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18 results on '"Morley C.P."'

1. Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

Author

Macedo, A., Evgrafov, O.V., McCarroll, S.A., Marder, S.R., Vawter, M.P., Bromet, E.J., Sullivan, P.F., Purcell, S.M., Azevedo, M.H., Kotov, R., Rakofsky, J.J., Nicolini, H., Moran, J.L., Pato, M.T., Genovese, G., Dumont, A.L., Fochtmann, L.J., Braff, D.L., Smoller, J.W., Peterson, R.E., Bigdeli, T.B, Chapman, S.B., Rapaport, M.H., Belliveau, R.A., Kennedy, J.L., Achtyes, E.D., O'Dushlaine, C., Nemesh, J., Sklar, B.M., Medeiros, H., Perkins, D.O., Sklar, P., Iyegbe, C.O., Escamilla, M.A., Bevilacqua, E., Knowles, J.A., Scolnick, E.M., Morley, C.P., Carvalho, C.B., Sobell, J.L., Genomic Psychiatry Cohort (GPC) Consortium, Malaspina, D., Lehrer, D.S., Gage, D., DeLisi, L.E., Macciardi, F., Dewan, M.J., Meyers, J.L., Consortium on the Genetics of Schizophrenia (COGS) Investigators, Abbott, C., Kinkead, B., Georgakopoulos, P., Gur, R.E., Stahl, E.A., Gur, R.C., Valderrama, J., Buckley, P.F., Byerley, W., and Pato, C.N.

Abstract

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke���s R2 = 0.032; liability R2 = 0.017; P < 10���52), Latino (Nagelkerke���s R2 = 0.089; liability R2 = 0.021; P < 10���58), and European individuals (Nagelkerke���s R2 = 0.089; liability R2 = 0.037; P < 10���113), further highlighting the advantages of incorporating data from diverse human populations.

Published
2020
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2. Organic compounds at different depths in a sandy soil and their role in water repellency

Author

Morley, C.P., Mainwaring, K.A., Doerr, S.H., Douglas, P., Llewellyn, C.T., and Dekker, L.W.

Subjects
Sandy soils, Soil moisture, Water, Underground, Organic compounds, Agricultural industry, Earth sciences
Abstract

The causes of soil water repellency are still only poorly understood. It is generally assumed that hydrophobic organic compounds are responsible, but those concerned have not previously been identified by comparison between samples taken from a water repellent topsoil and the wettable subsoil. In this study we separated, characterised, and compared the organic compounds present at 4 different depths in a sandy soil under permanent grass cover that is water repellent in the upper 0.30 m but wettable below this. Soil samples were extracted using a mixture of isopropanol and aqueous ammonia (7:3 v : v). Samples were wettable after extraction and re-application of the extract from each sample onto wettable sand induced water repellency. The chloroform-soluble portions of the extracts were analysed by gas chromatography and gas chromatography-mass spectrometry. The compounds identified at all soil depths included long-chain carboxylic acids ([C.sub.16]-[C.sub.24]), amides ([C.sub.14]-[C.sub.24]), alkanes ([C.sub.25]-[C.sub.31]), aldehydes or ketones ([C.sub.25]-[C.sub.29]), and more complex ring-containing structures. ¹H and [sup.13]C nuclear magnetic resonance spectroscopy, and the carbon/hydrogen ratio as determined by microanalysis, confirmed the predominantly aliphatic character of the extracts. Both wettable and water repellent samples contained hydrophobic compounds. The 3 water repellent samples contained far more organic material, although the amount extracted was not related to the degree of water repellency. Perhaps more importantly, they contained polar compounds of high relative molecular mass, which were almost absent from the wettable subsoil. It may be speculated that these are the compounds in this soil whose presence in significant amounts is necessary for water repellency to be exhibited. Additional keywords: hydrophobicity, gas chromatography., Introduction It is widely accepted that soil water repellency is caused by hydrophobic organic compounds deposited on soil mineral or aggregate surfaces or present as interstitial matter (Wallis and Home [...]

Published
2005

3. Extraction of compounds associated with water repellency in sandy soils of different origin

Author

Doerr, S.H., Llewellyn, C.T., Douglas, P., Morley, C.P., Mainwaring, K.A., Haskins, C., Johnsey, L., Ritsema, C.J., Stagnitti, F., Allinson, G., Ferreira, A.J.D., Keizer, J.J., Ziogas, A.K., and Diamantis, J.

Subjects
Soil moisture, Sandy soils, Water, Underground, Agricultural industry, Earth sciences
Abstract

After an initial evaluation of several solvents, the efficiency of Soxhlet extractions with isopropanol/ammonia (s.g. 0.88) (70:30 v:v; 24 h) in extracting compounds associated with water repellency in sandy soils was examined using a range of repellent and wettable control soils (n = 15 and 4) from Australia, Greece, Portugal, The Netherlands, and the UK. Extraction efficiency and the role of the extracts in causing soil water repellency was examined by determining extract mass, sample organic carbon content and water repellency (after drying at 20°C and 105°C) pre- and post-extraction, and amounts of aliphatic C-H removed using DRIFT, and by assessing the ability of extracts to cause repellency in acid-washed sand (AWS). Key findings are: (i) none of organic carbon content, amount of aliphatic C-H, or amount of material extracted give any significant correlation with repellency for this diverse range of soils; (ii) sample drying at 105°C is not necessarily useful before extraction, but may provide additional information on extraction effectiveness when used after extraction; (iii) the extraction removed repellency completely from 13 of the 15 repellent samples; (iv) extracts from all repellent and wettable control soils were capable of inducing repellency in AWS. The findings suggest that compounds responsible for repellency represent only a fraction of the extract composition and that their presence does not necessarily always cause repellency. Additional keywords: water repellency, water repellence, hydrophobicity, extraction, aliphatic, DRIFT., Introduction It has been proposed that water repellency is caused by the accumulation of hydrophobic organic compounds released from roots (Dekker and Ritsema 1996; Doerr et al. 1998), as fungal [...]

Published
2005

4. Effects of heating and post-heating equilibration times on soil water repellency

Author

Doerr, S.H., Douglas, P., Evans, R.C., Morley, C.P., Mullinger, N.J., Bryant, R., and Shakesby, R.A.

Subjects
Agricultural industry, Earth sciences
Abstract

The effects of variation in heating temperature T (50-300°C), heating duration (20-60 min), and postheating equilibration times (24-168h at 20°C and 50% relative humidity) on the wettability, as measured by the Critical Surface Tension (CST) method, of 4 initially water repellent soils from Canada, Portugal, and the UK are reported. All soils show an increase in water repellency following heating at temperatures in the range of 50 to 150°C, followed by a considerable decline after heating to 200-250°C, and, except for one soil, the eradication of repellency after heating to 300°C. For two soils with a comparatively high organic carbon content and fine texture, water repellency levels were also affected by the length of the post-heating equilibration period. The results demonstrate that (i) the common practice of heating samples to 105°C does not provide a viable standard procedure for the measurement of water repellency as it may alter repellency to different degrees, and (ii) where heat treatment is required, a post-heating equilibration time of 24 h is not necessarily sufficient for sample repellency levels to adjust to atmospheric laboratory conditions; therefore it is advisable to prolong equilibration to at least one week prior to measurement. Additional keywords: hydrophobicity, water repellence, water repellent., Introduction It has long been established that heating of potentially water repellent soils, whether in situ or in the laboratory, can influence their wettability. For example, drying soils at temperatures [...]

Published
2005

5. Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22

Author

Middleton, F.A., Pato, M.T., Gentile, K.L., Morley, C.P., Zhao, X., Eisener, A.F., Brown, A., Petryshen, T.L., Kirby, A.N., Medeiros, H., Carvalho, C., Macedo, A., Dourado, A., Coelho, I., Valente, J., Soares, M.J., Ferreira, C.P., Lei, M., Azevedo, M.H., Kennedy, J.L., Daly, M.J., Sklar, P., and Pato, C.N.

Subjects
Human genetics -- Research, Biological sciences
Published
2004

7. Failed promises of the cigarette industry and its effect on consumer misperceptions about the health risks of smoking

Author

Cummings, K.M., Morley, C.P., and Hyland, A.

Subjects
Tobacco Institute -- Management, Council for Tobacco Research - U.S.A. -- Management, Tobacco industry -- Management -- Health aspects, Smoking -- Health aspects, Health, Sociology and social work, Company business management, Management, Health aspects
Abstract

Background: In January 1954, US tobacco manufacturers jointly sponsored an advocacy advertisement entitled 'A Frank Statement to Cigarette Smokers' which appeared in 448 newspapers in 258 cities reaching an estimated [...]

Published
2002

8. Marketing to America's youth: evidence from corporate documents

Author

Cummings, K.M., Morley, C.P., Horan, J.K., Steger, C., and Leavell, N-R

Subjects
Tobacco industry -- Marketing -- Case studies, Smoking and youth -- Case studies, Business ethics -- Case studies, Marketing -- Case studies, Health, Sociology and social work, Company marketing practices, Case studies, Marketing
Abstract

Objective: To evaluate the claim that the tobacco industry does not market its products to youth. Design: The data for this study come from tobacco industry documents collected from the [...]

Published
2002

9. Tobacco Institute lobbying at the state and local levels of government in the 1990s

Author

Morley, C.P., Cummings, K.M., Hyland, A., Giovino, G.A., and Horan, J.K.

Subjects
Tobacco Institute -- Political activity, Tobacco industry -- Political activity -- Finance, Lobbying -- Finance, Health, Sociology and social work, Company financing, Political activity, Finance
Abstract

Objective: To describe variation in Tobacco Institute (TI) lobbying expenditures across states and test whether these expenditures vary in relationship to measures of tobacco control activity at the state level. [...]

Published
2002

10. Tax, price and cigarette smoking: evidence from the tobacco documents and implications for tobacco company marketing strategies

Author

Chaloupka, F.J., Cummings, K.M., Morley, C.P., and Horan, J.K.

Subjects
Tobacco industry -- Marketing -- Case studies, Smoking and youth -- Case studies, Smokers -- Case studies, Cigarettes -- Prices and rates -- Case studies -- Marketing, Health, Sociology and social work, Company marketing practices, Company pricing policy, Case studies, Prices and rates, Marketing
Abstract

Objective: To examine tobacco company documents to determine what the companies knew about the impact of cigarette prices on smoking among youth, young adults, and adults, and to evaluate how [...]

Published
2002

11. Organic compounds associated with water repellency in sandy soils

Author

Doerr, S.H., Douglas, P., Morley, C.P., Llewellyn, C.T., Mainwaring, K.A., Haskins, C., Johnsey, L., Ritsema, C.J., Stagnitti, F., Ferreira, A.J.D., and Ziogas, A.K.

Subjects
Soil Science Centre, Life Science, Alterra - Centrum Bodem, Wageningen Environmental Research
Published
2005

13. Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: Fine mapping adds support on chromosomes 6 and 11

Author

Pato, Carlos N., primary, Pato, M.T., additional, Kirby, A., additional, Petryshen, T.L., additional, Medeiros, H., additional, Carvalho, C., additional, Macedo, A., additional, Dourado, A., additional, Coelho, I., additional, Valente, J., additional, Soares, M.J., additional, Ferreira, C.P., additional, Lei, M., additional, Verner, A., additional, Hudson, T.J., additional, Morley, C.P., additional, Kennedy, J.L., additional, Azevedo, M.H., additional, Daly, M.J., additional, and Sklar, P., additional

Published
2004
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15. Investigation of the Temperature Behavior of Dye-Sensitised Solar Cells Prepared Using Different Binders.

Author

Schabauer, J., Morley, C.P., Baker, J., Dartnell, N., Douglas, P., and Winscom, C.

Subjects
*SOLAR cells, *SEMICONDUCTORS, *THIN films, *TITANIUM, *BUILDING-integrated photovoltaic systems, *SOLAR energy
Abstract

Dye-sensitised solar cells were made using variations of a standard procedure, including the introduction of new binder materials into the TiO2 semiconductor films. It was found that the degree of cracking of the films can be influenced by both their thickness and the nature of the binder. Photoelectric measurements of working solar cells were carried out. The changes of influential cell parameters with temperature are reported here, and discussed on the basis of the electrical cell equations. [ABSTRACT FROM AUTHOR]

Published
2007
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16. Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis.

Author

Sklar, P., Pato, M.T., Kirby, A., Petryshen, T.L., Madeiros, H., Carvalho, C., Macedo, A., Dourado, A., Coelho, I., Valente, J., Soares, M.J., Ferreira, C.P., Lei, M., Verner, A., Hudson, T.J., Morley, C.P., Kennedy, J.L., Azevedo, M.H., and Lander, E.

Subjects
GENETICS of schizophrenia, PSYCHOSES, MOLECULAR biology, PSYCHIATRY, BEHAVIORAL medicine, GENETICS
Abstract

Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31-5q35 with strong linkage (NPL=3.09, P=0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL=3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL=3.28 (P=0.00066) at markers D5S2112-D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL=3.03, P=0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases.Molecular Psychiatry (2004) 9, 213-218. doi:10.1038/sj.mp.4001418 Published online 30 December 2003 [ABSTRACT FROM AUTHOR]

Published
2004
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17. Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

Author

Bromet, E.J., Jur��us, A., Malaspina, D., Knowles, J.A., Belliveau, R.A., Jr., Morley, C.P., Perlis, R., Green, E.K., Medeiros, H., Fochtmann, L.J., Backlund, L., Chambert, K., Craddock, N., Lee, P.H., Forty, L., Pato, C.N., Sobell, J.L., Jones, I., Stahl, E.A., McCarroll, S.A., Perkins, D.O., Lehrer, D.S., Charney, A.W., Gordon-Smith, K., Lichtenstein, P., Schalling, M., Chen, C.-Y., Hultman, C.M., Smoller, J.W., Di Florio, A., Land��n, M., Fanous, A.H., Marder, S.R., Sklar, P., Purcell, S.M., Pato, M.T., Rakofsky, J.J., Nicolini, H., Burdick, K.E., Jones, L.A., Moran, J.L., Buckley, P.F., Ruderfer, D.M., Rapaport, M.H., Escamilla, M.A., and Bergen, S.E.

Subjects
mental disorders, 3. Good health
Abstract

Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. Methods: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. Results: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 �� 10���5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

18. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author

Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barišić, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale, Wellcome Trust, Department of Health, Institute of Neurology, UCL, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC), Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Singh T., Heyne H., Byrnes A., Churchhouse C., Watts N., Solomonson M., Lal D., Heinzen E.L., Dhindsa R.S., Stanley K.E., Cavalleri G.L., Hakonarson H., Helbig I., Krause R., May P., Weckhuysen S., Petrovski S., Kamalakaran S., Sisodiya S.M., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Kwan P., Marson A.G., Stewart R., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., McKenna K., Regan B.M., Bellows S.T., Leu C., 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., 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., Tumiene B., 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., Poduri A., Shiedley B.R., Shain C., 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., Reif A., McQuillin A., Bass N., McIntosh A., Blackwood D., Johnstone M., Palotie A., Pato M.T., Pato C.N., Bromet E.J., Carvalho C.B., Achtyes E.D., Azevedo M.H., Kotov R., Lehrer D.S., Malaspina D., Marder S.R., Medeiros H., Morley C.P., Perkins D.O., Sobell J.L., Buckley P.F., Macciardi F., Rapaport M.H., Knowles J.A., Fanous A.H., McCarroll S.A., Gupta N., Gabriel S.B., Daly M.J., Lander E.S., Lowenstein D.H., Goldstein D.B., Lerche H., Berkovic S.F., Neale B.M., Epi25 Collaborative, YÜCESAN, EMRAH, Institute for Molecular Medicine Finland, Children's Hospital, HUS Children and Adolescents, Department of Medical and Clinical Genetics, University Management, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
s.berkovic@unimelb.edu.au [Epi25 Collaborative. Electronic address], 0301 basic medicine, GAMMA-2-SUBUNIT, burden analysi, DNA Mutational Analysis, PROTEIN, Neurodegenerative, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, EPIDEMIOLOGY, Missense mutation, Exome, Aetiology, Genetics (clinical), Exome sequencing, 11 Medical and Health Sciences, seizures, GABRG2, Genetics, Genetics & Heredity, 0303 health sciences, biology, COMMON EPILEPSIES, 1184 Genetics, developmental biology, physiology, sequencing, Biological Sciences, Epi25 Collaborative, Phenotype, GENOME, epileptic encephalopathy, burden analysis, Neurological, Biotechnology, Genetic Markers, seizure, EEF1A2, Burden analysis, epilepsy, exome, Article, 03 medical and health sciences, Clinical Research, Exome Sequencing, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Gene, EPILEPTIC SEIZURES, METAANALYSIS, 030304 developmental biology, Human Genome, Neurosciences, Genetic Variation, 06 Biological Sciences, medicine.disease, Brain Disorders, 030104 developmental biology, Genetic marker, DE-NOVO MUTATIONS, Case-Control Studies, biology.protein, 3111 Biomedicine, Human medicine, 030217 neurology & neurosurgery
Abstract

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

Published
2019

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