz, M.S. (M. S.), Olafsson, S. (S.), Gustafsson, O. (Omar), Ingason, A. (A.), Unnsteinsdottir, U. (U.), Bjornsdottir, G. (G.), Walters, G.B. (Bragi), Zervas, M. (M.), Oddsson, A. (A.), Gudbjartsson, D.F. (Daniel), Steinberg, S. (Stacy), Stefansson, H. (Hreinn), and Stefansson, K. (K.)

Abstract

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

Published
2018
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4. Rare and Common Variants Conferring Risk of Tooth Agenesis

Author

Jonsson, L, Magnusson, TE, Thordarson, A, Jonsson, T, Geller, F, Feenstra, B, Melbye, M, Nohr, EA, Vucic, Strahinja, Dhamo, Bruna, Rivadeneira, Fernando, Ongkosuwito, Edwin, Wolvius, Eppo, Leslie, EJ, Marazita, ML, Howe, BJ, Uribe, LMM, Alonso, I, Santos, M, Pinho, T, Jonsson, R, Audolfsson, G, Gudmundsson, L, Nawaz, MS, Olafsson, S, Gustafsson, O, Ingason, A, Unnsteinsdottir, U, Bjornsdottir, G, Walters, GB, Zervas, M, Oddsson, A, Gudbjartsson, DF, Steinberg, S, Stefansson, H, Stefansson, K, Jonsson, L, Magnusson, TE, Thordarson, A, Jonsson, T, Geller, F, Feenstra, B, Melbye, M, Nohr, EA, Vucic, Strahinja, Dhamo, Bruna, Rivadeneira, Fernando, Ongkosuwito, Edwin, Wolvius, Eppo, Leslie, EJ, Marazita, ML, Howe, BJ, Uribe, LMM, Alonso, I, Santos, M, Pinho, T, Jonsson, R, Audolfsson, G, Gudmundsson, L, Nawaz, MS, Olafsson, S, Gustafsson, O, Ingason, A, Unnsteinsdottir, U, Bjornsdottir, G, Walters, GB, Zervas, M, Oddsson, A, Gudbjartsson, DF, Steinberg, S, Stefansson, H, and Stefansson, K

Published
2018

5. Rare and Common Variants Conferring Risk of Tooth Agenesis

Author

Jonsson, L., primary, Magnusson, T.E., additional, Thordarson, A., additional, Jonsson, T., additional, Geller, F., additional, Feenstra, B., additional, Melbye, M., additional, Nohr, E.A., additional, Vucic, S., additional, Dhamo, B., additional, Rivadeneira, F., additional, Ongkosuwito, E.M., additional, Wolvius, E.B., additional, Leslie, E.J., additional, Marazita, M.L., additional, Howe, B.J., additional, Moreno Uribe, L.M., additional, Alonso, I., additional, Santos, M., additional, Pinho, T., additional, Jonsson, R., additional, Audolfsson, G., additional, Gudmundsson, L., additional, Nawaz, M.S., additional, Olafsson, S., additional, Gustafsson, O., additional, Ingason, A., additional, Unnsteinsdottir, U., additional, Bjornsdottir, G., additional, Walters, G.B., additional, Zervas, M., additional, Oddsson, A., additional, Gudbjartsson, D.F., additional, Steinberg, S., additional, Stefansson, H., additional, and Stefansson, K., additional

Published
2018
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6. 15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia

Author

Ulfarsson, M O, primary, Walters, G B, additional, Gustafsson, O, additional, Steinberg, S, additional, Silva, A, additional, Doyle, O M, additional, Brammer, M, additional, Gudbjartsson, D F, additional, Arnarsdottir, S, additional, Jonsdottir, G A, additional, Gisladottir, R S, additional, Bjornsdottir, G, additional, Helgason, H, additional, Ellingsen, L M, additional, Halldorsson, J G, additional, Saemundsen, E, additional, Stefansdottir, B, additional, Jonsson, L, additional, Eiriksdottir, V K, additional, Eiriksdottir, G R, additional, Johannesdottir, G H, additional, Unnsteinsdottir, U, additional, Jonsdottir, B, additional, Magnusdottir, B B, additional, Sulem, P, additional, Thorsteinsdottir, U, additional, Sigurdsson, E, additional, Brandeis, D, additional, Meyer-Lindenberg, A, additional, Stefansson, H, additional, and Stefansson, K, additional

Published
2017
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7. Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort

Author

Bertelsen, B., Stefansson, H., Jensen, L., Melchior, L., Debes, N. Mol, Groth, C., Skov, L., Werge, T., Karagiannidis, I., Tarnok, Z., Barta, C., Nagy, P., Farkas, L., Brondum-Nielsen, K., Rizzo, R., Gulisano, M., Rujescu, D., Kiemeney, L.A.L.M., Tosato, S., Nawaz, M.S., Ingason, A., Unnsteinsdottir, U., Steinberg, S., Ludvigsson, P., Stefansson, K., Kuss, A.W., Paschou, P., Cath, D., Hoekstra, P.J., Muller-Vahl, K., Stuhrmann, M., Silahtaroglu, A., Pfundt, R.P., Tumer, Z., Bertelsen, B., Stefansson, H., Jensen, L., Melchior, L., Debes, N. Mol, Groth, C., Skov, L., Werge, T., Karagiannidis, I., Tarnok, Z., Barta, C., Nagy, P., Farkas, L., Brondum-Nielsen, K., Rizzo, R., Gulisano, M., Rujescu, D., Kiemeney, L.A.L.M., Tosato, S., Nawaz, M.S., Ingason, A., Unnsteinsdottir, U., Steinberg, S., Ludvigsson, P., Stefansson, K., Kuss, A.W., Paschou, P., Cath, D., Hoekstra, P.J., Muller-Vahl, K., Stuhrmann, M., Silahtaroglu, A., Pfundt, R.P., and Tumer, Z.

Abstract

Item does not contain fulltext, BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 x 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

Published
2016

8. Cornell University Life Sciences Core Laboratories Center

Author

VanEe, J., Schweitzer, P., Wang, W., Li, Y., Zhang, S., Williams, R., Deng, K.Y., Pillardy, J., Sun, Q., Stelick, T., Spisak, J., Paronett, E., Cote, L., Cameron, R., Zhao, J., Hover, B., Kresovich, J., Xin, Y., Figueroa, M., Shaknovich, R., Monni, S., Unnsteinsdottir, U., Sherwood, R., Ptak, C., Yan, H., Bayles, C., Xia, G., Doran, R., Bukowski, R., Myers, C., Ponnala, L., Stefanov, S., Howard, M., Flaherty, J., Manocchia, A., Dodge, E., Smith, K., Aquadro, C., Lin, D., Melnick, A., Zipfel, W., Soloway, P., Jin, M., Clark, A., Siepel, A., Rose, J.K.C., and Grills, G.S.

Subjects
Poster Session Abstracts
Abstract

CF-13

Published
2010

9. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.

Author

Bjornsdottir G, Chalmer MA, Stefansdottir L, Skuladottir AT, Einarsson G, Andresdottir M, Beyter D, Ferkingstad E, Gretarsdottir S, Halldorsson BV, Halldorsson GH, Helgadottir A, Helgason H, Hjorleifsson Eldjarn G, Jonasdottir A, Jonasdottir A, Jonsdottir I, Knowlton KU, Nadauld LD, Lund SH, Magnusson OT, Melsted P, Moore KHS, Oddsson A, Olason PI, Sigurdsson A, Stefansson OA, Saemundsdottir J, Sveinbjornsson G, Tragante V, Unnsteinsdottir U, Walters GB, Zink F, Rødevand L, Andreassen OA, Igland J, Lie RT, Haavik J, Banasik K, Brunak S, Didriksen M, T Bruun M, Erikstrup C, Kogelman LJA, Nielsen KR, Sørensen E, Pedersen OB, Ullum H, Masson G, Thorsteinsdottir U, Olesen J, Ludvigsson P, Thorarensen O, Bjornsdottir A, Sigurdardottir GR, Sveinsson OA, Ostrowski SR, Holm H, Gudbjartsson DF, Thorleifsson G, Sulem P, Stefansson H, Thorgeirsson TE, Hansen TF, and Stefansson K

Subjects
Humans, Genome-Wide Association Study, Phenotype, Migraine Disorders genetics, Migraine with Aura genetics, Epilepsy
Abstract

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes., (© 2023. The Author(s).)

Published
2023
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10. Physical and cognitive impact following SARS-CoV-2 infection in a large population-based case-control study.

Author

Holm H, Ivarsdottir EV, Olafsdottir T, Thorolfsdottir R, Eythorsson E, Norland K, Gisladottir R, Jonsdottir G, Unnsteinsdottir U, Sveinsdottir KE, Jonsson BA, Andresdottir M, Arnar DO, Arnthorsson AO, Birgisdottir K, Bjarnadottir K, Bjarnadottir S, Bjornsdottir G, Einarsson G, Eiriksdottir B, Gardarsdottir EE, Gislason T, Gottfredsson M, Gudmundsdottir S, Gudmundsson J, Gunnarsdottir K, Helgadottir A, Helgason D, Hinriksdottir I, Ingvarsson RF, Jonasdottir SS, Jonsdottir I, Karlsdottir TH, Kristinsdottir AM, Kristinsson SY, Kristjansdottir S, Love TJ, Ludviksdottir D, Masson G, Norddahl G, Olafsdottir T, Olafsson I, Rafnar T, Runolfsdottir HL, Saemundsdottir J, Sigurbjornsson S, Sigurdardottir K, Sigurdsson E, Sigurdsson MI, Sigurdsson EL, Steinthorsdottir V, Sveinbjornsson G, Thorarensen EA, Thorbjornsson B, Thorsteinsdottir B, Tragante V, Ulfarsson MO, Stefansson H, Gislason T, Kristjansson M, Palsson R, Sulem P, Thorsteinsdottir U, Thorgeirsson G, Gudbjartsson DF, and Stefansson K

Abstract

Background: Persistent symptoms are common after SARS-CoV-2 infection but correlation with objective measures is unclear., Methods: We invited all 3098 adults who tested SARS-CoV-2 positive in Iceland before October 2020 to the deCODE Health Study. We compared multiple symptoms and physical measures between 1706 Icelanders with confirmed prior infection (cases) who participated, and 619 contemporary and 13,779 historical controls. Cases participated in the study 5-18 months after infection., Results: Here we report that 41 of 88 symptoms are associated with prior infection, most significantly disturbed smell and taste, memory disturbance, and dyspnea. Measured objectively, cases had poorer smell and taste results, less grip strength, and poorer memory recall. Differences in grip strength and memory recall were small. No other objective measure associated with prior infection including heart rate, blood pressure, postural orthostatic tachycardia, oxygen saturation, exercise tolerance, hearing, and traditional inflammatory, cardiac, liver, and kidney blood biomarkers. There was no evidence of more anxiety or depression among cases. We estimate the prevalence of long Covid to be 7% at a median of 8 months after infection., Conclusions: We confirm that diverse symptoms are common months after SARS-CoV-2 infection but find few differences between cases and controls in objective parameters measured. These discrepancies between symptoms and physical measures suggest a more complicated contribution to symptoms related to prior infection than is captured with conventional tests. Traditional clinical assessment is not expected to be particularly informative in relating symptoms to a past SARS-CoV-2 infection., (© 2023. The Author(s).)

Published
2023
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11. Thirty novel sequence variants impacting human intracranial volume.

Author

Nawaz MS, Einarsson G, Bustamante M, Gisladottir RS, Walters GB, Jonsdottir GA, Skuladottir AT, Bjornsdottir G, Magnusson SH, Asbjornsdottir B, Unnsteinsdottir U, Sigurdsson E, Jonsson PV, Palmadottir VK, Gudjonsson SA, Halldorsson GH, Ferkingstad E, Jonsdottir I, Thorleifsson G, Holm H, Thorsteinsdottir U, Sulem P, Gudbjartsson DF, Stefansson H, Thorgeirsson TE, Ulfarsson MO, and Stefansson K

Abstract

Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume ( n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2022
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12. MAP1B mutations cause intellectual disability and extensive white matter deficit.

Author

Walters GB, Gustafsson O, Sveinbjornsson G, Eiriksdottir VK, Agustsdottir AB, Jonsdottir GA, Steinberg S, Gunnarsson AF, Magnusson MI, Unnsteinsdottir U, Lee AL, Jonasdottir A, Sigurdsson A, Jonasdottir A, Skuladottir A, Jonsson L, Nawaz MS, Sulem P, Frigge M, Ingason A, Love A, Norddhal GL, Zervas M, Gudbjartsson DF, Ulfarsson MO, Saemundsen E, Stefansson H, and Stefansson K

Subjects
Animals, Brain metabolism, Brain pathology, Cognition physiology, Corpus Callosum metabolism, Corpus Callosum pathology, Female, Fragile X Mental Retardation Protein genetics, Intellectual Disability genetics, Intellectual Disability physiopathology, Male, Mice, Mice, Knockout, Microtubule-Associated Proteins genetics, Mutation genetics, Pedigree, Fragile X Mental Retardation Protein metabolism, Microtubule-Associated Proteins metabolism, White Matter metabolism, White Matter pathology
Abstract

Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Whole-genome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (β = -2.1SD, P = 5.1 × 10 -8 ), 47% less corpus callosum (CC) volume (β = -2.4SD, P = 5.5 × 10 -10 ) and lower brain-wide fractional anisotropy (P = 6.7 × 10 -4 ). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.

Published
2018
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13. Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

Author

Bertelsen B, Stefánsson H, Riff Jensen L, Melchior L, Mol Debes N, Groth C, Skov L, Werge T, Karagiannidis I, Tarnok Z, Barta C, Nagy P, Farkas L, Brøndum-Nielsen K, Rizzo R, Gulisano M, Rujescu D, Kiemeney LA, Tosato S, Nawaz MS, Ingason A, Unnsteinsdottir U, Steinberg S, Ludvigsson P, Stefansson K, Kuss AW, Paschou P, Cath D, Hoekstra PJ, Müller-Vahl K, Stuhrmann M, Silahtaroglu A, Pfundt R, and Tümer Z

Subjects
Adult, Animals, Attention Deficit Disorder with Hyperactivity genetics, Cohort Studies, Comorbidity, Denmark, Exons, Female, Genotyping Techniques, Germany, Humans, Hungary, Iceland, Italy, Male, Mice, Netherlands, DNA Copy Number Variations genetics, Sequence Deletion genetics, Tourette Syndrome genetics
Abstract

Background: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations., Methods: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues., Results: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology., Conclusions: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Published
2016
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14. Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

Author

Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U, Kong A, Helisalmi S, Soininen H, Lah JJ, Aarsland D, Fladby T, Ulstein ID, Djurovic S, Sando SB, White LR, Knudsen GP, Westlye LT, Selbæk G, Giegling I, Hampel H, Hiltunen M, Levey AI, Andreassen OA, Rujescu D, Jonsson PV, Bjornsson S, Snaedal J, and Stefansson K

Subjects
Case-Control Studies, Genetic Association Studies, Genetic Predisposition to Disease, Haplotypes, Humans, Mutation, Risk, Sequence Analysis, DNA, ATP-Binding Cassette Transporters genetics, Alzheimer Disease genetics
Abstract

We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10(-15)).

Published
2015
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15. Isolation and characterization of a thermostable RNA ligase 1 from a Thermus scotoductus bacteriophage TS2126 with good single-stranded DNA ligation properties.

Author

Blondal T, Thorisdottir A, Unnsteinsdottir U, Hjorleifsdottir S, Aevarsson A, Ernstsson S, Fridjonsson OH, Skirnisdottir S, Wheat JO, Hermannsdottir AG, Sigurdsson ST, Hreggvidsson GO, Smith AV, and Kristjansson JK

Subjects
Amino Acid Sequence, Enzyme Stability, Molecular Sequence Data, RNA Ligase (ATP) genetics, RNA Ligase (ATP) isolation & purification, Sequence Alignment, Temperature, Thermus virology, Bacteriophages enzymology, DNA, Single-Stranded metabolism, RNA Ligase (ATP) metabolism
Abstract

We have recently sequenced the genome of a novel thermophilic bacteriophage designated as TS2126 that infects the thermophilic eubacterium Thermus scotoductus. One of the annotated open reading frames (ORFs) shows homology to T4 RNA ligase 1, an enzyme of great importance in molecular biology, owing to its ability to ligate single-stranded nucleic acids. The ORF was cloned, and recombinant protein was expressed, purified and characterized. The recombinant enzyme ligates single-stranded nucleic acids in an ATP-dependent manner and is moderately thermostable. The recombinant enzyme exhibits extremely high activity and high ligation efficiency. It can be used for various molecular biology applications including RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE). The TS2126 RNA ligase catalyzed both inter- and intra-molecular single-stranded DNA ligation to >50% completion in a matter of hours at an elevated temperature, although favoring intra-molecular ligation on RNA and single-stranded DNA substrates. The properties of TS2126 RNA ligase 1 makes it very attractive for processes like adaptor ligation, and single-stranded solid phase gene synthesis.

Published
2005
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