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3. Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

Author

Boen, R, Kaufmann, T, van der Meer, D, Frei, O, Agartz, I, Ames, D, Andersson, M, Armstrong, NJ, Artiges, E, Atkins, JR, Bauer, J, Benedetti, F, Boomsma, DI, Brodaty, H, Brosch, K, Buckner, RL, Cairns, MJ, Calhoun, V, Caspers, S, Cichon, S, Corvin, AP, Crespo-Facorro, B, Dannlowski, U, David, FS, de Geus, EJC, de Zubicaray, GI, Desrivieres, S, Doherty, JL, Donohoe, G, Ehrlich, S, Eising, E, Espeseth, T, Fisher, SE, Forstner, AJ, Fortaner-Uya, L, Frouin, V, Fukunaga, M, Ge, T, Glahn, DC, Goltermann, J, Grabe, HJ, Green, MJ, Groenewold, NA, Grotegerd, D, Grontvedt, GR, Hahn, T, Hashimoto, R, Hehir-Kwa, JY, Henskens, FA, Holmes, AJ, Haberg, AK, Haavik, J, Jacquemont, S, Jansen, A, Jockwitz, C, Joensson, EG, Kikuchi, M, Kircher, T, Kumar, K, Le Hellard, S, Leu, C, Linden, DE, Liu, J, Loughnan, R, Mather, KA, Mcmahon, KL, Mcrae, AF, Medland, SE, Meinert, S, Moreau, CA, Morris, DW, Mowry, BJ, Muehleisen, TW, Nenadic, I, Noethen, MM, Nyberg, L, Ophoff, RA, Owen, MJ, Pantelis, C, Paolini, M, Paus, T, Pausova, Z, Persson, K, Quide, Y, Marques, TR, Sachdev, PS, Sando, SB, Schall, U, Scott, RJ, Selbaek, G, Shumskaya, E, Silva, AI, Sisodiya, SM, Stein, F, Stein, DJ, Straube, B, Streit, F, Strike, LT, Teumer, A, Teutenberg, L, Thalamuthu, A, Tooney, PA, Tordesillas-Gutierrez, D, Trollor, JN, Van't Ent, D, van den Bree, MBM, van Haren, NEM, Vazquez-Bourgon, J, Voelzke, H, Wen, W, Wittfeld, K, Ching, CRK, Westlye, LT, Thompson, PM, Bearden, CE, Selmer, KK, Alnaes, D, Andreassen, OA, Sonderby, IE, Boen, R, Kaufmann, T, van der Meer, D, Frei, O, Agartz, I, Ames, D, Andersson, M, Armstrong, NJ, Artiges, E, Atkins, JR, Bauer, J, Benedetti, F, Boomsma, DI, Brodaty, H, Brosch, K, Buckner, RL, Cairns, MJ, Calhoun, V, Caspers, S, Cichon, S, Corvin, AP, Crespo-Facorro, B, Dannlowski, U, David, FS, de Geus, EJC, de Zubicaray, GI, Desrivieres, S, Doherty, JL, Donohoe, G, Ehrlich, S, Eising, E, Espeseth, T, Fisher, SE, Forstner, AJ, Fortaner-Uya, L, Frouin, V, Fukunaga, M, Ge, T, Glahn, DC, Goltermann, J, Grabe, HJ, Green, MJ, Groenewold, NA, Grotegerd, D, Grontvedt, GR, Hahn, T, Hashimoto, R, Hehir-Kwa, JY, Henskens, FA, Holmes, AJ, Haberg, AK, Haavik, J, Jacquemont, S, Jansen, A, Jockwitz, C, Joensson, EG, Kikuchi, M, Kircher, T, Kumar, K, Le Hellard, S, Leu, C, Linden, DE, Liu, J, Loughnan, R, Mather, KA, Mcmahon, KL, Mcrae, AF, Medland, SE, Meinert, S, Moreau, CA, Morris, DW, Mowry, BJ, Muehleisen, TW, Nenadic, I, Noethen, MM, Nyberg, L, Ophoff, RA, Owen, MJ, Pantelis, C, Paolini, M, Paus, T, Pausova, Z, Persson, K, Quide, Y, Marques, TR, Sachdev, PS, Sando, SB, Schall, U, Scott, RJ, Selbaek, G, Shumskaya, E, Silva, AI, Sisodiya, SM, Stein, F, Stein, DJ, Straube, B, Streit, F, Strike, LT, Teumer, A, Teutenberg, L, Thalamuthu, A, Tooney, PA, Tordesillas-Gutierrez, D, Trollor, JN, Van't Ent, D, van den Bree, MBM, van Haren, NEM, Vazquez-Bourgon, J, Voelzke, H, Wen, W, Wittfeld, K, Ching, CRK, Westlye, LT, Thompson, PM, Bearden, CE, Selmer, KK, Alnaes, D, Andreassen, OA, and Sonderby, IE

Abstract

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Published
2024

4. Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing

Author

Coppola, A, Krithika, S, Iacomino, M, Bobbili, D, Balestrini, S, Bagnasco, I, Bilo, L, Buti, D, Casellato, S, Cuccurullo, C, Ferlazzo, E, Leu, C, Giordano, L, Gobbi, G, Hernandez-Hernandez, L, Lench, N, Martins, H, Meletti, S, Messana, T, Nigro, V, Pinelli, M, Pippucci, T, Bellampalli, R, Salis, B, Sofia, V, Striano, P, Striano, S, Tassi, L, Vignoli, A, Vaudano, AE, Viri, M, Scheffer, IE, May, P, Zara, F, Sisodiya, SM, Coppola, A, Krithika, S, Iacomino, M, Bobbili, D, Balestrini, S, Bagnasco, I, Bilo, L, Buti, D, Casellato, S, Cuccurullo, C, Ferlazzo, E, Leu, C, Giordano, L, Gobbi, G, Hernandez-Hernandez, L, Lench, N, Martins, H, Meletti, S, Messana, T, Nigro, V, Pinelli, M, Pippucci, T, Bellampalli, R, Salis, B, Sofia, V, Striano, P, Striano, S, Tassi, L, Vignoli, A, Vaudano, AE, Viri, M, Scheffer, IE, May, P, Zara, F, and Sisodiya, SM

Abstract

OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. A

Published
2024

5. Relative cost of multidrug-resistant TB medicines in Europe

Author

Günther, G., Guglielmetti, L., Leu, C., van Leth, F., Lange, C., VU University medical center, Health Economics and Health Technology Assessment, APH - Global Health, and APH - Methodology

Subjects
Pulmonary and Respiratory Medicine, Infectious Diseases, 610 Medicine & health
Published
2023

7. 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

11. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

Koko, M, Motelow, JE, Stanley, KE, Bobbili, DR, Dhindsa, RS, May, P, Alldredge, BK, Allen, AS, Altmüller, J, Amrom, D, Andermann, E, Auce, P, Avbersek, A, Baulac, S, Bautista, JF, Becker, F, Bellows, Susannah, Berghuis, B, Berkovic, SF, Bluvstein, J, Boro, A, Bridgers, J, Burgess, R, Caglayan, H, Cascino, GD, Cavalleri, GL, Chung, SK, Cieuta-Walti, C, Cloutier, V, Consalvo, D, Cossette, P, Crumrine, P, Delanty, N, Depondt, C, Desbiens, R, Devinsky, O, Dlugos, D, Epstein, MP, Everett, K, Fiol, M, Fountain, NB, Francis, B, French, J, Freyer, C, Friedman, D, Gambardella, A, Geller, EB, Girard, S, Glauser, T, Glynn, S, Goldstein, DB, Gravel, M, Haas, K, Haut, SR, Heinzen, EL, Helbig, I, Hildebrand, MS, Johnson, MR, Jorgensen, A, Joshi, S, Kanner, A, Kirsch, HE, Klein, KM, Knowlton, RC, Koeleman, BPC, Kossoff, EH, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Langley, SR, LeGuern, E, Lehesjoki, AE, Lerche, H, Leu, C, Lortie, A, Lowenstein, DH, Marson, AG, Mebane, C, Mefford, HC, Meloche, C, Moreau, C, Motika, PV, Muhle, H, Møller, RS, Nabbout, R, Nguyen, DK, Nikanorova, M, Novotny, EJ, Nürnberg, P, Ottman, R, O’Brien, TJ, Paolicchi, JM, Parent, JM, Park, K, Peter, S, Petrou, S, Petrovski, S, Pickrell, WO, Poduri, A, Koko, M, Motelow, JE, Stanley, KE, Bobbili, DR, Dhindsa, RS, May, P, Alldredge, BK, Allen, AS, Altmüller, J, Amrom, D, Andermann, E, Auce, P, Avbersek, A, Baulac, S, Bautista, JF, Becker, F, Bellows, Susannah, Berghuis, B, Berkovic, SF, Bluvstein, J, Boro, A, Bridgers, J, Burgess, R, Caglayan, H, Cascino, GD, Cavalleri, GL, Chung, SK, Cieuta-Walti, C, Cloutier, V, Consalvo, D, Cossette, P, Crumrine, P, Delanty, N, Depondt, C, Desbiens, R, Devinsky, O, Dlugos, D, Epstein, MP, Everett, K, Fiol, M, Fountain, NB, Francis, B, French, J, Freyer, C, Friedman, D, Gambardella, A, Geller, EB, Girard, S, Glauser, T, Glynn, S, Goldstein, DB, Gravel, M, Haas, K, Haut, SR, Heinzen, EL, Helbig, I, Hildebrand, MS, Johnson, MR, Jorgensen, A, Joshi, S, Kanner, A, Kirsch, HE, Klein, KM, Knowlton, RC, Koeleman, BPC, Kossoff, EH, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Langley, SR, LeGuern, E, Lehesjoki, AE, Lerche, H, Leu, C, Lortie, A, Lowenstein, DH, Marson, AG, Mebane, C, Mefford, HC, Meloche, C, Moreau, C, Motika, PV, Muhle, H, Møller, RS, Nabbout, R, Nguyen, DK, Nikanorova, M, Novotny, EJ, Nürnberg, P, Ottman, R, O’Brien, TJ, Paolicchi, JM, Parent, JM, Park, K, Peter, S, Petrou, S, Petrovski, S, Pickrell, WO, and Poduri, A

Published
2022

12. A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies

Author

Altmann, A, Ryten, M, Di Nunzio, M, Ravizza, T, Tolomeo, D, Reynolds, RH, Somani, A, Bacigaluppi, M, Iori, V, Micotti, E, Di Sapia, R, Cerovic, M, Palma, E, Ruffolo, G, Botia, JA, Absil, J, Alhusaini, S, Alvim, MKM, Auvinen, P, Bargallo, N, Bartolini, E, Bender, B, Bergo, FPG, Bernardes, T, Bernasconi, A, Bernasconi, N, Bernhardt, BC, Blackmon, K, Braga, B, Caligiuri, ME, Calvo, A, Carlson, C, Carr, SJA, Cavalleri, GL, Cendes, F, Chen, J, Chen, S, Cherubini, A, Concha, L, David, P, Delanty, N, Depondt, C, Devinsky, O, Doherty, CP, Domin, M, Focke, NK, Foley, S, Franca, W, Gambardella, A, Guerrini, R, Hamandi, K, Hibar, DP, Isaev, D, Jackson, GD, Jahanshad, N, Kalviainen, R, Keller, SS, Kochunov, P, Kotikalapudi, R, Kowalczyk, MA, Kuzniecky, R, Kwan, P, Labate, A, Langner, S, Lenge, M, Liu, M, Martin, P, Mascalchi, M, Meletti, S, Morita-Sherman, ME, O'Brien, TJ, Pariente, JC, Richardson, MP, Rodriguez-Cruces, R, Rummel, C, Saavalainen, T, Semmelroch, MK, Severino, M, Striano, P, Thesen, T, Thomas, RH, Tondelli, M, Tortora, D, Vaudano, AE, Vivash, L, Podewils, F, Wagner, J, Weber, B, Wiest, R, Yasuda, CL, Zhang, G, Zhang, J, Leu, C, Avbersek, A, Thom, M, Whelan, CD, Thompson, P, McDonald, CR, Vezzani, A, Sisodiya, SM, Altmann, A, Ryten, M, Di Nunzio, M, Ravizza, T, Tolomeo, D, Reynolds, RH, Somani, A, Bacigaluppi, M, Iori, V, Micotti, E, Di Sapia, R, Cerovic, M, Palma, E, Ruffolo, G, Botia, JA, Absil, J, Alhusaini, S, Alvim, MKM, Auvinen, P, Bargallo, N, Bartolini, E, Bender, B, Bergo, FPG, Bernardes, T, Bernasconi, A, Bernasconi, N, Bernhardt, BC, Blackmon, K, Braga, B, Caligiuri, ME, Calvo, A, Carlson, C, Carr, SJA, Cavalleri, GL, Cendes, F, Chen, J, Chen, S, Cherubini, A, Concha, L, David, P, Delanty, N, Depondt, C, Devinsky, O, Doherty, CP, Domin, M, Focke, NK, Foley, S, Franca, W, Gambardella, A, Guerrini, R, Hamandi, K, Hibar, DP, Isaev, D, Jackson, GD, Jahanshad, N, Kalviainen, R, Keller, SS, Kochunov, P, Kotikalapudi, R, Kowalczyk, MA, Kuzniecky, R, Kwan, P, Labate, A, Langner, S, Lenge, M, Liu, M, Martin, P, Mascalchi, M, Meletti, S, Morita-Sherman, ME, O'Brien, TJ, Pariente, JC, Richardson, MP, Rodriguez-Cruces, R, Rummel, C, Saavalainen, T, Semmelroch, MK, Severino, M, Striano, P, Thesen, T, Thomas, RH, Tondelli, M, Tortora, D, Vaudano, AE, Vivash, L, Podewils, F, Wagner, J, Weber, B, Wiest, R, Yasuda, CL, Zhang, G, Zhang, J, Leu, C, Avbersek, A, Thom, M, Whelan, CD, Thompson, P, McDonald, CR, Vezzani, A, and Sisodiya, SM

Abstract

AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Published
2022

13. The role of common genetic variation in presumed monogenic epilepsies

Author

Campbell, C, Leu, C, Feng, Y-CA, Wolking, S, Moreau, C, Ellis, C, Ganesan, S, Martins, H, Oliver, K, Boothman, I, Benson, K, Molloy, A, Brody, L, Michaud, JL, Hamdan, FF, Minassian, BA, Lerche, H, Scheffer, IE, Sisodiya, S, Girard, S, Cosette, P, Delanty, N, Lal, D, Cavalleri, GL, Campbell, C, Leu, C, Feng, Y-CA, Wolking, S, Moreau, C, Ellis, C, Ganesan, S, Martins, H, Oliver, K, Boothman, I, Benson, K, Molloy, A, Brody, L, Michaud, JL, Hamdan, FF, Minassian, BA, Lerche, H, Scheffer, IE, Sisodiya, S, Girard, S, Cosette, P, Delanty, N, Lal, D, and Cavalleri, GL

Abstract

BACKGROUND: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. METHODS: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for 'all epilepsy', 'focal epilepsy', and 'genetic generalised epilepsy' (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. FINDINGS: Cases of presumed monogenic severe epilepsy had an increased PRS for 'all epilepsy' (p<0.0001), 'focal epilepsy' (p<0.0001), and 'GGE' (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. INTERPRETATION: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. FUNDING: Science foundation Ireland, Human Genome Research Institute

Published
2022

14. Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

Author

Oliver, KL, Ellis, CA, Scheffer, IE, Ganesan, S, Leu, C, Sadleir, LG, Heinzen, EL, Mefford, HC, Bass, AJ, Curtis, SW, Harris, R, Whiteman, DC, Helbig, I, Ottman, R, Epstein, MP, Bahlo, M, Berkovic, SF, Oliver, KL, Ellis, CA, Scheffer, IE, Ganesan, S, Leu, C, Sadleir, LG, Heinzen, EL, Mefford, HC, Bass, AJ, Curtis, SW, Harris, R, Whiteman, DC, Helbig, I, Ottman, R, Epstein, MP, Bahlo, M, and Berkovic, SF

Abstract

BACKGROUND: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies. METHODS: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry. FINDINGS: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5×10-9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5×10-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases. INTERPRETATION: The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known gene

Published
2022

15. Pain-autonomic interaction is a reliable measure of pain habituation in healthy subjects

Author

De Schoenmacker, Iara, Leu, C, Curt, A; https://orcid.org/0000-0003-0136-8467, Hubli, M, De Schoenmacker, Iara, Leu, C, Curt, A; https://orcid.org/0000-0003-0136-8467, and Hubli, M

Abstract

BACKGROUND: Habituation is a response decrement resulting from repeated stimuli. Reduced habituation to noxious stimuli is considered to be a proxy for central sensitization in subjects with chronic pain. Despite numerous investigations of pain habituation in relation to central sensitization, there is no consensus on the most sensitive and reliable readout, as well as analysis approach. Therefore, this study compared the usability and reliability of different readouts and habituation analysis approaches to measure pain habituation in response to repetitive heat simulation. METHODS: Three blocks of 20 contact heat stimuli were applied on the volar forearm of 20 healthy subjects on two separate visits. Habituation was assessed by three different readouts: pain ratings, contact heat evoked potentials (CHEPs) and heat-induced sympathetic skin responses (SSRs). In addition, two different habituation analysis approaches were used: between the three stimulation blocks (between-block) and within the first stimulation block (within-block). RESULTS: Significant between-block habituation for SSRs (p < 0.001), but not for pain ratings (p = 1.000) and CHEPs (p = 0.078) was found. There was significant within-block habituation for pain ratings (p = 0.012) and SSRs (p < 0.001), but not for CHEPs (p = 0.246). Only the between-block habituation of heat-induced SSR was reliable between the two visits (first to second block: intraclass correlation coefficient (ICC) = 0.58, p = 0.030; first to third block: ICC = 0.64, p = 0.015). CONCLUSION: Heat-induced SSR as a measure of pain-autonomic interaction revealed the strongest pain habituation and showed highest test-retest reliability.

Published
2022

17. OP02. Interrogating and correcting fine‐scale genetic structure in large (>36,000 samples) GWAS datasets using scalable haplotype sharing methods

Author

Gilbert, Edmund, O’Reilly, Seamus, Merrigan, Michael, McGettingan, Darren, Vitart, Veronique, Joshi, Peter K, Clark, David W, Campbell, Harry, Hayward, Caroline, Ring, Susan M, Golding, Jean, Goodfellow, Stephanie, Navarro, Pau, Kerr, Shona M, Amador, Carmen, Campbell, Archie, Haley, Chris S, Porteous, David J, Cavalleri, Gianpiero L, Wilson, James F, Byrne, RP, van Rheenen, W, Veldink, JH, McLaughlin, RL, Fitzgerald, Joan, Fahey, Laura, Whitton, Laura, Donohoe, Gary, Morris, Derek W, Smyth, LJ, Wooster, C, Kilner, J, Kee, F, Young, I, McGuinness, B, Maxwell, AP, McKay, GJ, McKnight, AJ, Maloney, DM, Chadderton, N, Millington-Ward, S, Farrar, GJ, Lambert, DM, Nguengang-Wakap, S, Olry, A, Rath, A, Murphy, D, Lynch, SA, Treacy, EP, Gunne, E, McGarvey, C, Hamilton, K, Savage, S, Rasheed, E, Rashid, A, Keogh, E, MacNamara, B, Collison, C, Brazil, N, Whatley, S, Crowley, VEF, Murphy, DN, Turner, J, Doyle, Samantha, Abidin, Zaza, Senanayake, Suranga, James, Stephanie, Yap, Mei, Hart, Caroline, Crushell, Ellen, Smyth, Shane, Green, Andrew, Treacy, Eileen, Lynch, Tim, Pastores, Gregory, Laffan, Aoife, O’Byrne, James, Palfi, A, Yesmambetov, A, Ormond, CM, Ryan, NM, Heron, EA, Gill, M, Corvin, AP, Kelly, CM, Doherty, MA, Hengeveld, JC, Campbell, C, Leu, C, Delanty, N, Lal, D, Cavalleri, GL, Angel, CZ, McNally, CJ, McKenna, DJ, Breslin, EM, Cassidy, LM, Martiniano, R, Mattiangeli, V, Silva, AM, Bradley, DG, Kearney, H, Balagura, G, Lewis-Smith, D, Ganesan, S, Gan, J, Galer, PD, Wang, Y, Tan, NCK, Lench, NJ, Steward, CA, Krause, R, Robinson, P, Helbig, I, Finnegan, LK, Kenna, P, Carty, M, Bowie, AG, Whelan, L, Dockery, A, Kenna, PF, Keegan, D, Silvestri, G, Khan, M, Cornelis, SS, Dhaenens, CM, Humphries, P, Cremers, FPM, Roosing, S, Broin, Pilib Ó, Morris, Derek, McVeigh, Úna M, McVeigh, Terri P, Miller, Nicola, Kerin, Michael J, Flaus, Andrew, Irwin, RE, Thursby, SJ, Ondičová, M, Pentieva, K, McNulty, H, Richmond, C, Caffrey, A, Lees-Murdock, DJ, McLaughlin, M, Cassidy, T, Suderman, M, Relton, CL, Walsh, CP, Carrigan, M, Maloney, D, Hanlon, K, Bookey, N, Drago, P, Parle-McDermott, A, Flynn, PM, Toulouse, A, Bermingham, N, Jansen, M, Hand, CK, Skelly, RD, Cole, J, Berkeley, M, Dinneen, Thomas, O’Cónail, A, Kirov, George, Lopez, Lorna M, Gallagher, Louise, Ning, Z, Williams, JM, Kumari, R, Baranov, PV, Moore, T, Bhandari, Sushil, Hillman, Sara, Dolma, Padma, Mukerji, Mitali, Prasher, Bhavana, Montgomery, Hugh E., Gunne, EA, Ward, A, Treacy, E, Lambert, D, Benson, KA, Murray, S, Senum, SR, Kennedy, C, Yachnin, K, Gangadharan, N, Harris, PC, Conlon, P, Zhu, J, Wynne, N, McKenna, C, Humphreys, M, McNerlan, S, Dabir, T, Rea, G, Morrison, PJ, Donnelly, DE, Jeffers, L, Sasaki, E, Kelly, H, Hayes, B, Ryan, K, Carolan, E, Betts, D, Green, A, Sheerin, A, Grabowsky, L, James, S, Senanayake, S, Abidin, Z, O’Byrne, J, Pastores, G, McConnell, V, Bradley, L, Reid, J, Fitzsimons, D, Dempster, M, Pentony, Michaela, Bradley, Lisa, Connor, Pamela O’, Kirk, Claire W, Donnelly, Deirdre E, Hardy, Rachel, Shepherd, Charles W, Morrison, Patrick J, Doyle, S, McVeigh, T, O’Byrne, JJ, Senanayake, SL, Sadok, S, Pastores, GM, Forde, R, Rakovac, A, Abdelfadil, S, Mac Namara, B, O’Connor, P, Heggarty, S, Hart, P, Morgan, NE, Dorris, E, Cummins, E, Adeeb, F, Taylor, C, Savic, S, Killeen, O, Fraser, A, Wilson, AG, Murphy, Jane, Kirk, Claire, Prendiville, Terence, Ward, Deirdre, Galvin, Joseph, Lynch, Sally Ann, Carroll, C, Kirk, C, Murphy, J, Duff, M, Mooney, E, Clark, T, King, C, Fallah, L, and Hinde, J

Subjects
Poster Presentations, Abstracts, Oral Presentations
Abstract

Background Age-related cognitive decline results in increased difficulty in performing tasks that require memory or rapid information processing. Cognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning. The polygenetic contribution to cognitive resilience requires large data sets for analysis. In addition, longitudinal data is needed to identify individual differences in cognitive performance over time. The UK Biobank cohort of over 500,000 participants over the age of 40 offers the potential to advance research on the genetics and biology of cognitive resilience. Methods We created a longitudinal cognitive resilience phenotype by combining the phenotypic cognitive parameter of current reaction time with a proxy phenotype of education years (EY). We used this resilience phenotype, in genome-wide association studies (GWAS) to identify genes and gene sets that influence the biological pathways involved in resilience. To remove the influence of the EY on the analysis we compared genetic data on participants that displayed resilience to those that showed expected cognitive decline. Results GWAS outputs analysis showed 273 significantly enriched genes for participants that demonstrated resilience. Genotype–tissue expression was significant in brain tissue, particularly in the anterior cingulate cortex, frontal cortex, and hippocampus. Biological Pathway analysis includes synapse, post synaptic density and neuron guidance. Conclusion This analysis shows an association between cognitive resilience and enrichment of neuronal activity. Confirmatory examination of these findings in datasets with strong longitudinal cognitive data, such and the Health and Retirement Study, is ongoing., Introduction Type 1 diabetes (T1D) is a polygenic disease characterised by autoimmune inflammatory destruction of the pancreas and subsequent hyperglycaemia. Several GWAS have identified loci associated with T1D risk, but recent evidence suggests that epigenetic changes in DNA methylation may have a causal role in T1D. Methods To identify potential methylation-based biomarkers of T1D, blood-derived DNA from 250 individuals with ≥15 years duration of T1D was compared to 391 controls with no evidence of diabetes. All individuals were from the British Isles. DNA was bisulphite treated using the EZ DNA Methylation Kit (Zymo). The Infinium HD Methylation Assay MethylationEPIC BeadChips (Illumina) were used to determine the methylation status of >850,000 CpG sites, gene bodies and promoters. Results MethylationEPIC data was analysed using GenomeStudio v2011 and Partek Genomics Suite v7.0. Comparing T1D with controls identified 1,706 CpG sites with significantly different (p±2 fold change). Genes including HLA‐DRB1, HLA‐DQA1 and PLEKHA1 have been previously linked to T1D and contained >2 differently methylated CpG sites ≥p, Introduction Rare diseases (RDs) are a public health priority but their scarcity and diversity leads to a lack of knowledge and expertise. Accurate epidemiological information about RDs is necessary to inform public policy, but without an Irish rare disease registry, there is a dearth of primary data. Methods Collaborative work with Orphanet Coordination derived a global point prevalence of RDs from the ‘Orphanet Epidemiological File’ (http://www.orphadata.org) by selecting RDs described by ‘point prevalence’ from predefined geographic regions, and summing point prevalences. In the National Rare Disease Office, expert opinion and disease-specific publications were used to adapt a ‘high prevalence’ list for Ireland. Results Globally, ‘point prevalence’ describes 5,304 RDs ≥85.9%). The minimum cumulative point prevalence of RDs is 3.5‐5.9% of the population. While globally 84.5% RDs analysed ≥n=3585) had a point prevalence of 1/100,000. To construct a comparable Irish ‘high‐ prevalence’ list, 191 RDs with known prevalence >1/100,000 across all countries were drawn from the global list. A further 147 diseases with possible prevalence >1/100,000 in Ireland due to ethnic, environmental or founder‐effect are currently under consideration for inclusion. Conclusion 3.5%‐5.9% is the first evidence‐based estimate of the global population prevalence of RDs. Creation of an Irish list of high‐prevalence RDs permits development of care pathways and systems that address the needs of the majority of Irish people with RDs. Implementation of RD codification in eHealth Ireland will provide more accurate data., Introduction The acute hepatic porphyrias, including acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HP) along with familial Porphyria Cutanea Tarda (fPCT) are autosomal dominantly inherited disorders affecting key enzymes in the haem biosynthetic pathway. Clinically these disorders may manifest as photosensitive skin lesions (VP, HP and PCT) and/or acute neuropathic episodes (AIP, VP and HP). All demonstrate variable penetrance and expressivity. Thus, while biochemical investigations, including blood, urine and faecal porphyrin analysis, are critical for the diagnosis of active porphyric disease, these investigations may not be sensitive enough to identify presymptomatic variant carriers. Hence molecular genetic analysis has become an important component in kindred follow-up for identifying porphyria susceptibility. Methods The Biochemistry Department, St James’s Hospital, Dublin, has established a molecular diagnostic service based on direct nucleotide sequencing to facilitate diagnosis of genetic susceptibility to AIP, VP, HCP and PCT respectively. Results To date over 30 different genetic variants linked with a porphyria phenotype have been identified in different kindreds including non‐Irish. The spectrum of variants includes missense, nonsense, splice‐site and small insertions and deletions e.g. HMBS ≥R26C, R26H, IVS4+1G>A), PPOX ≥IVS4‐1G>A, Q435X, W427X, A150D, Q375X) and CPO ≥R332Q, R332W, c.1291‐1292 ins TG). In addition, novel variants have been identified in collaboration with Cardiff Porphyria Centre. Conclusion This unique insight into the molecular basis of porphyrias in the ROI indicates that acute porphyrias and fPCT are genetically heterogeneous. Furthermore, the variant scanning assay in St James’s Hospital has identified pathogenic variants in >93% of confirmed porphyria kindreds, Background The developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies which co-present with intellectual disability, and occur in cases without a family history of epilepsy. Their severe phenotype means that DEEs are thought to be primarily monogenic, caused by highly damaging rare mutations. Currently, analysis of exome sequence data can identify a causative mutation in around 40% of DEEs. Little is known about the genetic architecture of the remaining DEEs which screen-negative after genomic analysis. Here, we used a method known as polygenic risk scoring (PRS) to test whether the burden of common genetic variation is relevant to the development of the DEEs. Methods Exome and GWAS data on DEE cases (n=745), and population controls (n=75,000) were obtained from the DDD cohort and Ukbiobank, respectively. Damaging mutations in known epilepsy genes were bioinformatically inferred. PRS were calculated using the most recent ILAE GWAS of epilepsy and compared between i) DEE cases and the general population, and ii) DEE cases with and without damaging mutations. Results DEE cases with and without inferred damaging mutations were found to have elevated PRS for epilepsy. We did not detect a significant difference in PRS between DEE cases with and without damaging mutations. Discussion This research provides the first evidence that common genetic variation contributes to the development of the DEEs. Our results suggest common genetic variation contributes to DEE status irrespective of the presence of a highly damaging rare genetic variant. Further work in additional cohorts is required to extend these results., Rationale The phenotypic features in a person with epilepsy are often complex with regards to seizure presentations, which is acknowledged by the most recent revision of the seizure classification by the International League Against Epilepsy (ILAE). We provide updated seizure-related human phenotype ontology (HPO) terms to facilitate a deep phenotypic interpretation of heretofore unexplained genetic epilepsies. Methods The Epilepsiome project is a Task Force of the Genetics Commission of the ILAE and represent the link to the gene curation efforts within the ClinGen Epilepsy Clinical Domain Working Group (CDWG). Within the efforts to align terminology used in the diagnostic space, the Epilepsiome Project revised HPO terms for epileptic seizures. The updated classification was built through an online portal and consensus was achieved through biweekly conference calls. Results Focal, generalised and neonatal HPO seizure terminologies were constructed according to the most recent ILAE classification and aligned with the existing HPO structure. This ontology allows capture of clinical information at various levels of detail and aims to preserve the onset, awareness and motor/non-motor nature of each seizure type, using multiple parentages. We integrated other frequently observed seizures currently not included in the ILAE, which required a separate branch within the ontology due to biological peculiarity of their age of onset, their clinical significance or genetic architecture. Conclusions Improvements in HPO terms for epileptic seizures will enable a more versatile seizure ontology leading to deep phenotyping of people with epilepsy to improve associations with genomic data in both a research and diagnostic setting., Purpose Target5000 aims to genetically characterise approximately 5000 people in Ireland with an inherited retinal degeneration (IRD). Thus far, over 1,000 IRD patients have been sequenced for variants in 260 IRD genes. One arm of the project focuses on improving detection of candidate variants by whole genome sequencing (WGS), by analysing non-coding mutations and performing functional analysis. Approach IRD patients are clinically diagnosed by Target5000 ophthalmologists. When informed consent is given, the Target5000 study employs target capture next generation sequencing (NGS), with a positive candidate detection rate of 68%. To improve detection rates, whole-gene or WGS was employed on a case-dependent basis to identify pathogenic intronic variants not previously captured. Results One common form of IRD is ABCA4-associated Stargardt disease (STGD1), often caused by deep-intronic variants. Thus far, 36 ‘unresolved’ STGD1 and cone-rod dystrophy cases have undergone targeted ABCA4 whole-gene sequencing, positively identifying a candidate in ~50% of cases. A variant in intron 30 resulting in a pseudoexon inclusion was particularly frequent and found in 5/16 (likely) solved cases. Furthermore, 40 patient samples have undergone WGS. Conclusions An objective of Target5000 is to provide actionable outcomes empowering patients with genetic diagnoses and potentially future access to clinical trials or approved treatments, where appropriate. The results presented highlight the significant value of a target capture NGS strategy as a preliminary diagnostic measure, with remaining elusive cases undergoing more extensive genetic analysis. This methodology improves variant detection rates and progresses the goal of fully elucidating the genetic architecture of IRDs in Ireland., Background Copy Number Variants (CNVs) are large genomic deletions/duplications of >1kb, spanning regions that can encompass one or many genes. Though a common form of structural variation, pathogenic CNVs, of population freq., The Ladakhi people dwell in the Jammu and Kashmir regions of India, between the Karakoram and Himalayan mountain ranges, at ≥3400 meters altitude. The Ladakhi share similar linguistic, cultural and religious practices with Tibetans. However, relative to Tibetans, the Ladakhi are very poorly studied at the level of population structure and genetic selection. In this context, we set out to conduct a genomic survey of population structure in representative samples of the Ladakhi people. Methods We genotyped 310 Ladakhi DNA samples using the Illumina Global Screening Array gene chip. We merged the Ladakhi with data from 800 individuals representing different reference language groups including; Sino-Tibetan (Tibetans, Sherpa, Han), Indo-European (Indo-Aryan, Hazara), Austroasiatic (Munda) and Burusho (a linguistic isolate in Jammu-Kashmir). We performed ADMIXTURE, principal component analysis (PCA), fineSTRUCTURE and ChromoPainter analysis on the combined autosomal data. Results In PCA plots, the Ladakhi population cluster together with Sherpa and Tibetans, forming a distinct Himalayan group, different from other mainland populations of South and East Asia. ADMIXTURE analysis at k=4 suggests ancestry proportions in the Ladakhi to be approximately 50% Highlander (Tibetan/Sherpa) and 50% Indo-European. These results suggest contemporary Ladakhi people are the admixed of Tibetans and Indo-Europeans. Conclusions Our results suggests a considerable component of the Ladakhi genome descends from ancestral highlander populations residing on the Tibetan plateau for the last 35,000 years, with subsequent admixture with neighbouring Indo-European populations., Background The EU recognises rare disease (RD) as life threatening with delays in establishing a diagnosis and treatment. The Irish National Plan for RDs (2014) recommended epidemiological studies of RD prevalence to improve both cost efficiencies and care of patients with RD’s. Objective To derive the incidence of paediatric RD and the number of paediatric RD mortality cases through analysis of records held at two major tertiary paediatric hospitals, for children born in the year 2000. Methods Cases were identified using electronic/manual records from: the National Paediatric Mortality Registry office; Clinical, Cytogenetics and Molecular genetics database; Radiology and the Hospital In-Patient Enquiry system (HIPE). In addition a detailed analysis of national death registration information for RDs from 2006-2016 was undertaken along with a 2year study (2015-2016) of inpatient RD deaths. Results There were 54,789 livebirths in 2000. Genetics records identified 801 cases of RDs Ongoing HIPE searches identified 1381 cases. Mortality data revealed that of all deaths on the Register (2006-2016), (n=4044) aged 0-14, 58.56% (n=2368) had a RD diagnosis with age distribution; Neonates, 56% (1140/2050), Post-neonates, 58% (450/778), Children aged 1-14 years, 64% (778/1216). Of the total (n=234) inpatient deaths with a RD from 2015-2016, 52.6% (n=123) were cared for at the two major centres. Conclusion This study to-date has identified > 2,200 RD patients presenting by age 17 giving a minimum incidence of 4% for paediatric RDs. We expect the final figure to be higher when we complete analysis of all the HIPE and sub-specialty data from these major centres., Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. ADPKD is primarily caused by variants in PKD1 and PKD2. Sequencing of PKD1 is difficult due to multiple pseudogenes. There is unexplained variance in the age-of-onset of PKD, even within families. Aim 1) Establish a targeted NGS panel to improve molecular diagnosis of PKD and 2) characterize large ‘super-families’ for the study of new ADPKD genes and genetic modifiers. Methods NGS was performed using a custom Roche SeqCap targeted panel (273 genes) and Illumina NextSeq. Bioinformatics was performed using an in-house GATK pipeline. Pathogenicity was assigned using American College of Medical Genetics and Genomics guidelines and Mayo Clinic PKD in-house methods. Gap-filling Sanger sequencing was utilized in unsolved cases Results 172 PKD patients were sequenced with average coverage 189X. A molecular diagnosis meeting pathogenicity criteria was obtained in 82% (141/172) of patients following gap-filling Sanger of PKD1 and PKD2 (n=41). 46 of the PKD-causing variants we detected were novel. We identified 13 rare, diagnostic PKD variants shared across multiple affected individuals recorded clinically as having no known familial relationship. Second-degree relatedness was confirmed via clinical follow-up. These families form the basis for the assembly of PKD ‘super-families’. Conclusions NGS is suitable for sequencing of PKD genes including PKD1, although some gap filling by Sanger is required for complete coverage. We have identified 13 potential ADPKD ‘super-families’ using genomic data for further study. These results are improving diagnostics of ADPKD in the Irish renal clinic., Purpose Target5000 is a genetic study to detect and characterise variants associated with inherited retinal degenerations (IRD). Choroideremia is an X-Linked recessive chorioretinal degenerative condition with progressive atrophy of several key cells of the retina and the surrounding blood retinal barrier. Here we describe a novel deletion in the CHM gene found in two Irish pedigrees. This 500kb deletion represents the largest yet detected IRD-associated deletion in Ireland. Approach As part of the Irish IRD registry, Target5000, patients with inherited retinal degenerative conditions are recruited. Target capture sequencing was employed to investigate variation in 254 IRD-associated genes. Upon detection of the deletion in CHM, PCR analysis was used to elucidate the full extent of the deletion. Results Two members of a large X-linked Retinitis Pigmentosa pedigree clinically presented with choroideremia and tested negative for the segregating RPGR variant found in other affected members of this pedigree. Both males were sequenced and found to possess large deletions spanning the CHM gene, totalling 500kb. This deletion has also been detected in a second Irish pedigree since its discovery. Two additional males and two carrier females from this second pedigree were all found to be severely affected with progressive choroideremia. Conclusions Typically, female carriers of CHM mutations show mild stationary signs with no symptoms, while males are severely affected. In this instance, females were more severely affected than expected with advanced signs of degeneration and progressive visual decline. This is possibly due to random X-inactivation and the severity of CHM gene deletion., Introduction The largest cohort of patients at The National Centre for Adult Inherited Metabolic Disorders (NCIMD) have Phenylketonuria (PKU). The NCIMD manages patients transitioned from Paediatric services upon reaching adulthood. Improved treatments have extended life expectancy and increased quality of life for patients with PKU; however diet and supplements remained the only means of treatment for life until the recent introduction of Sapropterin dihydrochloride. Aim To analyse the genotype of the PKU cohort in attendance at The NCIMD with a focus on responsiveness to Sapropterin dihydrochloride. Method The data are collated from when the Adult unit was first established in 2013 until the end of May 2019. Exclusion criteria include patients over the age of 53 and patients who have two negatively indicated genotypes for the use of Sapropterin dihydrochloride. Genotypes are recorded in a secured database onsite and descriptive analyses were performed. Results The total number of patients examined is 282; 104 were male (36.8%) and 178 were female (63.1%). The total samples processed and available for analysis were 148 (male= 46, 31%; female= 102, 68.9%). The frequency of Saptopterin dihydrochloride responsiveness in both alleles was observed (responsive= 15, 10%; unresponsive= 48, 48.33%; uncertain= 85, 57%). The most common alleles recorded were R408W (41.1%), F39L (13.8%), 165T (11.2%), and L249F (3.8%). Conclusion Due to the uncertainty surrounding Sapropterin dihydrochloride responsiveness for various common mutations in the Irish PKU cohort, there is a need for greater genetic and metabolic collaboration. Analysis and treatment may be impacted by time elapsed from sending samples to receiving results., Introduction The Department of Clinical Genetics at CHI provides services for individuals affected by or at risk of a genetic condition in the Republic of Ireland. There are currently 3,283 referrals waiting to be seen, of whom 930 are waiting longer that the HSE standard of 18 months. A negative consequence of a long waiting list is that patients die whilst waiting. Resulting harm includes: 1) no diagnosis 2) no genetic testing, no DNA stored, 3) family unaware of a hereditary disorder, denied screening, 4) relatives having unnecessary screening as no predictive test for family, 5) future pregnancy options limited if paediatric proband undiagnosed. As of 13/06/2019, we have recorded 33 deaths on our waiting list. We began to systematically collect data on deaths since March 2018. This study concentrates on these cases; n=15/33. Aims To identify the consequences to the relatives of these 15 referrals. Results Nine were adult cancer genetic referrals, 5/9 diagnostic, 3/9 predictive, and a further case had NF2. Only 1/9 had DNA stored. Two adult patients had a cardiac family history (Marfan syndrome, cardiomyopathy) respectively. Neither had DNA stored. Four paediatric patients had multiple malformations secondary to a chromosomal or genetic syndrome. In 3/4 a diagnosis had already been reached. The fourth case, who died unexpectedly of unrelated causes, had no DNA stored. Summary 11/15 patients who died did not have DNA stored, precluding diagnosis and risk calculation for their relatives. As each extended 3 generation Irish family has ~64 relatives, lack of diagnosis has far reaching consequences., Background Women who carry a pathogenic variant in either a BRCA1 or BRCA2 gene have a high lifetime risk of developing breast and tubo-ovarian cancer. To manage this risk, women may choose to undergo risk-reducing surgery to remove breast tissue, ovaries and fallopian tubes. Surgery should increase survival, but can impact women’s lives adversely at a psychological and psychosexual level. Interventions to facilitate psychological adjustment and improve quality of life post risk-reducing surgery are needed. Aim of Review To examine psychosocial interventions in female BRCA carriers who have undergone risk-reducing surgery and to evaluate the effectiveness of such interventions on psychological adjustment and quality of life. Methods We searched the Cochrane Central Register of Controlled trials (CENTRAL) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid, CINAHL, PsycINFO, Web of Science and Scopus up to April 2019. Results We identified two studies; one randomised controlled trial and one nonrandomised study. Conclusions The effect of psychosocial interventions on quality of life and emotional well-being in female BRCA carriers who undergo risk-reducing surgery is uncertain given limited high quality evidence. Next Generation Sequencing, along with targeted cancer treatments, increasing knowledge around the biology of cancers and the results of the 100K Genome Project will open up genetic testing to many more women. For as long as surgical interventions remain the dominant risk-reducing option for management of women with a deleterious BRCA gene, health professionals have a responsibility to ensure there is provision to holistically manage the outcomes of such surgery., Introduction FATCO (Fibular Aplasia, Tibial Campomelia and Oligosyndactyly) syndrome is a rare descriptive diagnosis first defined by Courtens et al. in 2005, who recognised a comparable pattern of malformations with his own case and 4 others described in the literature. Aetiology remains unknown, however defects involved in SHH (Sonic hedgehog) gene expression have been proposed. Case Description We report on a term male infant born with severe malformations. On examination, there was absence of the left radius and ulna, bilateral anterior angulation of lower limbs with skin dimpling overlying. Both ankle joints were dysplastic and there was oligosyndactly of both feet. Right upper limb was normal. X-rays of the limbs revealed dysplastic tibiae, absence of both fibulae, a right foot containing 3 ossified metatarsals with 2 formed digits, and a left foot with a single ossified metatarsal and two soft tissue digits with small bony elements. The infant had no other associated anomalies, and is developmentally appropriate at 1 year. Management included Symes amputation, prosthetics and following genetic referral FATCO syndrome was suggested as the best fitting diagnosis. Whole genome sequencing of the infants blood is currently being performed. Discussion This is an important case to report as there are very few descriptions in the literature, In keeping with the majority of reports, this case appears to be sporadic and development is normal. Our case is male, keeping with preponderance. Treatment aims at optimising functionality of limbs and stabilisations of joints., Introduction Fibrous cephalic plaques (FCP) are a characteristic manifestation of tuberous sclerosis complex (TSC) and occur in one third of cases. Their natural history and long term course is unknown, as is the outcome of long term follow-up of TSC cases in old age. Phenotype and methods We describe an 80 year old with TSC due to a c.2784dupC TSC2 mutation, who was diagnosed in infancy with an FCP and was regularly followed up at the TSC clinic over 8 decades with regular epilepsy treatment and renal monitoring. Results Regular clinical photography and clinical records document the plaque at different ages. The FCP naturally resolved at 74 years. Facial angiofibromas also faded with time in the last decade. His epilepsy and renal abnormalities remained under control with careful surveillance and monitoring. Discussion Natural aging in the eighth decade causes progressive laxity of collagen and leads to natural resolution of FCPs. This novel finding with a unique 80 year follow up yields valuable insights into the aging changes within FCPs and facial angiofibromas as the pathways linking facial angiofibromas and FCP’s through the TGF-β1 pathway are now being elucidated. Conclusion We present a clinical odyssey showing the natural progression and history of FCPs in TSC and comment on the mechanistic pathways allowing potential interventions in this disfiguring condition. TSC cases can be successfully managed and complications – particularly in the brain and kidney, can be avoided over an entire lifetime. This is encouraging for long term prospects for patients with TSC., Introduction Fabry disease is an X-linked inherited disorder due to deficient activity of the enzyme alpha-galactosidase A and progressive lysosomal deposition of globotriaosylceramide in cells. Aim To report the genotype/phenotype landscape of the adult Fabry disease cohort attending The National Centre for Adult Inherited Metabolic Disorders (NCIMD). Method All Fabry patients (N=70) attending NCIMD until end of May 2019 were included in this analysis. Genotypes and phenotypes were recorded by chart review. Descriptive analyses were performed. Result 26 (37.1%) were male (median age 43 [32:54]) and 44 (62.9%) were female (median age 46 [25:61]). The AGAL pathogenic variants were missense (52, 74.3%), deletion (9, 12.9%), nonsense (8, 11.4%) and duplication (1, 1.4%). Most missense variants occurred in exon 2 (25%), exon 3 (19.2%), exon 5 (23.1%) and exon 6 (21.2%). 21.2% of missense variants were N215S. 28 patients were on enzyme therapy and 2 were on oral chaperone therapy. The incidence of cardiac (M=18/26; F=18/44; p=0.021), renal (M=14/26; F=18/44; p=0.304), neurological (M=17/26; F=20/44; p=0.107) and hearing (M=14/26; F=19/44; p=0.399) involvement were observed. Within N215S cohort, 2 had hypertrophic cardiomyopathy and 5 with a degree of left ventricular hypertrophy. Conclusion Pathogenic variants were observed across the AGAL gene in the cohort. Incidence of cardiac involvement in both genders is similar. Females had more frequently observed renal, neurological and hearing involvement. N215S AGAL variant is the most common variant which is associated with a predominant cardiac phenotype, thus collaboration between clinical geneticists and cardiovascular physicians are important when establishing diagnosis and management., Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with a worldwide prevalence of 1:500. Genetic etiology is suspected in up to 50% of HCM patients. To gain insight into the diagnostic yield and mutation spectrum of HCM, a retrospective review was performed for 114 consecutive cases with a clinical suspicion of HCM who underwent multigene panel testing at our laboratory between 2014 and 2019. Method Data was manually extracted from laboratory reports with respect to indication for testing, number of genes on panel, variants identified and classification at the time of testing. Results A total of 114 patients with a diagnosis of HCM had samples submitted for diagnostic testing using a multigene panel of between 16 and 20 genes, depending on the year of testing. 56 patients had no genetic variant identified, 33 patients had a pathogenic or likely pathogenic variant identified and 25 had a variant of uncertain significance identified. One 11 year old patient had a normal result from an 18 gene panel for HCM, but was later diagnosed with Friedrich ataxia. One adult female patient had a normal result from a 19 gene panel but was later diagnosed with Fabry disease. Conclusion Clinically actionable ‘Pathogenic’ or ‘Likely pathogenic’ variants were identified in 29% of patients with a Clinical diagnosis of Hypertrophic Cardiomyopathy with VUS being identified in 22%. The most common 2 genes in which clinically actionable variants were found were MYH7 (47%) and MYBPC3 (31%)., Huntington’s disease (HD) is an inherited progressive neurodegenerative condition. In the Republic of Ireland genetic testing for HD is available via two routes. Symptomatic individuals can access testing via a Neurologist. Asymptomatic individuals with a known family history of HD can seek testing via a genetic counselling multi-step process. Aim The aim of the audit was to review the activity of the HD specialty clinic. Methods Retrospective chart, laboratory and clinical database review for HD referrals received for 2016, 2017 and 2018 was carried out. Parameters examined included: number of referrals, age profile, motivation for testing, results. Results Over this 3 year period 93 referrals were received. 80 referrals were for predictive testing and 13 for genetic counselling post testing through neurology. The youngest person was 18 years of age at time of referral. More females requested a referral for predictive testing than males, 48 (60%) and 32 (40%) respectfully. The most common motivation given for predictive testing was with regard to family planning and concerns for children and to help them plan for the future. Of the 30 tests carried out to date, 52% were mutation positive and 42% were mutation negative. The average age of those who proceeded with testing was 37yrs. Conclusion These findings reflect data published from the UK with regard to age of presentation and female to male bias. The most common motivation for testing was family planning unlike the UK where the most common reason provided was to reduce uncertainty.

Published
2020

18. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

Koko, M., Motelow, J. E., Stanley, K. E., Bobbili, D. R., Dhindsa, R. S., May, P., Alldredge, B. K., Allen, A. S., Altmuller, J., Amrom, D., Andermann, E., Auce, P., Avbersek, A., Baulac, S., Bautista, J. F., Becker, F., Bellows, S. T., Berghuis, B., Berkovic, S. F., Bluvstein, J., Boro, A., Bridgers, J., Burgess, R., Caglayan, H., Cascino, G. D., Cavalleri, G. L., Chung, S. -K., Cieuta-Walti, C., Cloutier, V., Consalvo, D., Cossette, P., Crumrine, P., Delanty, N., Depondt, C., Desbiens, R., Devinsky, O., Dlugos, D., Epstein, M. P., Everett, K., Fiol, M., Fountain, N. B., Francis, B., French, J., Freyer, C., Friedman, D., Gambardella, A., Geller, E. B., Girard, S., Glauser, T., Glynn, S., Goldstein, D. B., Gravel, M., Haas, K., Haut, S. R., Heinzen, E. L., Helbig, I., Hildebrand, M. S., Johnson, M. R., Jorgensen, A., Joshi, S., Kanner, A., Kirsch, H. E., Klein, K. M., Knowlton, R. C., Koeleman, B. P. C., Kossoff, E. H., Krause, R., Krenn, M., Kunz, W. S., Kuzniecky, R., Langley, S. R., Leguern, E., Lehesjoki, A. -E., Lerche, H., Leu, C., Lortie, A., Lowenstein, D. H., Marson, A. G., Mebane, C., Mefford, H. C., Meloche, C., Moreau, C., Motika, P. V., Muhle, H., Moller, R. S., Nabbout, R., Nguyen, D. K., Nikanorova, M., Novotny, E. J., Nurnberg, P., Ottman, R., O'Brien, T. J., Paolicchi, J. M., Parent, J. M., Park, K., Peter, S., Petrou, S., Petrovski, S., Pickrell, W. O., Poduri, A., Radtke, R. A., Rees, M. I., Regan, B. M., Ren, Z., Sadleir, L. G., Sander, J. W., Sander, T., Scheffer, I. E., Schubert, J., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Shinnar, S., Sills, G. J., Singh, R. K., Siren, A., Sirven, J., Sisodiya, S. M., Smith, M. C., Sonsma, A. C. M., Striano, P., Sullivan, J., Thio, L. L., Thomas, R. H., Venkat, A., Vining, E. P. G., Von Allmen, G. K., Wang, Q., Weber, Y. G., Weckhuysen, S., Weisenberg, J. L., Widdess-Walsh, P., Winawer, M. R., Wolking, S., Zara, F., Zimprich, F., Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium, Department of Medical and Clinical Genetics, Medicum, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Peter, Sarah, Petrou, Steven, Petrovski, Slavé, Pickrell, William O., Poduri, Annapurna, Radtke, Rodney A., Rees, Mark I., Regan, Brigid M., Ren, Zhong, Sadleir, Lynette G., Alldredge, Brian K., Sander, Josemir W., Sander, Thomas, Scheffer, Ingrid E., Schubert, Julian, Shellhaas, Renée A., Sherr, Elliott H., Shih, Jerry J., Shinnar, Shlomo, Sills, Graeme J., Singh, Rani K., Allen, Andrew S., Siren, Auli, Sirven, Joseph, Sisodiya, Sanjay M., Smith, Michael C., Sonsma, Anja C. M., Striano, Pasquale, Sullivan, Joseph, Thio, Liu Lin, Thomas, Rhys H., Venkat, Anu, Altmüller, Janine, Vining, Eileen P. G., Von Allmen, Gretchen K., Wang, Quanli, Weber, Yvonne G., Weckhuysen, Sarah, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Wolking, Stefan, Zara, Federico, Amrom, Dina, Zimprich, Fritz, Andermann, Eva, Auce, Pauls, Avbersek, Andreja, Baulac, Stéphanie, Bautista, Jocelyn F., Becker, Felicitas, Bellows, Susannah T., Berghuis, Bianca, Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Bridgers, Joshua, Burgess, Rosemary, Caglayan, Hande, Cascino, Gregory D., Cavalleri, Gianpiero L., Chung, Seo-Kyung, Cieuta-Walti, Cécile, Cloutier, Véronique, Consalvo, Damian, Cossette, Patrick, Crumrine, Patricia, Delanty, Norman, Depondt, Chantal, Desbiens, Richard, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Everett, Kate, Fiol, Miguel, Fountain, Nathan B., Francis, Ben, French, Jacqueline, Freyer, Catharine, Friedman, Daniel, Gambardella, Antonio, Geller, Eric B., Girard, Simon, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gravel, Micheline, Haas, Kevin, Haut, Sheryl R., Heinzen, Erin L., Helbig, Ingo, Hildebrand, Michael S., Johnson, Michael R., Jorgensen, Andrea, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Klein, Karl M., Knowlton, Robert C., Koeleman, Bobby P. C., Kossoff, Eric H., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Langley, Sarah R., LeGuern, Eric, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lortie, Anne, Lowenstein, Daniel H., Marson, Anthony G., Mebane, Caroline, Mefford, Heather C., Meloche, Caroline, Moreau, Claudia, Motika, Paul V., Muhle, Hiltrud, Møller, Rikke S., Nabbout, Rima, Nguyen, Dang K., Nikanorova, Marina, Novotny, Edward J., Nürnberg, Peter, Ottman, Ruth, O'Brien, Terence J., Paolicchi, Juliann M., Parent, Jack M., and Park, Kristen

Subjects
GABA receptors, Neurology [D14] [Human health sciences], Clinical Sciences, GABA(A) receptors, GABRG2, familial epilepsy, Article, Clinical Research, Receptors, Exome Sequencing, Genetics, 2.1 Biological and endogenous factors, Humans, GGE, Genetic Predisposition to Disease, sporadic epilepsy, EpiPGX Consortium, Aetiology, gamma-Aminobutyric Acid, GABAA receptors, Epi4K Consortium, Epilepsy, Neurology & Neurosurgery, Neurologie [D14] [Sciences de la santé humaine], Generalized, GABA-A, Prevention, Human Genome, Neurosciences, 1184 Genetics, developmental biology, physiology, 3112 Neurosciences, Receptors, GABA-A, EuroEPINOMICS-CoGIE Consortium, Neurology, Case-Control Studies, Epilepsy, Generalized, Canadian Epilepsy Network, Neurology (clinical), Genetics & genetic processes [F10] [Life sciences], 3111 Biomedicine, Human medicine, Génétique & processus génétiques [F10] [Sciences du vivant], Epilepsy Phenome/Genome Project
Abstract

ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p=1.8×10-5 ), approaching study-wide significance in familial GGE (p=3.0×10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR]=3.9, 95% confidence interval [CI]=1.9-7.8, false discovery rate [FDR]-adjusted p=.0024), whereas their association with sporadic GGE had marginally lower odds (OR=3.1, 95% CI=1.3-6.7, FDR-adjusted p=.022). URVs in GABAergic pathway genes were associated with familial GGE (OR=1.8, 95% CI=1.3-2.5, FDR-adjusted p=.0024) but not with sporadic GGE (OR=1.3, 95% CI=.9-1.9, FDR-adjusted p=.19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Published
2022

21. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author

Wolking, S., Moreau, C., Mccormack, M., Krause, R., Krenn, M., Berkovic, S., Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Kunz, W. S., Lerche, H., Marson, A. G., O'Brien, T. J., Petrovski, S., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Zimprich, F., Sisodiya, S. M., Girard, S. L., Cossette, P., Avbersek, A., Leu, C., Heggeli, K., Demurtas, R., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Berghuis, B., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Auce, P., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Hutton, J., Muhle, H., Klein, K. M., Moller, R. S., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Craig, J., and Stefansson, H.

Subjects
0301 basic medicine, Male, Candidate gene, Drug Resistant Epilepsy, Neurology [D14] [Human health sciences], Neurosciences. Biological psychiatry. Neuropsychiatry, Drug resistance, Bioinformatics, Polymorphism, Single Nucleotide, Whole Exome Sequencing, Cohort Studies, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Polymorphism, RC346-429, Gene, Exome sequencing, Research Articles, Genetic Association Studies, Neurologie [D14] [Sciences de la santé humaine], business.industry, General Neuroscience, Genetic variants, Genetic Variation, Single Nucleotide, medicine.disease, DEPDC5, Female, 030104 developmental biology, Cohort, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, RC321-571, Research Article
Abstract

Annals of Clinical and Translational Neurology 8(7), 1376-1387 (2021). doi:10.1002/acn3.51374, Published by Wiley, Chichester [u.a.]

Published
2021

22. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Sønderby, I.E., van der Meer, D., Moreau, C., Kaufmann, T., Walters, G.B., Ellegaard, M., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N.J., Bernard, M., Blackburn, N.B., Blangero, J., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Bülow, R., Bøen, R., Cahn, W., Calhoun, V.D., Caspers, S., Ching, C.R.K., Cichon, S., Ciufolini, S., Crespo-Facorro, B., Curran, J.E., Dale, A.M., Dalvie, S., Dazzan, P., de Geus, E.J.C., de Zubicaray, G.I., de Zwarte, S.M.C., Desrivières, S., Doherty, J.L., Donohoe, G., Draganski, B., Ehrlich, S., Eising, E., Espeseth, T., Fejgin, K., Fisher, S.E., Fladby, T., Frei, O., Frouin, V., Fukunaga, M., Gareau, T., Ge, T., Glahn, D.C., Grabe, H.J., Groenewold, N.A., Gústafsson, Ó., Haavik, J., Håberg, A.K., Hall, J., Hashimoto, R., Hehir-Kwa, J.Y., Hibar, D.P., Hillegers, M.H.J., Hoffmann, P., Holleran, L., Holmes, A.J., Homuth, G., Hottenga, J-J, Hulshoff Pol, H.E., Ikeda, M., Jahanshad, N., Jockwitz, C., Johansson, S., Jönsson, E.G., Jørgensen, N.R., Kikuchi, M., Knowles, E.E.M., Kumar, K., Le Hellard, S., Leu, C., Linden, D.E.J., Liu, J., Lundervold, A., Lundervold, A.J., Maillard, A.M., Martin, N.G., Martin-Brevet, S., Mather, K.A., Mathias, S.R., McMahon, K.L., McRae, A.F., Medland, S.E., Meyer-Lindenberg, A., Moberget, T., Modenato, C., Sánchez, J.M., Morris, D.W., Mühleisen, T.W., Murray, R.M., Nielsen, J., Nordvik, J.E., Nyberg, L., Loohuis, L.M.O., Ophoff, R.A., Owen, M.J., Paus, T., Pausova, Z., Peralta, J.M., Pike, G.B., Prieto, C., Quinlan, E.B., Reinbold, C.S., Marques, T.R., Rucker, J.J.H., Sachdev, P.S., Sando, S.B., Schofield, P.R., Schork, A.J., Schumann, G., Shin, J., Shumskaya, E., Silva, A.I., Sisodiya, S.M., Steen, V.M., Stein, D.J., Strike, L.T., Suzuki, I.K., Tamnes, C.K., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Uhlmann, A., Ulfarsson, M.O., van ‘t Ent, D., van den Bree, M.B.M., Vanderhaeghen, P., Vassos, E., Wen, W., Wittfeld, K., Wright, M.J., Agartz, I., Djurovic, S., Westlye, L.T., Stefánsson, H., Stefánsson, K., Jacquemont, S., Thompson, P.M., Andreassen, O.A., Sønderby, I.E., van der Meer, D., Moreau, C., Kaufmann, T., Walters, G.B., Ellegaard, M., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N.J., Bernard, M., Blackburn, N.B., Blangero, J., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Bülow, R., Bøen, R., Cahn, W., Calhoun, V.D., Caspers, S., Ching, C.R.K., Cichon, S., Ciufolini, S., Crespo-Facorro, B., Curran, J.E., Dale, A.M., Dalvie, S., Dazzan, P., de Geus, E.J.C., de Zubicaray, G.I., de Zwarte, S.M.C., Desrivières, S., Doherty, J.L., Donohoe, G., Draganski, B., Ehrlich, S., Eising, E., Espeseth, T., Fejgin, K., Fisher, S.E., Fladby, T., Frei, O., Frouin, V., Fukunaga, M., Gareau, T., Ge, T., Glahn, D.C., Grabe, H.J., Groenewold, N.A., Gústafsson, Ó., Haavik, J., Håberg, A.K., Hall, J., Hashimoto, R., Hehir-Kwa, J.Y., Hibar, D.P., Hillegers, M.H.J., Hoffmann, P., Holleran, L., Holmes, A.J., Homuth, G., Hottenga, J-J, Hulshoff Pol, H.E., Ikeda, M., Jahanshad, N., Jockwitz, C., Johansson, S., Jönsson, E.G., Jørgensen, N.R., Kikuchi, M., Knowles, E.E.M., Kumar, K., Le Hellard, S., Leu, C., Linden, D.E.J., Liu, J., Lundervold, A., Lundervold, A.J., Maillard, A.M., Martin, N.G., Martin-Brevet, S., Mather, K.A., Mathias, S.R., McMahon, K.L., McRae, A.F., Medland, S.E., Meyer-Lindenberg, A., Moberget, T., Modenato, C., Sánchez, J.M., Morris, D.W., Mühleisen, T.W., Murray, R.M., Nielsen, J., Nordvik, J.E., Nyberg, L., Loohuis, L.M.O., Ophoff, R.A., Owen, M.J., Paus, T., Pausova, Z., Peralta, J.M., Pike, G.B., Prieto, C., Quinlan, E.B., Reinbold, C.S., Marques, T.R., Rucker, J.J.H., Sachdev, P.S., Sando, S.B., Schofield, P.R., Schork, A.J., Schumann, G., Shin, J., Shumskaya, E., Silva, A.I., Sisodiya, S.M., Steen, V.M., Stein, D.J., Strike, L.T., Suzuki, I.K., Tamnes, C.K., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Uhlmann, A., Ulfarsson, M.O., van ‘t Ent, D., van den Bree, M.B.M., Vanderhaeghen, P., Vassos, E., Wen, W., Wittfeld, K., Wright, M.J., Agartz, I., Djurovic, S., Westlye, L.T., Stefánsson, H., Stefánsson, K., Jacquemont, S., Thompson, P.M., and Andreassen, O.A.

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021

23. Introduction of shock wave technology to fir wood preservation

Author

Sanne M., Kampe A., Lenz C., Gossel S., Wagner S., Haibel A., Melcher E., Leu C., Pfriem A., Lautner S., Sanne M., Kampe A., Lenz C., Gossel S., Wagner S., Haibel A., Melcher E., Leu C., Pfriem A., and Lautner S.

Abstract

Similar to a normal wave, a shock wave travels as energy through matter but it causes an abrupt rise of pressure, temperature and density. In this study, the influence of shock waves on wood structure were investigated in the light of possible future industrial utilization e.g. timber impregnating treatment. The constructed autoclave is capable of creating shock waves either by an electrical pulse breakdown of a spark gap arrangement or by electromagnetic actuators. The penetration depths of the fir wood test samples were measured using light microscopy, SEM and micro-computed tomography. Our results showed that by varying the intensity of the incident shock wave, the distance between the shock wave generating device and the test sample, and/or the orientation of test sample in relation to the shockwave, the wood tissue structure had been heavily disintegrated or hardly affected at all. An improvement on impregnation could not be found., Similar to a normal wave, a shock wave travels as energy through matter but it causes an abrupt rise of pressure, temperature and density. In this study, the influence of shock waves on wood structure were investigated in the light of possible future industrial utilization e.g. timber impregnating treatment. The constructed autoclave is capable of creating shock waves either by an electrical pulse breakdown of a spark gap arrangement or by electromagnetic actuators. The penetration depths of the fir wood test samples were measured using light microscopy, SEM and micro-computed tomography. Our results showed that by varying the intensity of the incident shock wave, the distance between the shock wave generating device and the test sample, and/or the orientation of test sample in relation to the shockwave, the wood tissue structure had been heavily disintegrated or hardly affected at all. An improvement on impregnation could not be found.

Published
2021

24. Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations

Author

Stevelink, R, Luykx, JJ, Lin, BD, Leu, C, Lal, D, Smith, AW, Schijven, D, Carpay, JA, Rademaker, K, Baldez, RAR, Devinsky, O, Braun, KPJ, Jansen, FE, Smit, DJA, Koeleman, BPC, Stevelink, R, Luykx, JJ, Lin, BD, Leu, C, Lal, D, Smith, AW, Schijven, D, Carpay, JA, Rademaker, K, Baldez, RAR, Devinsky, O, Braun, KPJ, Jansen, FE, Smit, DJA, and Koeleman, BPC

Abstract

OBJECTIVE: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations. METHODS: Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses. RESULTS: Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations. SIGNIFICANCE: Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.

Published
2021

25. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Sonderby, IE, van der Meer, D, Moreau, C, Kaufmann, T, Walters, GB, Ellegaard, M, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Buelow, R, Boen, R, Cahn, W, Calhoun, VD, Caspers, S, Ching, CRK, Cichon, S, Ciufolini, S, Crespo-Facorro, B, Curran, JE, Dale, AM, Dalvie, S, Dazzan, P, de Geus, EJC, de Zubicaray, GI, de Zwarte, SMC, Desrivieres, S, Doherty, JL, Donohoe, G, Draganski, B, Ehrlich, S, Eising, E, Espeseth, T, Fejgin, K, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Ge, T, Glahn, DC, Grabe, HJ, Groenewold, NA, Gustafsson, O, Haavik, J, Haberg, AK, Hall, J, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Holmes, AJ, Homuth, G, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jahanshad, N, Jockwitz, C, Johansson, S, Joensson, EG, Jorgensen, NR, Kikuchi, M, Knowles, EEM, Kumar, K, Le Hellard, S, Leu, C, Linden, DEJ, Liu, J, Lundervold, A, Lundervold, AJ, Maillard, AM, Martin, NG, Martin-Brevet, S, Mather, KA, Mathias, SR, McMahon, KL, McRae, AF, Medland, SE, Meyer-Lindenberg, A, Moberget, T, Modenato, C, Sanchez, JM, Morris, DW, Muehleisen, TW, Murray, RM, Nielsen, J, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, GB, Prieto, C, Quinlan, EB, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Schork, AJ, Schumann, G, Shin, J, Shumskaya, E, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Suzuki, IK, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, van 't Ent, D, van den Bree, MBM, Vanderhaeghen, P, Vassos, E, Wen, W, Wittfeld, K, Wright, MJ, Agartz, I, Djurovic, S, Westlye, LT, Stefansson, H, Stefansson, K, Jacquemont, S, Thompson, PM, Andreassen, OA, Sonderby, IE, van der Meer, D, Moreau, C, Kaufmann, T, Walters, GB, Ellegaard, M, Abdellaoui, A, Ames, D, Amunts, K, Andersson, M, Armstrong, NJ, Bernard, M, Blackburn, NB, Blangero, J, Boomsma, DI, Brodaty, H, Brouwer, RM, Buelow, R, Boen, R, Cahn, W, Calhoun, VD, Caspers, S, Ching, CRK, Cichon, S, Ciufolini, S, Crespo-Facorro, B, Curran, JE, Dale, AM, Dalvie, S, Dazzan, P, de Geus, EJC, de Zubicaray, GI, de Zwarte, SMC, Desrivieres, S, Doherty, JL, Donohoe, G, Draganski, B, Ehrlich, S, Eising, E, Espeseth, T, Fejgin, K, Fisher, SE, Fladby, T, Frei, O, Frouin, V, Fukunaga, M, Gareau, T, Ge, T, Glahn, DC, Grabe, HJ, Groenewold, NA, Gustafsson, O, Haavik, J, Haberg, AK, Hall, J, Hashimoto, R, Hehir-Kwa, JY, Hibar, DP, Hillegers, MHJ, Hoffmann, P, Holleran, L, Holmes, AJ, Homuth, G, Hottenga, J-J, Hulshoff Pol, HE, Ikeda, M, Jahanshad, N, Jockwitz, C, Johansson, S, Joensson, EG, Jorgensen, NR, Kikuchi, M, Knowles, EEM, Kumar, K, Le Hellard, S, Leu, C, Linden, DEJ, Liu, J, Lundervold, A, Lundervold, AJ, Maillard, AM, Martin, NG, Martin-Brevet, S, Mather, KA, Mathias, SR, McMahon, KL, McRae, AF, Medland, SE, Meyer-Lindenberg, A, Moberget, T, Modenato, C, Sanchez, JM, Morris, DW, Muehleisen, TW, Murray, RM, Nielsen, J, Nordvik, JE, Nyberg, L, Loohuis, LMO, Ophoff, RA, Owen, MJ, Paus, T, Pausova, Z, Peralta, JM, Pike, GB, Prieto, C, Quinlan, EB, Reinbold, CS, Marques, TR, Rucker, JJH, Sachdev, PS, Sando, SB, Schofield, PR, Schork, AJ, Schumann, G, Shin, J, Shumskaya, E, Silva, AI, Sisodiya, SM, Steen, VM, Stein, DJ, Strike, LT, Suzuki, IK, Tamnes, CK, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Uhlmann, A, Ulfarsson, MO, van 't Ent, D, van den Bree, MBM, Vanderhaeghen, P, Vassos, E, Wen, W, Wittfeld, K, Wright, MJ, Agartz, I, Djurovic, S, Westlye, LT, Stefansson, H, Stefansson, K, Jacquemont, S, Thompson, PM, and Andreassen, OA

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021

26. Postictal Psychosis in Epilepsy: A Clinicogenetic Study

Author

Braatz, V, Custodio, HM, Leu, C, Agro, L, Wang, B, Calafato, S, Rayner, G, Doyle, MG, Hengsbach, C, Bisulli, F, Weber, YG, Gambardella, A, Delanty, N, Cavalleri, G, Foong, J, Scheffer, IE, Berkovic, SF, Bramon, E, Balestrini, S, Sisodiya, SM, Braatz, V, Custodio, HM, Leu, C, Agro, L, Wang, B, Calafato, S, Rayner, G, Doyle, MG, Hengsbach, C, Bisulli, F, Weber, YG, Gambardella, A, Delanty, N, Cavalleri, G, Foong, J, Scheffer, IE, Berkovic, SF, Bramon, E, Balestrini, S, and Sisodiya, SM

Abstract

OBJECTIVE: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy-related psychoses, and has unknown causation. METHODS: We conducted a case-control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis; 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis; univariate associations with a p value < 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated. RESULTS: Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p < 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls (R2 = 3%, p = 6 × 10-3 ), but not significantly different from 945 independent patients with schizophrenia (R2 = 0.1%, p = 0.775). INTERPRETATION: Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021;90:464-476.

Published
2021

27. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB

Abstract

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

30. Polygenic burden in focal and generalized epilepsies

Author

Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

32. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author

Perucca, P., Anderson, A., Jazayeri, D., Hitchcock, A., Graham, J., Todaro, M., Tomson, T., Battino, D., Perucca, E., Ferri, M. M., Rochtus, A., Lagae, L., Canevini, M. P., Zambrelli, E., Campbell, E., Koeleman, B. P. C., Scheffer, I. E., Berkovic, S. F., Kwan, P., Sisodiya, S. M., Goldstein, D. B., Petrovski, S., Craig, J., Vajda, F. J. E., O'Brien, T. J., Leu, C., Wolking, S., Peter, S., Weber, Y. G., Weckhuysen, S., Moller, R. S., Nikanorova, M., Muhle, H., Avbersek, A., Heggeli, K., Striano, P., Gambardella, A., Langley, S. R., Krenn, M., Klein, K. M., Mccormack, M., Borghei, M., Willis, J., Berghuis, B., Jorgensen, A., Auce, P., Francis, B., Srivastava, P., Sonsma, A. C. M., Sander, Jw., Zimprich, F., Depondt, C., Johnson, M. M., Marson, A. G., Sills, G. J., Kunz, W. S., Cavalleri, G. L., Delanty, N., Zara, F., Krause, R., Lerche, H., Andrade, D., Sen, A., Bazil, C. W., Boland, M., Cavalleri, G., Choi, H., Colombo, S., Costello, D., Devinsky, O., Doherty, C. P., Dugan, P., Frankel, W., Heinzen, E., Johnson, M., Marson, T., Mikati, M., Ottman, R., Pandolfo, M., Radtke, R., Rees, M., Sadoway, T., Valley, N., Walley, N., Wood, N., and Zuberi, S.

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Paternal Age, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Pregnancy, Polymorphism (computer science), medicine, Humans, Exome, Copy-number variation, Indel, business.industry, Confounding, Infant, Newborn, Abnormalities, Drug-Induced, Genetic Variation, DNA, medicine.disease, Genetic load, Exact test, Teratogens, 030104 developmental biology, Neurology, Anticonvulsants, Female, Neurology (clinical), Genetic Load, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism which we investigated. METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children [median dnSNV/indel number/child (range): 3 (0-7) vs 3 (1-5), p = 0.50]. Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counselling. This article is protected by copyright. All rights reserved.

Published
2020

33. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sønderby, I.E., Gústafsson, Ó., Doan, N.T., Hibar, D.P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N.J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D.I., Bralten, J., Brattbak, H-R, Brodaty, H., Brouwer, R.M., Bülow, R., Calhoun, V., Caspers, S., Cavalleri, G., Chen, C-H, Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J.E., Dale, A.M., Dalvie, S., Dazzan, P., de Geus, E.J.C., de Zubicaray, G.I., de Zwarte, S.M.C., Delanty, N., den Braber, A., Desrivières, S., Donohoe, G., Draganski, B., Ehrlich, S., Espeseth, T., Fisher, S.E., Franke, B., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D.C., Grabe, H., Groenewold, N.A., Haavik, J., Håberg, A., Hashimoto, R., Hehir-Kwa, J.Y., Heinz, A., Hillegers, M.H.J., Hoffmann, P., Holleran, L., Hottenga, J-J, Hulshoff, H.E., Ikeda, M., Jahanshad, N., Jernigan, T., Jockwitz, C., Johansson, S., Jonsdottir, G.A., Jönsson, E.G., Kahn, R., Kaufmann, T., Kelly, S., Kikuchi, M., Knowles, E.E.M., Kolskår, K.K., Kwok, J.B., Hellard, S.L., Leu, C., Liu, J., Lundervold, A.J., Lundervold, A., Martin, N.G., Mather, K., Mathias, S.R., McCormack, M., McMahon, K.L., McRae, A., Milaneschi, Y., Moreau, C., Morris, D., Mothersill, D., Mühleisen, T.W., Murray, R., Nordvik, J.E., Nyberg, L., Olde Loohuis, L.M., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Peralta, J.M., Pike, B., Prieto, C., Pudas, S., Quinlan, E., Quintana, D.S., Reinbold, C.S., Marques, T.R., Reymond, A., Richard, G., Rodriguez-Herreros, B., Roiz-Santiañez, R., Rokicki, J., Rucker, J., Sachdev, P., Sanders, A-M, Sando, S.B., Schmaal, L., Schofield, P.R., Schork, A.J., Schumann, G., Shin, J., Shumskaya, E., Sisodiya, S., Steen, V.M., Stein, D.J., Steinberg, S., Strike, L., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J., Ueland, T., Uhlmann, A., Ulfarsson, M.O., van ’t Ent, D., van der Meer, D., van Haren, N.E.M., Vaskinn, A., Vassos, E., Walters, G.B., Wang, Y., Wen, W., Whelan, C.D., Wittfeld, K., Wright, M., Yamamori, H., Zayats, T., Agartz, I., Westlye, L.T., Jacquemont, S., Djurovic, S., Stefánsson, H., Stefánsson, K., Thompson, P., Andreassen, O.A., Sønderby, I.E., Gústafsson, Ó., Doan, N.T., Hibar, D.P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N.J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D.I., Bralten, J., Brattbak, H-R, Brodaty, H., Brouwer, R.M., Bülow, R., Calhoun, V., Caspers, S., Cavalleri, G., Chen, C-H, Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J.E., Dale, A.M., Dalvie, S., Dazzan, P., de Geus, E.J.C., de Zubicaray, G.I., de Zwarte, S.M.C., Delanty, N., den Braber, A., Desrivières, S., Donohoe, G., Draganski, B., Ehrlich, S., Espeseth, T., Fisher, S.E., Franke, B., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D.C., Grabe, H., Groenewold, N.A., Haavik, J., Håberg, A., Hashimoto, R., Hehir-Kwa, J.Y., Heinz, A., Hillegers, M.H.J., Hoffmann, P., Holleran, L., Hottenga, J-J, Hulshoff, H.E., Ikeda, M., Jahanshad, N., Jernigan, T., Jockwitz, C., Johansson, S., Jonsdottir, G.A., Jönsson, E.G., Kahn, R., Kaufmann, T., Kelly, S., Kikuchi, M., Knowles, E.E.M., Kolskår, K.K., Kwok, J.B., Hellard, S.L., Leu, C., Liu, J., Lundervold, A.J., Lundervold, A., Martin, N.G., Mather, K., Mathias, S.R., McCormack, M., McMahon, K.L., McRae, A., Milaneschi, Y., Moreau, C., Morris, D., Mothersill, D., Mühleisen, T.W., Murray, R., Nordvik, J.E., Nyberg, L., Olde Loohuis, L.M., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Peralta, J.M., Pike, B., Prieto, C., Pudas, S., Quinlan, E., Quintana, D.S., Reinbold, C.S., Marques, T.R., Reymond, A., Richard, G., Rodriguez-Herreros, B., Roiz-Santiañez, R., Rokicki, J., Rucker, J., Sachdev, P., Sanders, A-M, Sando, S.B., Schmaal, L., Schofield, P.R., Schork, A.J., Schumann, G., Shin, J., Shumskaya, E., Sisodiya, S., Steen, V.M., Stein, D.J., Steinberg, S., Strike, L., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J., Ueland, T., Uhlmann, A., Ulfarsson, M.O., van ’t Ent, D., van der Meer, D., van Haren, N.E.M., Vaskinn, A., Vassos, E., Walters, G.B., Wang, Y., Wen, W., Whelan, C.D., Wittfeld, K., Wright, M., Yamamori, H., Zayats, T., Agartz, I., Westlye, L.T., Jacquemont, S., Djurovic, S., Stefánsson, H., Stefánsson, K., Thompson, P., and Andreassen, O.A.

Abstract

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

Published
2020

34. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Author

Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, and Becker, F

Abstract

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The character

Published
2020

39. Diagnostic implications of genetic copy number variation in epilepsy plus

Author

Coppola, A., Cellini, E., Stamberger, H., Saarentaus, E., Cetica, V., Lal, D., Djemie, T., Bartnik-Glaska, M., Ceulemans, B., Helen Cross, J., Deconinck, T., Masi, S. D., Dorn, T., Guerrini, R., Hoffman-Zacharska, D., Kooy, F., Lagae, L., Lench, N., Lemke, J. R., Lucenteforte, E., Madia, F., Mefford, H. C., Morrogh, D., Nuernberg, P., Palotie, A., Schoonjans, A. -S., Striano, P., Szczepanik, E., Tostevin, A., Vermeesch, J. R., Van Esch, H., Van Paesschen, W., Waters, J. J., Weckhuysen, S., Zara, F., Jonghe, P. D., Sisodiya, S. M., Marini, C., Lehesjioki, A. -E., Craiu, D., Talvik, T., Caglayan, H., Serratosa, J., Sterbova, K., Moller, R. S., Hjalgrim, H., Lerche, H., Weber, Y., Helbig, I., von Spiczak, S., Barba, C., Bogaerts, A., Boni, A., Galizia, E. C., Chiari, S., Di Gacomo, G., Ferrari, A., Guarducci, S., Giglio, S., Holmgren, P., Leu, C., Melani, F., Novara, F., Pantaleo, M., Peeters, E., Pisano, T., Rosati, A., Sander, J., Schoeler, N., Stankiewicz, P., Striano, S., Suls, A., Traverso, M., Vandeweyer, G., Van Dijck, A., Zuffardi, O., Coppola, Antonietta, Cellini, Elena, Stamberger, Hannah, Saarentaus, Elmo, Cetica, Valentina, Lal, Denni, Djémié, Tania, Bartnik-Glaska, Magdalena, Ceulemans, Berten, Helen Cross, J., Deconinck, Tine, Masi, Salvatore De, Dorn, Thoma, Guerrini, Renzo, Hoffman-Zacharska, Dorotha, Kooy, Frank, Lagae, Lieven, Lench, Nichola, Lemke, Johannes R., Lucenteforte, Ersilia, Madia, Francesca, Mefford, Heather C., Morrogh, Deborah, Nuernberg, Peter, Palotie, Aarno, Schoonjans, An-Sofie, Striano, Pasquale, Szczepanik, Elzbieta, Tostevin, Anna, Vermeesch, Joris R., Van Esch, Hilde, Van Paesschen, Wim, Waters, Jonathan J, Weckhuysen, Sarah, Zara, Federico, Jonghe, Peter De, Sisodiya, Sanjay M., Marini, Carla, Lehesjioki, Anna-Elina, Craiu, Dana, Talvik, Tiina, Caglayan, Hande, Serratosa, Jose, Sterbova, Katalin, Møller, Rikke S., Hjalgrim, Helle, Lerche, Holger, Weber, Yvonne, Helbig, Ingo, von Spiczak, Sarah, Barba, Carmen, Bogaerts, Anneleen, Boni, Antonella, Galizia, Elisabeth Caruana, Chiari, Sara, Di Gacomo, Gianpiero, Ferrari, Annarita, Guarducci, Silvia, Giglio, Sabrina, Holmgren, Philip, Leu, Costin, Melani, Federico, Novara, Francesca, Pantaleo, Marilena, Peeters, Elke, Pisano, Tiziana, Rosati, Anna, Sander, Josemir, Schoeler, Natasha, Stankiewicz, Pawel, Striano, Salvatore, Suls, Arvid, Traverso, Monica, Vandeweyer, Geert, Van Dijck, Anke, and Zuffardi, Orsetta

Subjects
epilepsy gene, Epilepsy, DNA Copy Number Variations, Genotype, Comorbidity, array CGH, copy number variants, epilepsy genes, SNP array, Phenotype, Neurology, mental disorders, Full‐length Original Research, Humans, copy number variant, Genetic Predisposition to Disease, Neurology (clinical)
Abstract

Summary Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10−9). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Published
2019

40. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Author

Berghuis, B., Stapleton, C., Sonsma, A. C. M., Hulst, J., de Haan, G. -J., Lindhout, D., Demurtas, R., Krause, R., Depondt, C., Kunz, W. S., Zara, F., Striano, P., Craig, J., Auce, P., Marson, A. G., Stefansson, H., O'Brien, T. J., Johnson, M. R., Sills, G. J., Wolking, S., Lerche, H., Sisodiya, S. M., Sander, J. W., Cavalleri, G. L., Koeleman, B. P. C., Mccormack, M., Avbersek, A., Leu, C., Heggeli, K., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Delanty, N., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Petrovski, S., Hutton, J., Zimprich, F., Krenn, M., Muhle, H., Martin Klein, K., Moller, R., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Berghuis, Bianca, Stapleton, Caragh, Sonsma, Anja C. M., Hulst, Janic, de Haan, Gerrit-Jan, Lindhout, Dick, Demurtas, Rita, Krause, Roland, Depondt, Chantal, Kunz, Wolfram S., Zara, Federico, Striano, Pasquale, Craig, John, Auce, Paul, Marson, Anthony G., Stefansson, Hreinn, O'Brien, Terence J., Johnson, Michael R., Sills, Graeme J., Wolking, Stefan, Lerche, Holger, Sisodiya, Sanjay M., Sander, Josemir W., Cavalleri, Gianpiero L., Koeleman, Bobby P. C., Mccormack, Mark, Weckhuysen, Sarah, EpiPGX Consortium, Imperial College Healthcare NHS Trust- BRC Funding, and Commission of the European Communities

Subjects
medicine.medical_specialty, hyponatremia, Clinical Neurology, Gastroenterology, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, adverse effects, antiepileptic drugs, EpiPGX Consortium, GWAS, antiepileptic drug, Internal medicine, adverse effect, medicine, Oxcarbazepine, Adverse effect, 030304 developmental biology, 0303 health sciences, business.industry, Généralités, Carbamazepine, medicine.disease, 3. Good health, Neurology, Cohort, Full‐length Original Research, Phenobarbital, Human medicine, Neurology (clinical), Hyponatremia, business, 030217 neurology & neurosurgery, Drug metabolism, medicine.drug
Abstract

Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

41. Diagnostic implications of genetic copy number variation in epilepsy plus

Author

Coppola, A1, 2, 3, Cellini, E4, Stamberger, H5, 6, 7, Saarentaus, E8, 9, 10, Cetica, V4, Lal, D10, 11, 12, Djémié, T5, 6, Bartnik-Glaska, M13, Ceulemans, B14, Cross, JH15, 16, 17, Deconinck, T5, De Masi S7, Dorn, T18, Guerrini, R, Hoffman-Zacharska, D14, Kooy, F19, Lagae, L20, Lench, N21, Lemke, JR22, Lucenteforte, E23, Madia, F25, Mefford, HC26, Morrogh, D21, Nuernberg, P27, Palotie, A11, Schoonjans, AS15, Striano, P28, Szczepanik, E29, Tostevin, A1, 2, Vermeesch, JR30, Van Esch H30, Van Paesschen W31, Waters, JJ21, Weckhuysen, S5, 6, 12, Zara, F25, De Jonghe P5, Sisodiya, SM1, Marini, C, EuroEPINOMICS-RES, Consortium, Lehesjioki AE, EpiCNV Consortium., Craiu, D, Talvik, T, Caglayan, H, Serratosa, J, Sterbova, K, Møller, Rs, Hjalgrim, H, Lerche, H, Weber, Y, Helbig, I, von Spiczak, S, Barba, C, Bogaerts, A, Boni, A, Galizia, Ec, Chiari, S, Di Gacomo, G, Ferrari, A, Garducci, S, Giglio, S, Holmgren, P, Leu, C, Melani, F, Novara, F, Pantaleo, M, Peeters, E, Pisano, T, Rosati, A, Sander, J, Schoeler, N, Stankiewicz, P, Striano, S, Suls, A, Traverso, M, Vandeweyer, G, Van Dijck, A, and Zuffardi, O.

Subjects
epilepsy
Published
2019

46. Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sønderby, I.E., Gústafsson, Ó., Doan, N.T., Hibar, D.P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N.J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D.I., Bralten, J., Brattbak, H-R, Brodaty, H., Brouwer, R.M., Bülow, R., Calhoun, V., Caspers, S., Cavalleri, G., Chen, C-H, Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J.E., Dale, A.M., Dalvie, S., Dazzan, P., de Geus, E.J.C., de Zubicaray, G.I., de Zwarte, S.M.C., Delanty, N., den Braber, A., Desrivières, S., Donohoe, G., Draganski, B., Ehrlich, S., Espeseth, T., Fisher, S.E., Franke, B., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D.C., Grabe, H., Groenewold, N.A., Haavik, J., Håberg, A., Hashimoto, R., Hehir-Kwa, J.Y., Heinz, A., Hillegers, M.H.J., Hoffmann, P., Holleran, L., Hottenga, J-J, Hulshoff, H.E., Ikeda, M., Jahanshad, N., Jernigan, T., Jockwitz, C., Johansson, S., Jonsdottir, G.A., Jönsson, E.G., Kahn, R., Kaufmann, T., Kelly, S., Kikuchi, M., Knowles, E.E.M., Kolskår, K.K., Kwok, J.B., Hellard, S.L., Leu, C., Liu, J., Lundervold, A.J., Lundervold, A., Martin, N.G., Mather, K., Mathias, S.R., McCormack, M., McMahon, K.L., McRae, A., Milaneschi, Y., Moreau, C., Morris, D., Mothersill, D., Mühleisen, T.W., Murray, R., Nordvik, J.E., Nyberg, L., Olde Loohuis, L.M., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Peralta, J.M., Pike, B., Prieto, C., Pudas, S., Quinlan, E., Quintana, D.S., Reinbold, C.S., Marques, T.R., Reymond, A., Richard, G., Rodriguez-Herreros, B., Roiz-Santiañez, R., Rokicki, J., Rucker, J., Sachdev, P., Sanders, A-M, Sando, S.B., Schmaal, L., Schofield, P.R., Schork, A.J., Schumann, G., Shin, J., Shumskaya, E., Sisodiya, S., Steen, V.M., Stein, D.J., Steinberg, S., Strike, L., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J.S., Ueland, T., Uhlmann, A., Ulfarsson, M.O., van ’t Ent, D., van der Meer, D., van Haren, N.E.M., Vaskinn, A., Vassos, E., Walters, G.B., Wang, Y., Wen, W., Whelan, C.D., Wittfeld, K., Wright, M., Yamamori, H., Zayats, T., Agartz, I., Westlye, L.T., Jacquemont, S., Djurovic, S., Stefánsson, H., Stefánsson, K., Thompson, P., Andreassen, O.A., Sønderby, I.E., Gústafsson, Ó., Doan, N.T., Hibar, D.P., Martin-Brevet, S., Abdellaoui, A., Ames, D., Amunts, K., Andersson, M., Armstrong, N.J., Bernard, M., Blackburn, N., Blangero, J., Boomsma, D.I., Bralten, J., Brattbak, H-R, Brodaty, H., Brouwer, R.M., Bülow, R., Calhoun, V., Caspers, S., Cavalleri, G., Chen, C-H, Cichon, S., Ciufolini, S., Corvin, A., Crespo-Facorro, B., Curran, J.E., Dale, A.M., Dalvie, S., Dazzan, P., de Geus, E.J.C., de Zubicaray, G.I., de Zwarte, S.M.C., Delanty, N., den Braber, A., Desrivières, S., Donohoe, G., Draganski, B., Ehrlich, S., Espeseth, T., Fisher, S.E., Franke, B., Frouin, V., Fukunaga, M., Gareau, T., Glahn, D.C., Grabe, H., Groenewold, N.A., Haavik, J., Håberg, A., Hashimoto, R., Hehir-Kwa, J.Y., Heinz, A., Hillegers, M.H.J., Hoffmann, P., Holleran, L., Hottenga, J-J, Hulshoff, H.E., Ikeda, M., Jahanshad, N., Jernigan, T., Jockwitz, C., Johansson, S., Jonsdottir, G.A., Jönsson, E.G., Kahn, R., Kaufmann, T., Kelly, S., Kikuchi, M., Knowles, E.E.M., Kolskår, K.K., Kwok, J.B., Hellard, S.L., Leu, C., Liu, J., Lundervold, A.J., Lundervold, A., Martin, N.G., Mather, K., Mathias, S.R., McCormack, M., McMahon, K.L., McRae, A., Milaneschi, Y., Moreau, C., Morris, D., Mothersill, D., Mühleisen, T.W., Murray, R., Nordvik, J.E., Nyberg, L., Olde Loohuis, L.M., Ophoff, R., Paus, T., Pausova, Z., Penninx, B., Peralta, J.M., Pike, B., Prieto, C., Pudas, S., Quinlan, E., Quintana, D.S., Reinbold, C.S., Marques, T.R., Reymond, A., Richard, G., Rodriguez-Herreros, B., Roiz-Santiañez, R., Rokicki, J., Rucker, J., Sachdev, P., Sanders, A-M, Sando, S.B., Schmaal, L., Schofield, P.R., Schork, A.J., Schumann, G., Shin, J., Shumskaya, E., Sisodiya, S., Steen, V.M., Stein, D.J., Steinberg, S., Strike, L., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J.S., Ueland, T., Uhlmann, A., Ulfarsson, M.O., van ’t Ent, D., van der Meer, D., van Haren, N.E.M., Vaskinn, A., Vassos, E., Walters, G.B., Wang, Y., Wen, W., Whelan, C.D., Wittfeld, K., Wright, M., Yamamori, H., Zayats, T., Agartz, I., Westlye, L.T., Jacquemont, S., Djurovic, S., Stefánsson, H., Stefánsson, K., Thompson, P., and Andreassen, O.A.

Abstract

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

Published
2019

48. Polygenic burden in focal and generalized epilepsies

Author

Leu, C, Stevelink, R, Smith, AW, Goleva, SB, Kanai, M, Ferguson, L, Campbell, C, Kamatani, Y, Okada, Y, Sisodiya, SM, Cavalleri, GL, Koeleman, BPC, Lerche, H, Jehi, L, Davis, LK, Najm, IM, Palotie, A, Daly, MJ, Busch, RM, Lal, D, Leu, C, Stevelink, R, Smith, AW, Goleva, SB, Kanai, M, Ferguson, L, Campbell, C, Kamatani, Y, Okada, Y, Sisodiya, SM, Cavalleri, GL, Koeleman, BPC, Lerche, H, Jehi, L, Davis, LK, Najm, IM, Palotie, A, Daly, MJ, Busch, RM, and Lal, D

Abstract

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.3

Published
2019

49. Analysis of shared heritability in common disorders of the brain

Author

Anttila, V. Bulik-Sullivan, B. Finucane, H.K. Walters, R.K. Bras, J. Duncan, L. Escott-Price, V. Falcone, G.J. Gormley, P. Malik, R. Patsopoulos, N.A. Ripke, S. Wei, Z. Yu, D. Lee, P.H. Turley, P. Grenier-Boley, B. Chouraki, V. Kamatani, Y. Berr, C. Letenneur, L. Hannequin, D. Amouyel, P. Boland, A. Deleuze, J.-F. Duron, E. Vardarajan, B.N. Reitz, C. Goate, A.M. Huentelman, M.J. Ilyas Kamboh, M. Larson, E.B. Rogaeva, E. George-Hyslop, P.S. Hakonarson, H. Kukull, W.A. Farrer, L.A. Barnes, L.L. Beach, T.G. Yesim Demirci, F. Head, E. Hulette, C.M. Jicha, G.A. Kauwe, J.S.K. Kaye, J.A. Leverenz, J.B. Levey, A.I. Lieberman, A.P. Pankratz, V.S. Poon, W.W. Quinn, J.F. Saykin, A.J. Schneider, L.S. Smith, A.G. Sonnen, J.A. Stern, R.A. Van Deerlin, V.M. Van Eldik, L.J. Harold, D. Russo, G. Rubinsztein, D.C. Bayer, A. Tsolaki, M. Proitsi, P. Fox, N.C. Hampel, H. Owen, M.J. Mead, S. Passmore, P. Morgan, K. Nöthen, M.M. Rossor, M. Lupton, M.K. Hoffmann, P. Kornhuber, J. Lawlor, B. McQuillin, A. Al-Chalabi, A. Bis, J.C. Ruiz, A. Boada, M. Seshadri, S. Beiser, A. Rice, K. Van Der Lee, S.J. De Jager, P.L. Geschwind, D.H. Riemenschneider, M. Riedel-Heller, S. Rotter, J.I. Ransmayr, G. Hyman, B.T. Cruchaga, C. Alegret, M. Winsvold, B. Palta, P. Farh, K.-H. Cuenca-Leon, E. Furlotte, N. Kurth, T. Ligthart, L. Terwindt, G.M. Freilinger, T. Ran, C. Gordon, S.D. Borck, G. Adams, H.H.H. Lehtimäki, T. Wedenoja, J. Buring, J.E. Schürks, M. Hrafnsdottir, M. Hottenga, J.-J. Penninx, B. Artto, V. Kaunisto, M. Vepsäläinen, S. Martin, N.G. Montgomery, G.W. Kurki, M.I. Hämäläinen, E. Huang, H. Huang, J. Sandor, C. Webber, C. Muller-Myhsok, B. Schreiber, S. Salomaa, V. Loehrer, E. Göbel, H. Macaya, A. Pozo-Rosich, P. Hansen, T. Werge, T. Kaprio, J. Metspalu, A. Kubisch, C. Ferrari, M.D. Belin, A.C. Van Den Maagdenberg, A.M.J.M. Zwart, J.-A. Boomsma, D. Eriksson, N. Olesen, J. Chasman, D.I. Nyholt, D.R. Avbersek, A. Baum, L. Berkovic, S. Bradfield, J. Buono, R. Catarino, C.B. Cossette, P. De Jonghe, P. Depondt, C. Dlugos, D. Ferraro, T.N. French, J. Hjalgrim, H. Jamnadas-Khoda, J. Kälviäinen, R. Kunz, W.S. Lerche, H. Leu, C. Lindhout, D. Lo, W. Lowenstein, D. McCormack, M. Møller, R.S. Molloy, A. Ng, P.-W. Oliver, K. Privitera, M. Radtke, R. Ruppert, A.-K. Sander, T. Schachter, S. Schankin, C. Scheffer, I. Schoch, S. Sisodiya, S.M. Smith, P. Sperling, M. Striano, P. Surges, R. Neil Thomas, G. Visscher, F. Whelan, C.D. Zara, F. Heinzen, E.L. Marson, A. Becker, F. Stroink, H. Zimprich, F. Gasser, T. Gibbs, R. Heutink, P. Martinez, M. Morris, H.R. Sharma, M. Ryten, M. Mok, K.Y. Pulit, S. Bevan, S. Holliday, E. Attia, J. Battey, T. Boncoraglio, G. Thijs, V. Chen, W.-M. Mitchell, B. Rothwell, P. Sharma, P. Sudlow, C. Vicente, A. Markus, H. Kourkoulis, C. Pera, J. Raffeld, M. Silliman, S. Perica, V.B. Thornton, L.M. Huckins, L.M. William Rayner, N. Lewis, C.M. Gratacos, M. Rybakowski, F. Keski-Rahkonen, A. Raevuori, A. Hudson, J.I. Reichborn-Kjennerud, T. Monteleone, P. Karwautz, A. Mannik, K. Baker, J.H. O'Toole, J.K. Trace, S.E. Davis, O.S.P. Helder, S.G. Ehrlich, S. Herpertz-Dahlmann, B. Danner, U.N. Van Elburg, A.A. Clementi, M. Forzan, M. Docampo, E. Lissowska, J. Hauser, J. Tortorella, A. Maj, M. Gonidakis, F. Tziouvas, K. Papezova, H. Yilmaz, Z. Wagner, G. Cohen-Woods, S. Herms, S. Julia, A. Rabionet, R. Dick, D.M. Ripatti, S. Andreassen, O.A. Espeseth, T. Lundervold, A.J. Steen, V.M. Pinto, D. Scherer, S.W. Aschauer, H. Schosser, A. Alfredsson, L. Padyukov, L. Halmi, K.A. Mitchell, J. Strober, M. Bergen, A.W. Kaye, W. Szatkiewicz, J.P. Cormand, B. Ramos-Quiroga, J.A. Sánchez-Mora, C. Ribasés, M. Casas, M. Hervas, A. Arranz, M.J. Haavik, J. Zayats, T. Johansson, S. Williams, N. Dempfle, A. Rothenberger, A. Kuntsi, J. Oades, R.D. Banaschewski, T. Franke, B. Buitelaar, J.K. Vasquez, A.A. Doyle, A.E. Reif, A. Lesch, K.-P. Freitag, C. Rivero, O. Palmason, H. Romanos, M. Langley, K. Rietschel, M. Witt, S.H. Dalsgaard, S. Børglum, A.D. Waldman, I. Wilmot, B. Molly, N. Bau, C.H.D. Crosbie, J. Schachar, R. Loo, S.K. McGough, J.J. Grevet, E.H. Medland, S.E. Robinson, E. Weiss, L.A. Bacchelli, E. Bailey, A. Bal, V. Battaglia, A. Betancur, C. Bolton, P. Cantor, R. Celestino-Soper, P. Dawson, G. De Rubeis, S. Duque, F. Green, A. Klauck, S.M. Leboyer, M. Levitt, P. Maestrini, E. Mane, S. Moreno-De-Luca, D. Parr, J. Regan, R. Reichenberg, A. Sandin, S. Vorstman, J. Wassink, T. Wijsman, E. Cook, E. Santangelo, S. Delorme, R. Roge, B. Magalhaes, T. Arking, D. Schulze, T.G. Thompson, R.C. Strohmaier, J. Matthews, K. Melle, I. Morris, D. Blackwood, D. McIntosh, A. Bergen, S.E. Schalling, M. Jamain, S. Maaser, A. Fischer, S.B. Reinbold, C.S. Fullerton, J.M. Guzman-Parra, J. Mayoral, F. Schofield, P.R. Cichon, S. Mühleisen, T.W. Degenhardt, F. Schumacher, J. Bauer, M. Mitchell, P.B. Gershon, E.S. Rice, J. Potash, J.B. Zandi, P.P. Craddock, N. Nicol Ferrier, I. Alda, M. Rouleau, G.A. Turecki, G. Ophoff, R. Pato, C. Anjorin, A. Stahl, E. Leber, M. Czerski, P.M. Cruceanu, C. Jones, I.R. Posthuma, D. Andlauer, T.F.M. Forstner, A.J. Streit, F. Baune, B.T. Air, T. Sinnamon, G. Wray, N.R. MacIntyre, D.J. Porteous, D. Homuth, G. Rivera, M. Grove, J. Middeldorp, C.M. Hickie, I. Pergadia, M. Mehta, D. Smit, J.H. Jansen, R. De Geus, E. Dunn, E. Li, Q.S. Nauck, M. Schoevers, R.A. Beekman, A.T.F. Knowles, J.A. Viktorin, A. Arnold, P. Barr, C.L. Bedoya-Berrio, G. Joseph Bienvenu, O. Brentani, H. Burton, C. Camarena, B. Cappi, C. Cath, D. Cavallini, M. Cusi, D. Darrow, S. Denys, D. Derks, E.M. Dietrich, A. Fernandez, T. Figee, M. Freimer, N. Gerber, G. Grados, M. Greenberg, E. Hanna, G.L. Hartmann, A. Hirschtritt, M.E. Hoekstra, P.J. Huang, A. Huyser, C. Illmann, C. Jenike, M. Kuperman, S. Leventhal, B. Lochner, C. Lyon, G.J. Macciardi, F. Madruga-Garrido, M. Malaty, I.A. Maras, A. McGrath, L. Miguel, E.C. Mir, P. Nestadt, G. Nicolini, H. Okun, M.S. Pakstis, A. Paschou, P. Piacentini, J. Pittenger, C. Plessen, K. Ramensky, V. Ramos, E.M. Reus, V. Richter, M.A. Riddle, M.A. Robertson, M.M. Roessner, V. Rosário, M. Samuels, J.F. Sandor, P. Stein, D.J. Tsetsos, F. Van Nieuwerburgh, F. Weatherall, S. Wendland, J.R. Wolanczyk, T. Worbe, Y. Zai, G. Goes, F.S. McLaughlin, N. Nestadt, P.S. Grabe, H.-J. Depienne, C. Konkashbaev, A. Lanzagorta, N. Valencia-Duarte, A. Bramon, E. Buccola, N. Cahn, W. Cairns, M. Chong, S.A. Cohen, D. Crespo-Facorro, B. Crowley, J. Davidson, M. DeLisi, L. Dinan, T. Donohoe, G. Drapeau, E. Duan, J. Haan, L. Hougaard, D. Karachanak-Yankova, S. Khrunin, A. Klovins, J. Kučinskas, V. Keong, J.L.C. Limborska, S. Loughland, C. Lönnqvist, J. Maher, B. Mattheisen, M. McDonald, C. Murphy, K.C. Nenadic, I. Van Os, J. Pantelis, C. Pato, M. Petryshen, T. Quested, D. Roussos, P. Sanders, A.R. Schall, U. Schwab, S.G. Sim, K. So, H.-C. Stögmann, E. Subramaniam, M. Toncheva, D. Waddington, J. Walters, J. Weiser, M. Cheng, W. Cloninger, R. Curtis, D. Gejman, P.V. Henskens, F. Mattingsdal, M. Oh, S.-Y. Scott, R. Webb, B. Breen, G. Churchhouse, C. Bulik, C.M. Daly, M. Dichgans, M. Faraone, S.V. Guerreiro, R. Holmans, P. Kendler, K.S. Koeleman, B. Mathews, C.A. Price, A. Scharf, J. Sklar, P. Williams, J. Wood, N.W. Cotsapas, C. Palotie, A. Smoller, J.W. Sullivan, P. Rosand, J. Corvin, A. Neale, B.M. The Brainstorm Consortium

Abstract

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology. © 2018 American Association for the Advancement of Science. All rights reserved.

Published
2018

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