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201. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author: Hendricks, A.E. Bochukova, E.G. Marenne, G. Keogh, J.M. Atanassova, N. Bounds, R. Wheeler, E. Mistry, V. Henning, E. Körner, A. Muddyman, D. McCarthy, S. Hinney, A. Hebebrand, J. Scott, R.A. Langenberg, C. Wareham, N.J. Surendran, P. Howson, J.M. Butterworth, A.S. Danesh, J. Nordestgaard, Bø.G. Nielsen, S.F. Afzal, S. Papadia, S. Ashford, S. Garg, S. Millhauser, G.L. Palomino, R.I. Kwasniewska, A. Tachmazidou, I. O'Rahilly, S. Zeggini, E. Barroso, I. Farooqi, I.S. Benzeval, M. Burton, J. Buck, N. Jäckle, A. Kumari, M. Laurie, H. Lynn, P. Pudney, S. Rabe, B. Wolke, D. Overvad, K. Tjønneland, A. Clavel-Chapelon, F. Kaaks, R. Boeing, H. Trichopoulou, A. Ferrari, P. Palli, D. Krogha, V. Panico, S. Tuminoa, R. Matullo, G. Boer, J. Van Der Schouw, Y. Weiderpass, E. Quiros, J.R. Sánchez, M.-J. Navarro, C. Moreno-Iribas, C. Arriola, L. Melander, O. Wennberg, P. Key, T.J. Riboli, E. Turki, S.A. Anderson, C.A. Anney, R. Antony, D. Soler Artigas, M. Ayub, M. Bala, S. Barrett, J.C. Beales, P. Bentham, J. Bhattacharyaa, S. Birney, E. Blackwooda, D. Bobrow, M. Bolton, P.F. Boustred, C. Breen, G. Calissanoa, M. Carss, K. Charlton, R. Chatterjee, K. Chen, L. Ciampia, A. Cirak, S. Clapham, P. Clement, G. Coates, G. Coccaa, M. Collier, D.A. Cosgrove, C. Coxa, T. Craddock, N. Crooks, L. Curran, S. Curtis, D. Daly, A. Danecek, P. Day, I.N.M. Day-Williams, A. Dominiczak, A. Down, T. Du, Y. Dunham, I. Durbin, R. Edkins, S. Ekong, R. Ellis, P. Evansa, D.M. Fitzpatrick, D.R. Flicek, P. Floyd, J. Foley, A.R. Franklin, C.S. Futema, M. Gallagher, L. Gaunt, T.R. Geihs, M. Geschwind, D. Greenwood, C.M.T. Griffin, H. Grozeva, D. Guo, X. Guo, X. Gurling, H. Hart, D. Holmans, P. Howie, B. Huang, J. Huang, L. Hubbard, T. Humphries, S.E. Hurles, M.E. Hysi, P. Iotchkova, V. Jackson, D.K. Jamshidi, Y. Joyce, C. Karczewski, K.J. Kaye, J. Keane, T. Kemp, J.P. Kennedy, K. Kent, A. Khawaja, F. Van Kogelenberg, M. Kolb-Kokocinski, A. Lachance, G. Langford, C. Lawson, D. Lee, I. Lek, M. Li, R. Li, Y. Liang, J. Lin, H. Liu, R. Lönnqvist, J. Lopes, L.R. Lopes, M. MacArthur, D.G. Mangino, M. Marchini, J. Maslen, J. Mathieson, I. McGuffin, P. McIntosh, A.M. McKechanie, A.G. McQuillin, A. Memari, Y. Metrustry, S. Migone, N. Min, J.L. Mitchison, H.M. Moayyeri, A. Morris, A. Morris, J. Muntoni, F. Northstone, K. O'Donovan, M.C. Onoufriadis, A. Oualkacha, K. Owen, M.J. Palotie, A. Panoutsopoulou, K. Parker, V. Parr, J.R. Paternoster, L. Paunio, T. Payne, F. Payne, S.J. Perry, J.R.B. Pietilainen, O. Plagnol, V. Pollitt, R.C. Porteous, D.J. Povey, S. Quail, M.A. Quaye, L. Raymond, F.L. Rehnström, K. Richards, J.B. Ridout, C.K. Ring, S. Ritchie, G.R.S. Roberts, N. Robinson, R.L. Savage, D.B. Scambler, P. Schiffels, S. Schmidts, M. Schoenmakers, N. Scott, R.H. Semple, R.K. Serra, E. Sharp, S.I. Shaw, A. Shihab, H.A. Shin, S.-Y. Skuse, D. Small, K.S. Smee, C. Smith, B.H. Davey Smith, G. Soranzo, N. Southam, L. Spasic-Boskovic, O. Spector, T.D. St Clair, D. St Pourcain, B. Stalker, J. Stevens, E. Sun, J. Surdulescu, G. Suvisaari, J. Syrris, P. Taylor, R. Tian, J. Timpson, N.J. Tobin, M.D. Valdes, A.M. Vandersteen, A.M. Vijayarangakannan, P. Visscher, P.M. Wain, L.V. Walter, K. Walters, J.T.R. Wang, G. Wang, J. Wang, Y. Ward, K. Whyte, T. Williams, H.J. Williamson, K.A. Wilson, C. Wilson, S.G. Wong, K. Xu, C. Yang, J. Zhang, F. Zhang, P. Zheng, H.-F.
Abstract: Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies. © 2017 The Author(s).
Published: 2017

202. A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium

Author: Hess, Jonathan L., Mattheisen, Manuel, Greenwood, Tiffany A., Tsuang, Ming T., Edenberg, Howard J., Holmans, Peter, Faraone, Stephen V., and Glatt, Stephen J.
Abstract: Identifying heritable factors that moderate the genetic risk for schizophrenia (SCZ) could help clarify why some individuals remain unaffected despite having relatively high genetic liability. Previously, we developed a framework to mine genome‐wide association (GWAS) data for common genetic variants that protect high‐risk unaffected individuals from SCZ, leading to derivation of the first‐ever “polygenic resilience score” for SCZ (resilient controls n= 3786; polygenic risk score‐matched SCZ cases n= 18,619). Here, we performed a replication study to verify the moderating effect of our polygenic resilience score on SCZ risk (OR = 1.09, p= 4.03 × 10−5) using newly released GWAS data from 23 independent case–control studies collated by the Psychiatric Genomics Consortium (PGC) (resilient controls n= 2821; polygenic risk score‐matched SCZ cases n= 5150). Additionally, we sought to optimize our polygenic resilience‐scoring formula to improve subsequent modeling of resilience to SCZ and other complex disorders. We found significant replication of the polygenic resilience score, and found that strict pruning of SNPs based on linkage disequilibrium to known risk SNPs and their linked loci optimizes the performance of the polygenic resilience score.
Published: 2024
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203. Association of Genetic Liability to Psychotic Experiences With Neuropsychotic Disorders and Traits.

Author: Legge, Sophie E., Jones, Hannah J., Kendall, Kimberley M., Pardiñas, Antonio F., Menzies, Georgina, Bracher-Smith, Matthew, Escott-Price, Valentina, Rees, Elliott, Davis, Katrina A. S., Hotopf, Matthew, Savage, Jeanne E., Posthuma, Danielle, Holmans, Peter, Kirov, George, Owen, Michael J., O'Donovan, Michael C., Zammit, Stanley, and Walters, James T. R.
Subjects: GENETIC correlations, AUTISM spectrum disorders, MENTAL depression, ATTENTION-deficit hyperactivity disorder, CANNABINOID receptors, NEUROBEHAVIORAL disorders, RESEARCH, SEQUENCE analysis, TISSUE banks, GENETICS, PSYCHOSES, SCHIZOPHRENIA, RESEARCH methodology, CELL receptors, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, GENOMES, DISEASE susceptibility, QUESTIONNAIRES, RESEARCH funding, BIPOLAR disorder, PHENOTYPES, LONGITUDINAL method
Abstract: Importance: Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance.Objectives: To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences.Design, Setting and Participants: Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses.Main Outcomes and Measures: Genetic associations with psychotic experience phenotypes.Results: The study included a total of 127 966 participants (56.0% women and 44.0% men; mean [SD] age, 64.0 [7.6] years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio [OR], 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10-4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10-3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 [GenBank NM_020987]) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10-8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 [GenBank NM_001841]) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10-8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism-based heritability estimate (h2 = 1.71%; 95% CI, 1.02%-2.40%).Conclusions and Relevance: A large genetic association study of psychotic experiences from the population-based UK Biobank sample found support for a shared genetic liability between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]
Published: 2019
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204. Erratum: Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

Author: Hamshere, M L, Walters, J T R, Smith, R, Richards, A L, Green, E, Grozeva, D, Jones, I, Forty, L, Jones, L, Gordon-Smith, K, Riley, B, O'Neill, T, Kendler, K S, Sklar, P, Purcell, S, Kranz, J, Morris, D, Gill, M, Holmans, P, Craddock, N, Corvin, A, Owen, M J, and O'Donovan, M C
Published: 2013
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205. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Author: Lambert, J. C., Ibrahim-Verbaas, C. A., Russo, G., Mayhaus, M., Lannefelt, L., Hakonarson, H., Pichler, S., Carrasquillo, M. M., Ingelsson, M., Beekly, D., Alvarez, V., Zou, F., Valladares, O., Thorton-Wells, T. A., Younkin, S. G., Coto, E., Hamilton-Nelson, K. L., Gu, W., Razquin, C., Pastor, P., Mateo, I., Owen, M. J., Faber, K. M., Jonsson, P. V., Jones, N., Combarros, O., O'Donovan, M. C., Cantwell, L. B., Soininen, H., Blacker, D., Mead, S., Mosley, T. H., Bennett, D. A., Harris, T. B., Fratiglioni, L., Smith, A. V., Holmes, C., de Bruijn, R. F., Passmore, P., Montine, T. J., Bettens, K., Rotter, J. I., Brice, A., Morgan, K., Foroud, T. M., Kukull, W. A., Chouraki, V., Hannequin, D., Powell, J. F., Nalls, M. A., Ritchie, K., Lunetta, K. L., Kauwe, J. S., Boerwinkle, E., Riemenschneider, M., Boada, M., Hiltuenen, M., Thomas, C., Martin, E. R., Schmidt, R., Rujescu, D., Wang, L. S., Dartigues, J. F., Mayeux, R., Tzourio, C., Hofman, A., Nöthen, M. M., Graff, C., Ikram, M. A., Psaty, B. M., Jones, L., Haines, J. L., Holmans, P. A., Lathrop, M., Pericak-Vance, M. A., Launer, L. J., Farrer, L. A., van Duijn, C. M., Van Broeckhoven, C., Zelenika, D., Moskvina, V., Seshadri, S., Williams, J., Schellenberg, G. D., Amouyel, P., Alpérovitch, A., Boland, A., Delépoine, M., Dubois, B., Duron, E., Vardarajan, B. N., Epelbaum, J., Van Cauwenberghe, C., Engelborghs, S., Vandenberghe, R., De Deyn, P. P., Ferri, R., Romano, C., Caltagirone, C., Orfei, M. D., Ciaramella, A., Kamatani, Y., Scarpini, E., Fenoglio, C., Siciliano, G., Bonuccelli, U., Bagnoli, S., Bracco, L., Bessi, V., Cecchetti, R., Bastgiani, P., Squassina, A., Harold, D., Lin, C. F., Seripa, D., Frank-García, A., Sastre, I., Blesa, R., Alcolea, D., Suárez-Clavet, M., Sánchez-Juan, P., Muñoz Fernandez, C., Aladro Benito, Y., Thonberg, H., Gerrish, A., Forshell, C., Lilus, L., Kinhult-Ståhlbom, A., Giedraitis, V., Kilander, L., Brundin, R. M., Concari, L., Helisalmi, S., Koivisto, A. M., Haapasalo, A., Schmidt, H., Solfrizzi, V., Frisardi, V., Ott, J., Carney, R. M., Mash, D. C., Albert, M. S., Albin, R. L., Apostolova, L. G., Arnold, S. E., Barmada, M. M., Kunkle, B., Barnes, L. L., Beach, T. G., Bigio, E. H., Bird, T. D., Boeve, B. F., Bowen, J. D., Boxer, A., Burk, J. R., Cairns, N. J., Cao, C., Dunstan, M. L., Carlson, C. S., Carroll, S. L., Chibnik, L. B., Chui, H. C., Clark, D. G., Corneveaux, J., Cribbs, D. G., DeCarli, C., DeKosky, S. T., Demirci, F. Y., Ruiz, A., Dick, M., Dickson, D. W., Duara, R., Ertekin-Taner, N., Fallon, K. B., Farlow, M. R., Ferris, S., Frosch, M. P., Galasko, G. R., Ganguli, M., Bihoreau, M. T., Gearing, M., Geschwind, D. H., Ghetti, B., Gilman, S., Glass, J. D., Growdon, J. H., Hamilton, R. L., Harrell, L. E., Head, E., Honig, L. S., Choi, S. H., Hulette, C. M., Hyman, B. T., Jarvik, G. P., Jicha, G. A., Jin, L. W., Karydas, A., Kaye, J. A., Kim, R., Koo, E. H., Reitz, C., Kowall, N. W., Kramer, J. H., Kramer, P., LaFerla, F. M., Lah, J. J., Levernez, J. B., Levey, A. I., Li, G., Lieberman, A. P., Lyketsos, C. G., Pasquier, F., Mack, W. J., Marson, D. C., Martiniuk, F., Masliah, E., McCormick, W. C., McCurry, S. M., McDavid, A. N., McKee, A. C., Mesulam, M., Miller, B. L., Naj, A. C., Cruchaga, C., Miller, C. A., Miller, J. W., Morris, J. C., Murrell, J. R., Olichney, J. M., Pankratz, V. S., Parasi, J. E., Peskind, E., Peterson, R. C., Pierce, A., Craig, D., Poon, W. W., Potter, H., Quinn, J. F., Raj, A., Raskind, M., Raiman, E. M., Reisberg, B., Ringman, J. M., Roberson, E. D., Rosen, H. J., Amin, N., Rosenberg, R. N., Sano, M., Saykin, A. J., Schneider, J. A., Schneider, L. S., Seely, W. W., Smith, A. G., Sonnen, J. A., Spina, S., Stern, R. A., Berr, C., Tanzi, R. E., Trojanowski, J. Q., Troncoso, J. C., Van Deerlin, V. M., Van Eldik, L. J., Vinters, H. V., Vonsattel, J. P., Weintraub, S., Welsh-Bohmer, K. A., Williamson, J., Lopez, O. L., Woltjer, R. L., Yu, C. E., Barber, R., Au, R., Wolf, P. A., Beiser, A., Debette, S., Yang, Q., Weinstein, G., Johnson, A. D., De Jager, P. L., Wang, J., Uitterlinden, A. G., Rivadeneira, F., Koudstgaal, P. J., Longstreth, W. T., Becker, J. T., Kuller, L. H., Lumley, T., Rice, K., Garcia, M., Deramecourt, V., Aspelund, T., Marksteiner, J. J., Dal-Bianco, P., Töglhofer, A. M., Freudenberger, P., Ransmayr, G., Benke, T., Toeglhofer, A. M., Bressler, J., Breteler, M. M., Johnston, J. A., Fornage, M., Hernández, I., Rosende Roca, M., Ana Mauleón, M., Alegrat, M., RamÍrez-Lorca, R., González-Perez, A., Chapman, J., Stretton, A., Morgan, A., Evans, D., Kehoe, P. G., Medway, C., Lord, J., Turton, J., Hooper, N. M., Vardy, E., Warren, J. D., Schott, J. M., Uphill, J., Ryan, N., Lovestone, S., Rossor, M., Ben-Shlomo, Y., Makrina, D., Gkatzima, O., Lupton, M., Koutroumani, M., Avramidou, D., Germanou, A., Jessen, F., Riedel-Heller, S., Sims, R., Letenneur, L., Dichgans, M., Heun, R., Kölsch, H., Schürmann, B., Herold, C., Lacour, A., Drichel, D., Hoffman, P., Kornhuber, J., Morón, F. J., Feulner, T., van den Bussche, H., Lawlor, B., Lynch, A., Mann, D., Smith, A. D., Warden, D., Wilcock, G., Heuser, I., Wiltgang, J., Rubinsztein, D. C., Frölich, L., Hüll, M., Mayo, K., Livingston, G., Bass, N. J., Gurling, H., McQuillen, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Eiriksdottir, G., Shaw, C. E., Singleton, A. B., Guerreiro, R., Jöckel, K. H., Klopp, N., Wichmann, H. E., Graff-Radford, N. R., Ma, L., Bisceglio, G., Sleegers, K., Fisher, E., Warner, N., Pickering-Brown, S., Becker, Tim, Goate, A. M., Fiévet, N., Huentelman, M. W., Gill, M., Brown, K., Bellenguez, C., Kamboh, M. I., Keller, L., Barberger-Gateau, P., McGuiness, B., Larson, E. B., Green, R., Myers, A. J., Dufouil, C., Todd, S., Wallon, D., DeStafano, A. L., Love, S., Rogaeva, E., Gallacher, J., St George-Hyslop, P., Clarimon, J., Lleo, A., Bayer, A., Tsuang, D. W., Yu, L., Tsolaki, M., Bis, J. C., Bossù, P., Spalletta, G., Proitsi, P., Collinge, J., Sorbi, S., Sanchez-Garcia, F., Fox, N. C., Hardy, J., Deniz Naranjo, M. C., Bosco, P., Beecham, G. W., Clarke, R., Brayne, C., Galimberti, D., Mancuso, M., Matthews, F., Initiative, European Alzheimer's Disease, Disease, Genetic and Environmental Risk in Alzheimer's, Consortium, Alzheimer's Disease Genetic, Epidemiology, Cohorts for Heart and Aging Research in Genomic, Moebus, S., Grenier-Boley, B., Mecocci, P., Del Zompo, M., Maier, W., Hampel, H., Pilotto, A., Bullido, M., Panza, F., Caffarra, P., Nacmias, B., Gilbert, J. R., Neurology, Radiology & Nuclear Medicine, and Epidemiology
Subjects: Male, Apolipoprotein E, epidemiology [Alzheimer Disease], SORL1, Medizin, genetics [Alzheimer Disease], Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, PICALM, Cohort Studies, Alzheimer Disease, ddc:570, PSEN2, Genetics, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Aged, Genetic association, Aged, 80 and over, Middle Aged, medicine.disease, Genetic Loci, Case-Control Studies, Female, Human medicine, Alzheimer's disease, statistics & numerical data [Genome-Wide Association Study], Genome-Wide Association Study
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Published: 2013
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206. Schizophrenia genetic variants are not associated with intelligence

Author: van Scheltinga, Af, Bakker, Sc, van Haren, Ne, Derks, Em, Buizer Voskamp, Je, Cahn, W, Ripke, S, Sanders, A, Kendler, K, Levinson, D, Sklar, P, Holmans, P, Lin, D., Duan, J, Ophoff, R, Andreassen, O, Scolnick, E, Cichon, S, St Clair, D, Corvin, A, Gurling, H, Werge, T, Rujescu, D, Blackwood, D, Pato, C, Malhotra, A, Purcell, S, Dudbridge, F, Neale, B, Rossin, L, Visscher, P, Posthuma, D, Ruderfer, D, Fanous, A, Stefansson, H, Steinberg, S, Mowry, B, Golimbet, V, Hert, De, M, Jonsson, E, Bitter, I, Pietilainen, O, Collier, D, Tosato, Sarah, Agartz, I, Albus, M, Alexander, M, Amdur, R, Amin, F, Bass, N, Bergen, S, Black, D, Børglum, A, Brown, M, Bruggeman, R, Buccola, N, Byerley, W, Cantor, R, Carr, V, Catts, S, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, P, Datta, S, Haan, De, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Donohoe, G, Duong, L, Dwyer, S, Fink Jensen, A, Freedman, R, Freimer, N, Friedl, M, Georgieva, L, Giegling, I, Gill, M, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, A, Henskens, F, Hougaard, D, Hultman, C, Ingason, A, Jablensky, A, Jakobsen, K, Jay, M, Jurgens, G, Kahn, R, Keller, M, Kenis, G, Kenny, E, Kim, Y, Kirov, G, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, V, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, K, Lichtenstein, P, Lieberman, J, Linszen, D, Lonnqvist, J, Loughland, C, Maclean, A, Maher, B, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, Mcghee, K, Mcgrath, J, Mcintosh, A, Mclean, D, Mcquillin, A, Melle, I, Michie, P, Milanova, V, Morris, D, Mors, O, Mortensen, P, Moskvina, V, Muglia, P, Myin Germeys, I, Nertney, D, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nothen, M, O'Dushlaine, C, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, T, Owen, M, Pantelis, C, Papadimitriou, G, Pato, M, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, A, Puri, V, Quested, D, Quinn, E, Rasmussen, H, Rethelyi, Jm, Ribble, R, Rietschel, M, Riley, B, Ruggeri, Mirella, Schall, U, Schulze, T, Schwab, S, Scott, R, Shi, J, Sigurdsson, E, Silverman, J, Spencer, C, Stefansson, K, Strange, A, Strengman, E, Stroup, T, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, J, Timm, S, Toncheva, D, van den Oord, E, van Os, J, van Winkel, R, Veldink, J, Walsh, D, Wang, A, Wiersma, D, Wildenauer, D, Williams, H, Williams, N, Wormley, B, Zammit, S, Sullivan, P, O'Donovan, M, Daly, M, Gejman, P), Ophoff, Ra, Kahn, Rs, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Adult Psychiatry
Subjects: Oncology, Adult, Male, Psychosis, medicine.medical_specialty, Multifactorial Inheritance, DNA Copy Number Variations, Endophenotypes, Schizophrenia (object-oriented programming), Intelligence, SNP, Single-nucleotide polymorphism, Genome-wide association study, polygenic, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Cognition, Internal medicine, mental disorders, medicine, Humans, Genetic Predisposition to Disease, deletion, Cognitive decline, Applied Psychology, Genetic association, Genetics, Wechsler Scales, Wechsler Adult Intelligence Scale, medicine.disease, endophenotype, Psychiatry and Mental health, duplication, IQ, Endophenotype, Schizophrenia, Female, Psychology, cognition, schizophrenia, Genome-Wide Association Study
Abstract: BackgroundSchizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence.MethodIQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls.ResultsAlthough significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R2 = 0.055, p = 2.1 × 10−7) and with IQ in the entire sample (R2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status.ConclusionsOur data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.
Published: 2013
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207. Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia

Author: Witt, S. H., Streit, F., Jungkunz, M., Frank, J., Awasthi, S., Reinbold, C. S., Treutlein, J., Degenhardt, F., Forstner, A. J., Heilmann-Heimbach, S., Dietl, L., Schwarze, C. E., Schendel, D., Strohmaier, J., Abdellaoui, A., Adolfsson, Rolf, Air, T. M., Akil, H., Alda, M., Alliey-Rodriguez, N., Andreassen, O. A., Babadjanova, G., Bass, N. J., Bauer, M., Baune, B. T., Bellivier, F., Bergen, S., Bethell, A., Biernacka, J. M., Blackwood, D. H. R., Boks, M. P., Boomsma, D. I., Borglum, A. D., Borrmann-Hassenbach, M., Brennan, P., Budde, M., Buttenschon, H. N., Byrne, E. M., Cervantes, P., Clarke, T-K, Craddock, N., Cruceanu, C., Curtis, D., Czerski, P. M., Dannlowski, U., Davis, T., de Geus, E. J. C., Di Florio, A., Djurovic, S., Domenici, E., Edenberg, H. J., Etain, B., Fischer, S. B., Forty, L., Fraser, C., Frye, M. A., Fullerton, J. M., Gade, K., Gershon, E. S., Giegling, I., Gordon, S. D., Gordon-Smith, K., Grabe, H. J., Green, E. K., Greenwood, T. A., Grigoroiu-Serbanescu, M., Guzman-Parra, J., Hall, L. S., Hamshere, M., Hauser, J., Hautzinger, M., Heilbronner, U., Herms, S., Hitturlingappa, S., Hoffmann, P., Holmans, P., Hottenga, J-J, Jamain, S., Jones, I., Jones, L. A., Jureus, A., Kahn, R. S., Kammerer-Ciernioch, J., Kirov, G., Kittel-Schneider, S., Kloiber, S., Knott, S. V., Kogevinas, M., Landen, M., Leber, M., Leboyer, M., Li, Q. S., Lissowska, J., Lucae, S., Martin, N. G., Mayoral-Cleries, F., McElroy, S. L., McIntosh, A. M., McKay, J. D., McQuillin, A., Medland, S. E., Middeldorp, C. M., Milaneschi, Y., Mitchell, P. B., Montgomery, G. W., Morken, G., Mors, O., Muehleisen, T. W., Mueller-Myhsok, B., Myers, R. M., Nievergelt, C. M., Nurnberger, J. I., O'Donovan, M. C., Loohuis, L. M. O., Ophoff, R., Oruc, L., Owen, M. J., Paciga, S. A., Penninx, B. W. J. H., Perry, A., Pfennig, A., Potash, J. B., Preisig, M., Reif, A., Rivas, F., Rouleau, G. A., Schofield, P. R., Schulze, T. G., Schwarz, M., Scott, L., Sinnamon, G. C. B., Stahl, E. A., Strauss, J., Turecki, G., Van der Auwera, S., Vedder, H., Vincent, J. B., Willemsen, G., Witt, C. C., Wray, N. R., Xi, H. S., Tadic, A., Dahmen, N., Schott, B. H., Cichon, S., Noethen, M. M., Ripke, S., Mobascher, A., Rujescu, D., Lieb, K., Roepke, S., Schmahl, C., Bohus, M., Rietschel, M., Witt, S. H., Streit, F., Jungkunz, M., Frank, J., Awasthi, S., Reinbold, C. S., Treutlein, J., Degenhardt, F., Forstner, A. J., Heilmann-Heimbach, S., Dietl, L., Schwarze, C. E., Schendel, D., Strohmaier, J., Abdellaoui, A., Adolfsson, Rolf, Air, T. M., Akil, H., Alda, M., Alliey-Rodriguez, N., Andreassen, O. A., Babadjanova, G., Bass, N. J., Bauer, M., Baune, B. T., Bellivier, F., Bergen, S., Bethell, A., Biernacka, J. M., Blackwood, D. H. R., Boks, M. P., Boomsma, D. I., Borglum, A. D., Borrmann-Hassenbach, M., Brennan, P., Budde, M., Buttenschon, H. N., Byrne, E. M., Cervantes, P., Clarke, T-K, Craddock, N., Cruceanu, C., Curtis, D., Czerski, P. M., Dannlowski, U., Davis, T., de Geus, E. J. C., Di Florio, A., Djurovic, S., Domenici, E., Edenberg, H. J., Etain, B., Fischer, S. B., Forty, L., Fraser, C., Frye, M. A., Fullerton, J. M., Gade, K., Gershon, E. S., Giegling, I., Gordon, S. D., Gordon-Smith, K., Grabe, H. J., Green, E. K., Greenwood, T. A., Grigoroiu-Serbanescu, M., Guzman-Parra, J., Hall, L. S., Hamshere, M., Hauser, J., Hautzinger, M., Heilbronner, U., Herms, S., Hitturlingappa, S., Hoffmann, P., Holmans, P., Hottenga, J-J, Jamain, S., Jones, I., Jones, L. A., Jureus, A., Kahn, R. S., Kammerer-Ciernioch, J., Kirov, G., Kittel-Schneider, S., Kloiber, S., Knott, S. V., Kogevinas, M., Landen, M., Leber, M., Leboyer, M., Li, Q. S., Lissowska, J., Lucae, S., Martin, N. G., Mayoral-Cleries, F., McElroy, S. L., McIntosh, A. M., McKay, J. D., McQuillin, A., Medland, S. E., Middeldorp, C. M., Milaneschi, Y., Mitchell, P. B., Montgomery, G. W., Morken, G., Mors, O., Muehleisen, T. W., Mueller-Myhsok, B., Myers, R. M., Nievergelt, C. M., Nurnberger, J. I., O'Donovan, M. C., Loohuis, L. M. O., Ophoff, R., Oruc, L., Owen, M. J., Paciga, S. A., Penninx, B. W. J. H., Perry, A., Pfennig, A., Potash, J. B., Preisig, M., Reif, A., Rivas, F., Rouleau, G. A., Schofield, P. R., Schulze, T. G., Schwarz, M., Scott, L., Sinnamon, G. C. B., Stahl, E. A., Strauss, J., Turecki, G., Van der Auwera, S., Vedder, H., Vincent, J. B., Willemsen, G., Witt, C. C., Wray, N. R., Xi, H. S., Tadic, A., Dahmen, N., Schott, B. H., Cichon, S., Noethen, M. M., Ripke, S., Mobascher, A., Rujescu, D., Lieb, K., Roepke, S., Schmahl, C., Bohus, M., and Rietschel, M.
Abstract: Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
Published: 2017
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208. Erratum: Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype

Author: Craddock, N, Jones, L, Jones, I R, Kirov, G, Green, E K, Grozeva, D, Moskvina, V, Nikolov, I, Hamshere, M L, Vukcevic, D, Caesar, S, Gordon-Smith, K, Fraser, C, Russell, E, Norton, N, Breen, G, St Clair, D, Collier, D A, Young, A H, Ferrier, I N, Farmer, A, McGuffin, P, Holmans, P A, Donnelly, P, Owen, M J, and O'Donovan, M C
Published: 2010
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209. Common alleles contribute to schizophrenia in CNV carriers

Author: Tansey, K. E., Rees, E., Linden, D. E., Ripke, S., Chambert, D., Moran, J. L., McCarroll, S. A., Holmans, P., Kirov, G., Walters, J., Owen, M. J., and O'Donovan, M. C.
Subjects: R1
Abstract: The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10−17) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.
Published: 2016

210. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2

Author: O'Donovan, MC, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, JL, Spencer, CCA, Howie, B, Leung, H-T, Giegling, I, Hartmann, AM, Möller, H-J, Morris, DW, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rietschel, M, Zammit, S, Schumacher, J, Quinn, EM, Schulze, TG, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, AR, Levinson, DF, Adolfsson, R, Ösby, U, Terenius, L, Jönsson, EG, Cichon, S, Nöthen, MM, Gill, M, Corvin, AP, Rujescu, D, Gejman, PV, Kirov, G, Craddock, N, Williams, NM, Owen, MJ, Buccola, NG, Mowry, BJ, Freedman, R, Amin, F, Black, DW, Silverman, JM, Byerley, WJ, and Cloninger, CR
Subjects: Adult, Male, Linkage disequilibrium, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Cellular and Molecular Neuroscience, Young Adult, Gene Frequency, Meta-Analysis as Topic, Polymorphism (computer science), SNP, Humans, Genetic Predisposition to Disease, Allele, Receptor, Fibroblast Growth Factor, Type 2, Molecular Biology, Allele frequency, Aged, Genetics, Aged, 80 and over, Fibroblast growth factor receptor 2, Chromosomes, Human, Pair 10, Middle Aged, Psychiatry and Mental health, Schizophrenia, Female, Genome-Wide Association Study
Abstract: We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P
Published: 2016
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211. Presenilin-1 polymorphism and Alzheimer's disease [6]

Author: Kehoe, P., Williams, J., Lovestone, S., Wilcock, G., Owen, M. J., Holmans, P., Liddell, M., Holmes, C., Powall, J., Neal, J., Bouras, C., Panteleimon Giannakopoulos, Schioi, J., Tezapsidis, N., Robakis, N. K., Higuchi, S., Muramatsu, T., Matsushita, S., and Arai, H.
Published: 2016

212. Genome-wide and fine-resolution association analysis of malaria in West Africa

Author: Muminatou, Jallow, Yik Ying Teo, Small, Kerrin S., Rockett, Kirk A., Panos, Deloukas, Clark, Taane G., Katja, Kivinen, Bojang, Kalifa A., Conway, David J., Margaret, Pinder, Giorgio, Sirugo, Fatou Sisay Joof, Stanley, Usen, Sarah, Auburn, Bumpstead, Suzannah J., Susana, Campino, Alison, Coffey, Andrew, Dunham, Fry, Andrew E., Angela, Green, Rhian, Gwilliam, Hunt, Sarah E., Michael, Inouye, Jeffreys, Anna E., Alieu, Mendy, Aarno, Palotie, Simon, Potter, Jiannis, Ragoussis, Jane, Rogers, Kate, Rowlands, Elilan, Somaskantharajah, Pamela, Whittaker, Claire, Widden, Peter, Donnelly, Bryan, Howie, Jonathan, Marchini, Andrew, Morris, Miguel, Sanjoaquin, Eric Akum Achidi, Tsiri, Agbenyega, Angela, Allen, Olukemi, Amodu, Patrick, Corran, Abdoulaye, Djimde, Amagana, Dolo, Doumbo, Ogobara K., Chris, Drakeley, Sarah, Dunstan, Jennifer, Evans, Jeremy, Farrar, Hien Tt, Fernando D., Horstmann, R. D., Ibrahim, M., Karunaweera, N., Kokwaro, G., Koram, K. A., Lemnge, M., Makani, J., Marsh, K., Michon, P., David, Modiano, Molyneux, M. E., Mueller, I., Parker, M., Peshu, N., Plowe, C. V., Puijalon, O., Reeder, J., Reyburn, H., Riley, E. M., Sakuntabhai, A., Singhasivanon, P., Sirima, S., Tall, A., Taylor, T. E., Thera, M., Troye Blomberg, M., Williams, T. N., Wilson, M., Wellcome Trust Case Control Consortium Kwiatkowski, D. P., Epidemiology Network: Achidi, Malaria Genomic E. A., Agbenyega, T., Ahmad, T., Alcock, D., Allen, S., Amenga Etego, L., Amodu, O., Apinjoh, T. O., Attwood, A. P., Auburn, S., Ball, S. G., Balmforth, A. J., Ban, M., Barbour, J., Barnwell, D., Barrett, J. C., Barrett, J. H., Barton, A., Bentley, D., Bishop, D. T., Bojang, K., Boorman, J. P., Bougouma, E., Bradbury, L. A., Braga Marcano, C. A., Braund, P. S., Bredin, F., Breen, G., Brown, M. A., Brown, M. J., Bruce, I. N., Bryan, C., Bull, S., Bumpstead, S. J., Burke, B., Burton, P. R., Caesar, S., Campino, S., Cant, B., Cardin, N. J., Cardon, L. R., Carucci, D., Caulfield, M., Chaney, A., Clark, T., Clayton, D. G., Collier, D. A., Compston, A., Compston, D. A., Connell, J., Conway, D., Cook, K., Corran, P., Craddock, N., Cummings, F. R., Davison, D., Deloukas, P., Devries, J., Dewasurendra, R., Diakite, M., Dixon, R. J., Djimde, A., Dobson, R., Dolo, A., Dominiczak, A., Donnelly, P., Donovan, H., Doumbo, O., Downes, K., Doyle, A., Drakeley, C., Drummond, H., Duffy, P., Duncanson, A., Dunger, D. B., Dunstan, S., Duombo, O., Easton, D., Elkin, A., Elliott, K. S., Elzein, A., Enimil, A., Evans, D., Evans, J., Everson, U., Eyre, S., Farmer, A., Farrall, M., Farrar, C., Farrar, J., Fernando, D., Ferreira, T., Ferrier, I. N., Fisher, S. A., Fitzpatrick, K., Forbes, A., Franklyn, J. A., Fraser, C., Frayling, T. M., Freathy, R. M., Ghansah, A., Ghori, J., Gilbert, P. D., Gordon Smith, K., Goris, A., Gottlieb, M., Gough, S. C., Green, A., Green, E. K., Groves, C. J., Grozeva, D., Gungadoo, J., Gwilliam, R., Hall, A. S., Hallgrimsdóttir, I. B., Hamshere, M. L., Hart, L., Hattersley, A. T., Heward, J. M., Hider, S. L., Tran Tinh Hien, Hill, A. V., Hilton, E., Hinks, A. M., Hitman, G. A., Holmans, P. A., Horstmann, Rolf D., Howie, B. N., Hubbart, C., Hughes, C., Hunt, S. E., Hussein, A., Hussey, J. M., Muntaser, Ibrahim, Iles, M. M., Inouye, M., Ishengoma, D., Jallow, M., Jeffreys, A. E., Jewell, D. P., John, Sl, Jolley, J. D., Jones, I. R., Jones, L., Jones, R. W., Nadira, Karunaweera, Keniry, A., King, E., Kirov, G., Kivinen, K., Knight, A. S., Koch, K., Gilbert, Kokwaro, Koram, Kwadwo A., Lango, H., Lathrop, G. M., Lee, K. L., Lees, C. W., Martha, Lemnge, Leung, H. T., Lewis, C. M., Lin, E., Lindgren, C. M., Ly, A., Macinnis, B., Julie, Makani, Mangano, Valentina, Mangino, M., Manjurano, A., Manning, L., Mansfield, J. C., Manske, M., Maqbool, A., Marchini, J. L., Kevin, Marsh, Maslen, G., Mathew, C. G., Mcardle, W. L., Mccarthy, M. I., Mccreight, M., Mcginnis, R., Mcguffin, P., Meech, E., Mendy, A., Pascal, Michon, Mohiuddin, M. K., Molyneux, Malcolm E., Morris, A. P., Moskvina, V., Moyes, C., Ivo, Mueller, Munroe, P. B., Mutabingwa, T., Ndila, C. M., Newhouse, S. J., Newport, M., Nikolov, I., Nimmo, E. R., Nutland, S., Nyirongo, V., O'Donovan, M. C., Oluoch, T., Onipinla, A., Onnie, C. M., Ouwehand, W. H., Owen, M. J., Michael, Parker, Parkes, M., Pembrey, M., Pereira Gale, J., Perry, J. R., Norbert, Peshu, Plowe, Christopher V., Pointon, J. J., Potter, C., Potter, S., Prescott, N. J., Prowse, C. V., Odile, Puijalon, Quyen, N. T., Ragoussis, J., Rahman, N., Ravindrarajah, R., Rayner, N. W., John, Reeder, Hugh, Reyburn, Riley, Eleanor M., Ring, S. M., Risley, P., Rockett, K. A., Rogers, J., Rowlands, K., Anavaj, Sakuntabhai, Samani, N. J., Sanderson, J., Sanjoaquin, M., Satsangi, J., Sawcer, S. J., Seal, S., Shields, B. M., Silman, A. J., Simmonds, M. J., Pratap, Singhasivanon, Sodiomon, Sirima, Sirugo, G., Small, K. S., Somaskantharajah, E., Spencer, C. C., St Clair, D., Stevens, H. E., Stevens, M., Stevens, S., Strachan, D. P., Stratton, M. R., Su, Z., Suriyaphol, P., Symmons, D. P., Adama, Tall, Taylor, N. C., Taylor, Terrie E., Teo, Y., Teo, Y. Y., Mahamadou, Thera, Thompson, J. R., Thomson, W., Timpson, N. J., Tobin, M. D., Todd, J. A., Todhunter, C. E., Toure, O., Tremelling, M., Marita Troye Blomberg, Vanderwal, A., Vukcevic, D., Walker, M., Walker, N. M., Wallace, C., Walters, G. R., Walton, R., Watkins, N. A., Watson, R., Webster, J., Weedon, M. N., Whittaker, P., Widmer, B., Williams, Thomas N., Williamson, R., Michael, Wilson, Winzer, T., Withers, D., Wordsworth, P., Worthington, J., Wrigley, R., Xue, M., Young, A. H., Yuldasheva, N., and Zeggini, E.
Subjects: Linkage disequilibrium, Hemoglobin, Sickle, Population, Genome-wide association study, Locus (genetics), Biology, Population stratification, Polymorphism, Single Nucleotide, Severity of Illness Index, Linkage Disequilibrium, Article, Gene mapping, Reference Values, Ethnicity, Genetics, Humans, education, Genetic association, education.field_of_study, Polymorphism, Genetic, Chromosome Mapping, Genetic Variation, Malaria, Gambia, Imputation (genetics), Genome-Wide Association Study
Abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
Published: 2009
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213. Identification of Biological Pathways to Alzheimer's Disease Using Polygenic Scores

Author: Harrison, J., primary, Baker, E., additional, Hubbard, L., additional, Linden, D., additional, Williams, J., additional, Escott-Price, V., additional, and Holmans, P., additional
Published: 2017
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214. De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1in schizophrenia

Author: Rees, Elliott, Han, Jun, Morgan, Joanne, Carrera, Noa, Escott-Price, Valentina, Pocklington, Andrew J., Duffield, Madeleine, Hall, Lynsey S., Legge, Sophie E., Pardiñas, Antonio F., Richards, Alexander L., Roth, Julian, Lezheiko, Tatyana, Kondratyev, Nikolay, Kaleda, Vasilii, Golimbet, Vera, Parellada, Mara, González-Peñas, Javier, Arango, Celso, Gawlik, Micha, Kirov, George, Walters, James T. R., Holmans, Peter, O’Donovan, Michael C., and Owen, Michael J.
Abstract: Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n= 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.
Published: 2020
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215. Genetic Implication of Specific Glutamatergic Neurons of the Prefrontal Cortex in the Pathophysiology of Schizophrenia

Author: Tume, Claire E., Chick, Sophie L., Holmans, Peter A., Rees, Elliott, O’Donovan, Michael C., Cameron, Darren, and Bray, Nicholas J.
Abstract: The prefrontal cortex (PFC) has been strongly implicated in the pathophysiology of schizophrenia. We here combine high-resolution single nuclei RNA sequencing (snRNA-Seq) data from the human PFC with large-scale genomic data for schizophrenia to identify constituent cell populations likely to mediate genetic liability to the disorder.
Published: 2024
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216. Psychiatric gene discoveries shape evidence on ADHD's biology

Author: Thapar, A., Martin, J., Mick, E., Arias Vasquez, A., Langley, K., Scherer, S.W., Schachar, R., Crosbie, J., Williams, N., Franke, B., Elia, J., Glessner, J., Hakonarson, H., Owen, M.J., Faraone, S.V, O'Donovan, M.C., Holmans, P., Thapar, A., Martin, J., Mick, E., Arias Vasquez, A., Langley, K., Scherer, S.W., Schachar, R., Crosbie, J., Williams, N., Franke, B., Elia, J., Glessner, J., Hakonarson, H., Owen, M.J., Faraone, S.V, O'Donovan, M.C., and Holmans, P.
Abstract: Contains fulltext : 168080pub.pdf (publisher's version ) (Open Access), A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 x 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.
Published: 2016

217. Erratum: A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia

Author: Williams, J, Spurlock, G, Holmans, P, Mant, R, Murphy, K, Jones, L, Cardno, A, Asherson, P, Blackwood, D, Muir, W, Meszaros, K, Aschauer, H, Mallet, J, Laurent, C, Pekkarinen, P, Seppala, J, Stefanis, C N, Papadimitriou, G N, Macciardi, F, Verga, M, Pato, C, Azevedo, H, Crocq, M-A, Gurling, H, Kalsi, G, McGuffin, P, and Owen, M J
Published: 1998
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218. Genome‐wide meta‐analysis of late‐onset Alzheimer's disease using rare variant imputation in 65,602 subjects identifies risk loci with roles in memory, neurodevelopment, and cardiometabolic traits: The international genomics of...

Author: Naj, Adam C., Sha, Jin, Zhao, Yi, Leonenko, Ganna, Jian, Xueqiu, Grenier‐Boley, Benjamin, Dalmasso, Maria Carolina, van der Lee, Sven J., Sims, Rebecca, Chouraki, Vincent, Bis, Josh C., Kuzma, Amanda B., Kunkle, Brian W., Karamujić‐Čomić, Hata, Pitsillides, Achilleas N., Xia, Rui, Fulton‐Howard, Brian, Holmans, Peter, Dupuis, Josée, and Wang, Li‐San
Abstract: Background: Recent meta‐analyses of genome‐wide association studies (GWAS) have identified ∼30 susceptibility LOAD loci in addition to APOE, however the majority are common variants (minor allele frequency (MAF)>0.02). We used the dense, high‐resolution Haplotype Reference Consortium (HRC) r1.1 reference panel (64,976 haplotypes/39,235,157 SNPs), which allows imputation of rare variants (MAF>0.0008), to impute 44 GWAS datasets of the IGAP consortia to identify novel rare variant, gene, and pathway associations. Method: We imputed 25,192 cases and 40,410 controls to the HRC r1.1 panel using Minimac3 on the Michigan Imputation Server. Converting imputed genotype probabilities to minor allele dosage, we ran logistic regression using SNPTEST on individual variants with MAF > 0.01 (and using generalized linear mixed models in R with family‐based datasets), and performed a fixed‐effects, inverse‐variance‐weighted meta‐analysis using METAL. Variants with MAF ≤ 0.01 were meta‐analyzed using score‐based tests via SeqMeta/R. Both analyses adjusted for age‐at‐onset(cases)/age‐at‐exam(controls), sex, and principal components for population substructure. Gene‐based associations were done with SKAT‐O and burden testing, while pathway associations were examined using VEGAS2. Result: Discovery analyses of ∼39.2M genotyped or imputed SNVs confirmed single variant associations in 26 of 30 known IGAP LOAD loci at suggestive levels of significance (P < 10−5), with 12 known loci attaining genome‐wide statistical significance (P < 5 × 10−8) (Figure 1). Newly observed associations included common variants (MAF>0.01) in or near homologs of known AD loci, EPHA5 (rs17086136, OR[95% CI] = 1.23 [1.13,1.33], P = 6.36 × 10−7) and ADAM28 (rs10096379, OR[95% CI] = 0.86 [0.81,0.92], P = 3.02 × 10−6); in/near neuronal development genes including DAB1 (neuronal migration; 1:57700874:T:G, OR[95% CI] = 0.71 [0.62, 0.81], P = 6.94 × 10−7) and DCC (axon guidance; rs2054289, OR[95% CI] = 0.71 [0.62, 0.83], P = 6.69 × 10−6); and in/near genes involved in cardiometabolic traits including THADA (type 2 diabetes; rs77101426, OR[95% CI] = 0.89 [0.85, 0.95], P = 2.37 × 10−6). Several known AD loci demonstrated novel rare variant associations with genome‐wide significance, including CR1, PICALM, and the MS4A region (Figure 2), and novel rare variant associations were observed in or near genes involved in memory and cognitive function, including HS3ST4 and DBX1. Independent replication in external datasets including the UK Biobank is on‐going. Conclusion: Several novel LOAD candidate loci, including those with prior associations with neurodevelopment and cardiometabolic traits, were identified using high‐quality imputation of rare and low‐frequency variants in IGAP. [ABSTRACT FROM AUTHOR]
Published: 2020
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219. Identifying gene-environment interactions in schizophrenia: Contemporary challenges for integrated, large-scale investigations

Author: Van Os, J. Rutten, B.P. Myin-Germeys, I. Delespaul, P. Viechtbauer, W. Van Zelst, C. Bruggeman, R. Reininghaus, U. Morgan, C. Murray, R.M. Di Forti, M. McGuire, P. Valmaggia, L.R. Kempton, M.J. Gayer-Anderson, C. Hubbard, K. Beards, S. Stilo, S.A. Onyejiaka, A. Bourque, F. Modinos, G. Tognin, S. Calem, M. O'Donovan, M.C. Owen, M.J. Holmans, P. Williams, N. Craddock, N. Richards, A. Humphreys, I. Meyer-Lindenberg, A. Leweke, F.M. Tost, H. Akdeniz, C. Rohleder, C. Bumb, J.M. Schwarz, E. Alptekin, K. Üçok, A. Saka, M.C. Atbagoǧlu, E.C. Gülöksüz, S. Gumus-Akay, G. Cihan, B. Karadaǧ, H. Soygür, H. Cankurtaran, E.S. Ulusoy, S. Akdede, B. Binbay, T. Ayer, A. Noyan, H. Karadayi, G. Akturan, E. Ulaş, H. Arango, C. Parellada, M. Bernardo, M. Sanjuán, J. Bobes, J. Arrojo, M. Santos, J.L. Cuadrado, P. Solano, J.J.R. Carracedo, A. Bernardo, E.G. Roldán, L. López, G. Cabrera, B. Cruz, S. Mesa, E.M.D. Pouso, M. Jiménez, E. Sánchez, T. Rapado, M. González, E. Martínez, C. Sánchez, E. Olmeda, M.S. De Haan, L. Velthorst, E. Van Der Gaag, M. Selten, J.-P. Van Dam, D. Van Der Ven, E. Van Der Meer, F. Messchaert, E. Kraan, T. Burger, N. Leboyer, M. Szoke, A. Schürhoff, F. Llorca, P.-M. Jamain, S. Tortelli, A. Frijda, F. Vilain, J. Galliot, A.-M. Baudin, G. Ferchiou, A. Richard, J.-R. Bulzacka, E. Charpeaud, T. Tronche, A.-M. De Hert, M. Van Winkel, R. Decoster, J. Derom, C. Thiery, E. Stefanis, N.C. Sachs, G. Aschauer, H. Lasser, I. Winklbaur, B. Schlögelhofer, M. Riecher-Rössler, A. Borgwardt, S. Walter, A. Harrisberger, F. Smieskova, R. Rapp, C. Ittig, S. Soguel-Dit-Piquard, F. Studerus, E. Klosterkötter, J. Ruhrmann, S. Paruch, J. Julkowski, D. Hilboll, D. Sham, P.C. Cherny, S.S. Chen, E.Y.H. Campbell, D.D. Li, M. Romeo-Casabona, C.M. Cirión, A.E. Mora, A.U. Jones, P. Kirkbride, J. Cannon, M. Rujescu, D. Tarricone, I. Berardi, D. Bonora, E. Seri, M. Marcacci, T. Chiri, L. Chierzi, F. Storbini, V. Braca, M. Minenna, M.G. Donegani, I. Fioritti, A. La Barbera, D. La Cascia, C.E. Mulè, A. Sideli, L. Sartorio, R. Ferraro, L. Tripoli, G. Seminerio, F. Marinaro, A.M. McGorry, P. Nelson, B. Amminger, G.P. Pantelis, C. Menezes, P.R. Del-Ben, C.M. Tenan, S.H.G. Shuhama, R. Ruggeri, M. Tosato, S. Lasalvia, A. Bonetto, C. Ira, E. Nordentoft, M. Krebs, M.-O. Barrantes-Vidal, N. Cristóbal, P. Kwapil, T.R. Brietzke, E. Bressan, R.A. Gadelha, A. Maric, N.P. Andric, S. Mihaljevic, M. Mirjanic, T.
Abstract: Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. © 2014 The Author.
Published: 2014

220. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

Author: Smith, D J, primary, Escott-Price, V, additional, Davies, G, additional, Bailey, M E S, additional, Colodro-Conde, L, additional, Ward, J, additional, Vedernikov, A, additional, Marioni, R, additional, Cullen, B, additional, Lyall, D, additional, Hagenaars, S P, additional, Liewald, D C M, additional, Luciano, M, additional, Gale, C R, additional, Ritchie, S J, additional, Hayward, C, additional, Nicholl, B, additional, Bulik-Sullivan, B, additional, Adams, M, additional, Couvy-Duchesne, B, additional, Graham, N, additional, Mackay, D, additional, Evans, J, additional, Smith, B H, additional, Porteous, D J, additional, Medland, S E, additional, Martin, N G, additional, Holmans, P, additional, McIntosh, A M, additional, Pell, J P, additional, Deary, I J, additional, and O'Donovan, M C, additional
Published: 2016
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221. GENETIC VARIANTS OF UNCERTAIN SIGNIFICANCE (VUS) IN FAMILIAL HYPERCHOLESTEROLAEMIA (FH) IN WALES: YEAR 2 UPDATE

Author: Haralambos, K., primary, Whatley, S.D., additional, Edwards, R., additional, Gingell, R., additional, Townsend, D., additional, Holmans, P., additional, Clarke, A., additional, Datta, D.B.N., additional, Butler, R., additional, Palmer-Smith, S., additional, Wood, M., additional, and McDowell, I.F.W., additional
Published: 2016
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222. Exome arrays capture polygenic rare variant contributions to schizophrenia

Author: Richards, A. L., primary, Leonenko, G., additional, Walters, J. T., additional, Kavanagh, D. H., additional, Rees, E. G., additional, Evans, A., additional, Chambert, K. D., additional, Moran, J. L., additional, Goldstein, J., additional, Neale, B. M., additional, McCarroll, S. A., additional, Pocklington, A. J., additional, Holmans, P. A., additional, Owen, M. J., additional, and O'Donovan, M. C., additional
Published: 2016
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223. Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

Author: University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Rees, E., Kirov, G., Walters, J. T., Richards, A. L., Howrigan, D., Kavanagh, D. H., Pocklington, A. J., Fromer, M., Ruderfer, D. M., Georgieva, L., Carrera, N., Gormley, P., Palta, P., Williams, H., Dwyer, S., Johnson, J. S., Roussos, P., Barker, D. D., Banks, E., Milanova, V., Rose, S. A., Chambert, K., Mahajan, M., Scolnick, E. M., Moran, J. L., Tsuang, M. T., Glatt, S. J., Chen, W. J., Hwu, H-G, Neale, B. M., Palotie, A., Sklar, P., Purcell, S. M., McCarroll, S. A., Holmans, P., Owen, M. J., O'Donovan, M. C., Taiwanese Trios Exome Sequencing C, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Rees, E., Kirov, G., Walters, J. T., Richards, A. L., Howrigan, D., Kavanagh, D. H., Pocklington, A. J., Fromer, M., Ruderfer, D. M., Georgieva, L., Carrera, N., Gormley, P., Palta, P., Williams, H., Dwyer, S., Johnson, J. S., Roussos, P., Barker, D. D., Banks, E., Milanova, V., Rose, S. A., Chambert, K., Mahajan, M., Scolnick, E. M., Moran, J. L., Tsuang, M. T., Glatt, S. J., Chen, W. J., Hwu, H-G, Neale, B. M., Palotie, A., Sklar, P., Purcell, S. M., McCarroll, S. A., Holmans, P., Owen, M. J., O'Donovan, M. C., and Taiwanese Trios Exome Sequencing C
Abstract: Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF
Published: 2015

224. The UK10K project identifies rare variants in health and disease

Author: Walter, K, Min, JL, Huang, J, Crooks, L, Memari, Y, McCarthy, S, Perry, JRB, Xu, C, Futema, M, Lawson, D, Iotchkova, V, Schiffels, S, Hendricks, AE, Danecek, P, Li, R, Floyd, J, Wain, LV, Barroso, I, Humphries, SE, Hurles, ME, Zeggini, E, Barrett, JC, Plagnol, V, Richards, JB, Greenwood, CMT, Timpson, NJ, Durbin, R, Soranzo, N, Bala, S, Clapham, P, Coates, G, Cox, T, Daly, A, Du, Y, Edkins, S, Ellis, P, Flicek, P, Guo, X, Huang, L, Jackson, DK, Joyce, C, Keane, T, Kolb-Kokocinski, A, Langford, C, Li, Y, Liang, J, Lin, H, Liu, R, Maslen, J, Muddyman, D, Quail, MA, Stalker, J, Sun, J, Tian, J, Wang, G, Wang, J, Wang, Y, Wong, K, Zhang, P, Birney, E, Boustred, C, Chen, L, Clement, G, Cocca, M, Smith, GD, Day, INM, Day-Williams, A, Down, T, Dunham, I, Evans, DM, Gaunt, TR, Geihs, M, Hart, D, Howie, B, Hubbard, T, Hysi, P, Jamshidi, Y, Karczewski, KJ, Kemp, JP, Lachance, G, Lek, M, Lopes, M, MacArthur, DG, Marchini, J, Mangino, M, Mathieson, I, Metrustry, S, Moayyeri, A, Northstone, K, Panoutsopoulou, K, Paternoster, L, Quaye, L, Ring, S, Ritchie, GRS, Shihab, HA, Shin, S-Y, Small, KS, Artigas, MS, Southam, L, Spector, TD, St Pourcain, B, Surdulescu, G, Tachmazidou, I, Tobin, MD, Valdes, AM, Visscher, PM, Ward, K, Wilson, SG, Yang, J, Zhang, F, Zheng, H-F, Anney, R, Ayub, M, Blackwood, D, Bolton, PF, Breen, G, Collier, DA, Craddock, N, Curran, S, Curtis, D, Gallagher, L, Geschwind, D, Gurling, H, Holmans, P, Lee, I, Lonnqvist, J, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Morris, J, O'Donovan, MC, Owen, MJ, Palotie, A, Parr, JR, Paunio, T, Pietilainen, O, Rehnstrom, K, Sharp, SI, Skuse, D, St Clair, D, Suvisaari, J, Walters, JTR, Williams, HJ, Bochukova, E, Bounds, R, Dominiczak, A, Farooqi, IS, Keogh, J, Marenne, GL, Morris, A, O'Rahilly, S, Porteous, DJ, Smith, BH, Wheeler, E, Al Turki, S, Anderson, CA, Antony, D, Beales, P, Bentham, J, Bhattacharya, S, Calissano, M, Carss, K, Chatterjee, K, Cirak, S, Cosgrove, C, Fitzpatrick, DR, Foley, AR, Franklin, CS, Grozeva, D, Mitchison, HM, Muntoni, F, Onoufriadis, A, Parker, V, Payne, F, Raymond, FL, Roberts, N, Savage, DB, Scambler, P, Schmidts, M, Schoenmakers, N, Semple, RK, Serra, E, Spasic-Boskovic, O, Stevens, E, van Kogelenberg, M, Vijayarangakannan, P, Williamson, KA, Wilson, C, Whyte, T, Ciampi, A, Oualkacha, K, Bobrow, M, Griffin, H, Kaye, J, Kennedy, K, Kent, A, Smee, C, Charlton, R, Ekong, R, Khawaja, F, Lopes, LR, Migone, N, Payne, SJ, Pollitt, RC, Povey, S, Ridout, CK, Robinson, RL, Scott, RH, Shaw, A, Syrris, P, Taylor, R, Vandersteen, AM, Amuzu, A, Casas, JP, Chambers, JC, Dedoussis, G, Gambaro, G, Gasparini, P, Isaacs, A, Johnson, J, Kleber, ME, Kooner, JS, Langenberg, C, Luan, J, Malerba, G, Maerz, W, Matchan, A, Morris, R, Nordestgaard, BG, Benn, M, Scott, RA, Toniolo, D, Traglia, M, Tybjaerg-Hansen, A, van Duijn, CM, van Leeuwen, EM, Varbo, A, Whincup, P, Zaza, G, Zhang, W, Walter, K, Min, JL, Huang, J, Crooks, L, Memari, Y, McCarthy, S, Perry, JRB, Xu, C, Futema, M, Lawson, D, Iotchkova, V, Schiffels, S, Hendricks, AE, Danecek, P, Li, R, Floyd, J, Wain, LV, Barroso, I, Humphries, SE, Hurles, ME, Zeggini, E, Barrett, JC, Plagnol, V, Richards, JB, Greenwood, CMT, Timpson, NJ, Durbin, R, Soranzo, N, Bala, S, Clapham, P, Coates, G, Cox, T, Daly, A, Du, Y, Edkins, S, Ellis, P, Flicek, P, Guo, X, Huang, L, Jackson, DK, Joyce, C, Keane, T, Kolb-Kokocinski, A, Langford, C, Li, Y, Liang, J, Lin, H, Liu, R, Maslen, J, Muddyman, D, Quail, MA, Stalker, J, Sun, J, Tian, J, Wang, G, Wang, J, Wang, Y, Wong, K, Zhang, P, Birney, E, Boustred, C, Chen, L, Clement, G, Cocca, M, Smith, GD, Day, INM, Day-Williams, A, Down, T, Dunham, I, Evans, DM, Gaunt, TR, Geihs, M, Hart, D, Howie, B, Hubbard, T, Hysi, P, Jamshidi, Y, Karczewski, KJ, Kemp, JP, Lachance, G, Lek, M, Lopes, M, MacArthur, DG, Marchini, J, Mangino, M, Mathieson, I, Metrustry, S, Moayyeri, A, Northstone, K, Panoutsopoulou, K, Paternoster, L, Quaye, L, Ring, S, Ritchie, GRS, Shihab, HA, Shin, S-Y, Small, KS, Artigas, MS, Southam, L, Spector, TD, St Pourcain, B, Surdulescu, G, Tachmazidou, I, Tobin, MD, Valdes, AM, Visscher, PM, Ward, K, Wilson, SG, Yang, J, Zhang, F, Zheng, H-F, Anney, R, Ayub, M, Blackwood, D, Bolton, PF, Breen, G, Collier, DA, Craddock, N, Curran, S, Curtis, D, Gallagher, L, Geschwind, D, Gurling, H, Holmans, P, Lee, I, Lonnqvist, J, McGuffin, P, McIntosh, AM, McKechanie, AG, McQuillin, A, Morris, J, O'Donovan, MC, Owen, MJ, Palotie, A, Parr, JR, Paunio, T, Pietilainen, O, Rehnstrom, K, Sharp, SI, Skuse, D, St Clair, D, Suvisaari, J, Walters, JTR, Williams, HJ, Bochukova, E, Bounds, R, Dominiczak, A, Farooqi, IS, Keogh, J, Marenne, GL, Morris, A, O'Rahilly, S, Porteous, DJ, Smith, BH, Wheeler, E, Al Turki, S, Anderson, CA, Antony, D, Beales, P, Bentham, J, Bhattacharya, S, Calissano, M, Carss, K, Chatterjee, K, Cirak, S, Cosgrove, C, Fitzpatrick, DR, Foley, AR, Franklin, CS, Grozeva, D, Mitchison, HM, Muntoni, F, Onoufriadis, A, Parker, V, Payne, F, Raymond, FL, Roberts, N, Savage, DB, Scambler, P, Schmidts, M, Schoenmakers, N, Semple, RK, Serra, E, Spasic-Boskovic, O, Stevens, E, van Kogelenberg, M, Vijayarangakannan, P, Williamson, KA, Wilson, C, Whyte, T, Ciampi, A, Oualkacha, K, Bobrow, M, Griffin, H, Kaye, J, Kennedy, K, Kent, A, Smee, C, Charlton, R, Ekong, R, Khawaja, F, Lopes, LR, Migone, N, Payne, SJ, Pollitt, RC, Povey, S, Ridout, CK, Robinson, RL, Scott, RH, Shaw, A, Syrris, P, Taylor, R, Vandersteen, AM, Amuzu, A, Casas, JP, Chambers, JC, Dedoussis, G, Gambaro, G, Gasparini, P, Isaacs, A, Johnson, J, Kleber, ME, Kooner, JS, Langenberg, C, Luan, J, Malerba, G, Maerz, W, Matchan, A, Morris, R, Nordestgaard, BG, Benn, M, Scott, RA, Toniolo, D, Traglia, M, Tybjaerg-Hansen, A, van Duijn, CM, van Leeuwen, EM, Varbo, A, Whincup, P, Zaza, G, and Zhang, W
Abstract: The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
Published: 2015

225. Erratum: Common alleles contribute to schizophrenia in CNV carriers

Author: Tansey, K E, primary, Rees, E, additional, Linden, D E, additional, Ripke, S, additional, Chambert, K D, additional, Moran, J L, additional, McCarroll, S A, additional, Holmans, P, additional, Kirov, G, additional, Walters, J, additional, Owen, M J, additional, and O'Donovan, M C, additional
Published: 2015
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226. Altered form of subunit 6 of mitochondrial ATP synthase complex in oligomycin-resistant mutants of Chinese hamster ovary cells

Author: Holmans, Priscilla L. and Breen, Gail A. M.
Published: 1987
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227. TREM2 variants in Alzheimer's disease

Author: Guerreiro, R, Wojtas, A, Bras, J, Carrasquillo, M, Rogaeva, E, Majounie, E, Cruchaga, C, Sassi, C, Kauwe, Js, Lupton, Mk, Ryten, M, Brown, K, Lowe, J, Ridge, Pg, Hammer, Mb, Wakutani, Y, Hazrati, L, Proitsi, P, Newhouse, S, Lohmann, E, Erginel Unaltuna, N, Medway, C, Hanagasi, H, Troakes, C, Gurvit, H, Bilgic, B, Al Sarraj, S, Benitez, B, Cooper, B, Carrell, D, Emre, M, Zou, F, Ma, L, Murray, M, Dickson, D, Younkin, S, Petersen, Rc, Corcoran, Cd, Cai, Y, Oliveira, C, Ribeiro, Mh, Santana, I, Tschanz, Jt, Gibbs, J, Norton, Mc, Kloszewska, I, Mecocci, Patrizia, Soininen, H, Tsolaki, M, Vellas, B, Munger, Rg, Mann, Dm, Pickering Brown, S, Lovestone, S, Beck, J, Mead, S, Collinge, J, Parsons, L, Pocock, J, Morris, Jc, Revesz, T, Lashley, T, Fox, Nc, Rossor, Mn, Grenier Boley, B, Bellenguez, C, Moskvina, V, Sims, R, Harold, D, Williams, J, Lambert, Jc, Amouyel, P, Graff Radford, N, Goate, A, Rademakers, R, Morgan, K, Powell, J, St George Hyslop, P, Singleton, A, Hardy, J, Gerrish, A, Chapman, J, Abraham, R, Hollingworth, P, Hamshere, M, Pahwa, Js, Dowzell, K, Williams, A, Jones, N, Thomas, C, Stretton, A, Morgan, A, Williams, K, Thomas, S, Brayne, C, Rubinsztein, Dc, Gill, M, Lawlor, B, Lynch, A, Passmore, P, Craig, D, Mcguinness, B, Johnston, Ja, Todd, S, Holmes, C, Smith, A, Love, S, Kehoe, Pg, Maier, W, Jessen, F, Heun, R, Kölsch, H, Schürmann, B, Ramirez, A, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Hüll, M, Rujescu, D, Nowotny, P, Mayo, K, Livingston, G, Bass, Nj, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Nöthen, Mm, Holmans, P, O'Donovan, M, Owen, Mj, Zelenika, D, Epelbaum, J, Dartigues, Jf, Tzourio, C, Berr, C, Boland, A, Campion, D, Alpérovitch, A, Lathrop, M, Smith, C, Trabzuni, D, Walker, R, Weale, M., Wiltfang, J. (Beitragende*r), EADI Consortium, GERAD Consortium, UKBE Consortium, and Alzheimer Genetic Anal Grp
Subjects: Genetics, TREM2, SORL1, Medizin, Genome-wide association study, General Medicine, Biology, medicine.disease, PSEN2, medicine, Dementia, Human medicine, Alzheimer's disease, Exome, Common disease-common variant
Abstract: BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P
Published: 2013

228. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Author: Ripke, S, O'Dushlaine, C, Chambert, K, Moran, Jl, Kähler, Ak, Akterin, S, Bergen, Se, Collins, Al, Crowley, Jj, Fromer, M, Kim, Y, Lee, Sh, Magnusson, Pk, Sanchez, N, Stahl, Ea, Williams, S, Wray, Nr, Xia, K, Bettella, F, Borglum, Ad, Bulik Sullivan, Bk, Cormican, P, Craddock, N, Leeuw, De, C, Durmishi, N, Gill, M, Golimbet, V, Hamshere, Ml, Holmans, P, Hougaard, Dm, Kendler, Ks, Lin, K, Morris, Dw, Mors, O, Mortensen, Pb, Neale, Bm, O'Neill, Fa, Owen, Mj, Milovancevic, Mp, Posthuma, D, Powell, J, Richards, Al, Riley, Bp, Ruderfer, D, Rujescu, D, Sigurdsson, E, Silagadze, T, Smit, Ab, Stefansson, H, Steinberg, S, Suvisaari, J, Tosato, Sarah, Verhage, M, Walters, Jt, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, Df, Gejman, Pv, Laurent, C, Mowry, Bj, O'Donovan, Mc, Pulver, Ae, Schwab, Sg, Wildenauer, Db, Dudbridge, F, Shi, J, Albus, M, Alexander, M, Campion, D, Cohen, D, Dikeos, D, Duan, J, Eichhammer, P, Godard, S, Hansen, M, Lerer, Fb, Liang, Ky, Maier, W, Mallet, J, Nertney, Da, Nestadt, G, Norton, N, Papadimitriou, Gn, Ribble, R, Sanders, Ar, Silverman, Jm, Walsh, D, Williams, Nm, Wormley, B, Psychosis Endophenotypes International Consortium, Arranz, Mj, Bakker, S, Bender, S, Bramon, E, Collier, D, Crespo Facorro, B, Hall, J, Iyegbe, C, Jablensky, A, Kahn, Rs, Kalaydjieva, L, Lawrie, S, Lewis, Cm, Linszen, Dh, Mata, I, Mcintosh, A, Murray, Rm, Ophoff, Ra, Van, Os, J, Walshe, M, Weisbrod, M, Wiersma, D, Wellcome Trust Case Control Consortium 2, Donnelly, P, Barroso, I, Blackwell, Jm, Brown, Ma, Casas, Jp, Corvin, Ap, Deloukas, P, Duncanson, A, Jankowski, J, Markus, Hs, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, Rd, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Tashakkori Ghanbaria, A, Waller, Mj, Weston, P, Widaa, S, Whittaker, P, Mccarthy, Mi, Stefansson, K, Scolnick, E, Purcell, S, Mccarroll, Sa, Sklar, P, Hultman, Cm, Sullivan, P. F., Functional Genomics, Molecular and Cellular Neurobiology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Adult Psychiatry, Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Lee, Sang Hong, Sullivan, Patrick F, Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA deCODE Genet, Reykjavik, Iceland Aarhus Univ Hosp, Risskov, Denmark Aarhus Univ, Ctr Integrat Sequencing iSEQ, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Copenhagen, Denmark Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland Cardiff Univ, Sch Med, Ctr Psychiat Genet & Genom, MRC, Cardiff CF10 3AX, S Glam, Wales Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje, Macedonia Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Dublin 2, Ireland Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia Statens Serum Inst, DK-2300 Copenhagen, Denmark Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA Kings Coll London, Inst Psychiat, London, England Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark Aarhus Univ, Natl Ctr Register Based Res, Aarhus, DenmarkQueens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Belgrade, Fac Med, Belgrade, Serbia Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands Kings Coll London, Dept Neurosci, London, England Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA Univ Halle, Dept Psychiat, Halle, Germany Univ Munich, Dept Psychiat, D-80539 Munich, Germany Univ Iceland, Dept Psychiat, Reykjavik, Iceland Landspitali University Hospital Reykjavik, Iceland Tbilisi State Univ, Dept Psychiat, GE-380086 Tbilisi, Rep of Georgia Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Amsterdam, Netherlands Vrije Univ Amsterdam, Dept Mol & Cellular Neurosci, Amsterdam, Netherlands Natl Inst Hlth & Welf, Mental Hlth & Subst Abuse Serv, Helsinki, Finland Univ Verona, Sect Psychiat, I-37100 Verona, Italy UCL, Inst Cognit Neurosci, London, England UCL, Mental Hlth Sci Unit, London, England Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA Harvard Univ, Sch Med, Dept Genet, Boston, MA USA, Child and Adolescent Psychiatry / Psychology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Human genetics, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health
Subjects: Male, Candidate gene, SNP, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, heritability, neuronal calcium signaling, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, GWAS, Genetic Predisposition to Disease, Bipolar disorder, 030304 developmental biology, Genetic association, Sweden, Genetics & Heredity, 0303 health sciences, medicine.disease, 3. Good health, genome sequencing, schizophrenia, Schizophrenia, Meta-analysis, Case-Control Studies, genetic variation, Female, genome-wide scan, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder. NIMH R01 MH077139 R01 MH095034 Stanley Center for Psychiatric Research Sylvan Herman Foundation Friedman Brain Institute at the Mount Sinai School of Medicine Karolinska Institutet, Karolinska University Hospital Swedish Research Council Swedish County Council Soderstrom Konigska Foundation Netherlands Scientific Organization NWO 645-000-003 info:eu-repo/grantAgreement/EC/FP7/223423 Danish Strategic Research Council H. Lundbeck A/S Faculty of Health Sciences at Aarhus University Lundbeck Foundation Stanley Research Foundation Wellcome Trust 085475/B/08/Z 085475/Z/08/Z
Published: 2013
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229. Association Between Schizophrenia-Related Polygenic Liability and the Occurrence and Level of Mood-Incongruent Psychotic Symptoms in Bipolar Disorder.

Author: Allardyce, Judith, Leonenko, Ganna, Hamshere, Marian, Pardiñas, Antonio F., Forty, Liz, Knott, Sarah, Gordon-Smith, Katherine, Porteous, David J., Haywood, Caroline, Di Florio, Arianna, Jones, Lisa, McIntosh, Andrew M., Owen, Michael J., Holmans, Peter, Walters, James T. R., Craddock, Nicholas, Jones, Ian, O’Donovan, Michael C., Escott-Price, Valentina, and Pardiñas, Antonio F
Subjects: BIPOLAR disorder, SCHIZOPHRENIA, PSYCHOSES, MOOD (Psychology), MONOGENIC & polygenic inheritance (Genetics)
Abstract: Importance: Bipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes and mechanisms.Objective: To investigate the association between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRSs), and psychotic presentations of BD.Design, Setting, and Participants: This case-control study in the United Kingdom used multinomial logistic regression to estimate differential PRS associations across categories of cases and controls. Participants included in the final analyses were 4436 cases of BD from the Bipolar Disorder Research Network. These cases were compared with the genotypic data for 4976 cases of schizophrenia and 9012 controls from the Type 1 Diabetes Genetics Consortium study and the Generation Scotland study. Data were collected between January 1, 2000, and December 31, 2013. Data analysis was conducted from March 1, 2016, to February 28, 2017.Exposures: Standardized PRSs, calculated using alleles with an association threshold of P < .05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, were adjusted for the first 10 population principal components and genotyping platforms.Main Outcomes and Measures: Multinomial logit models estimated PRS associations with BD stratified by Research Diagnostic Criteria subtypes of BD, by lifetime occurrence of psychosis, and by lifetime mood-incongruent psychotic features. Ordinal logistic regression examined PRS associations across levels of mood incongruence. Ratings were derived from the Schedules for Clinical Assessment in Neuropsychiatry interview and the Bipolar Affective Disorder Dimension Scale.Results: Of the 4436 cases of BD, 2966 (67%) were female patients, and the mean (SD) age at interview was 46 [12] years. Across clinical phenotypes, there was an exposure-response gradient, with the strongest PRS association for schizophrenia (risk ratio [RR] = 1.94; 95% CI, 1.86-2.01), followed by schizoaffective BD (RR = 1.37; 95% CI, 1.22-1.54), bipolar I disorder subtype (RR = 1.30; 95% CI, 1.24-1.36), and bipolar II disorder subtype (RR = 1.04; 95% CI, 0.97-1.11). Within BD cases, there was an effect gradient, indexed by the nature of psychosis. Prominent mood-incongruent psychotic features had the strongest association (RR = 1.46; 95% CI, 1.36-1.57), followed by mood-congruent psychosis (RR = 1.24; 95% CI, 1.17-1.33) and BD with no history of psychosis (RR = 1.09; 95% CI, 1.04-1.15).Conclusions and Relevance: For the first time to date, a study shows a polygenic-risk gradient across schizophrenia and BD, indexed by the occurrence and level of mood-incongruent psychotic symptoms. [ABSTRACT FROM AUTHOR]
Published: 2018
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230. Genotype–phenotype associations in children with copy number variants associated with high neuropsychiatric risk in the UK (IMAGINE-ID): a case-control cohort study

Author: Chawner, Samuel J R A, Owen, Michael J, Holmans, Peter, Raymond, F Lucy, Skuse, David, Hall, Jeremy, and van den Bree, Marianne B M
Abstract: Several copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (referred to as ND-CNVs). We aimed to characterise the effect of ND-CNVs on childhood development and investigate whether different ND-CNVs lead to distinct and specific patterns of cognitive and behavioural outcomes.
Published: 2019
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231. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author: Kunkle, Brian W., Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C., Damotte, Vincent, Naj, Adam C., Boland, Anne, Vronskaya, Maria, van der Lee, Sven J., Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R., Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L., Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B., Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N., Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W., Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L., Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V., Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C., Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T., Adams, Hieab H., Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A., Dombroski, Beth A., Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B., Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S., Meslage, Stéphane, Kornhuber, Johannes, White, Charles C., Song, Yuenjoo, Barber, Robert C., Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M., Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L. Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujić-Čomić, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roshchupkin, Gennady, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernández, Isabel, Kamboh, M. Ilyas, Brundin, RoseMarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluís, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, W. T., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome I., Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Andre Uitterlinden, A. G., Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, George-Hyslop, Peter St, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Inés, Carracedo, Ángel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Frölich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Kölsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Hüll, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Jöckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan I., Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Nöthen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O’Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossù, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stéphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, C. O’Donovan, Michael, DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.
Abstract: Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1,and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P= 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Published: 2019
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232. Predictive modeling of schizophrenia from genomic data: Comparison of polygenic risk score with kernel support vector machines approach

Author: Vivian‐Griffiths, Timothy, Baker, Emily, Schmidt, Karl M., Bracher‐Smith, Matthew, Walters, James, Artemiou, Andreas, Holmans, Peter, O'Donovan, Michael C., Owen, Michael J., Pocklington, Andrew, and Escott‐Price, Valentina
Abstract: A major controversy in psychiatric genetics is whether nonadditive genetic interaction effects contribute to the risk of highly polygenic disorders. We applied a support vector machines (SVMs) approach, which is capable of building linear and nonlinear models using kernel methods, to classify cases from controls in a large schizophrenia case–control sample of 11,853 subjects (5,554 cases and 6,299 controls) and compared its prediction accuracy with the polygenic risk score (PRS) approach. We also investigated whether SVMs are a suitable approach to detecting nonlinear genetic effects, that is, interactions. We found that PRS provided more accurate case/control classification than either linear or nonlinear SVMs, and give a tentative explanation why PRS outperforms both multivariate regression and linear kernel SVMs. In addition, we observe that nonlinear kernel SVMs showed higher classification accuracy than linear SVMs when a large number of SNPs are entered into the model. We conclude that SVMs are a potential tool for assessing the presence of interactions, prior to searching for them explicitly.
Published: 2019
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233. Genome-wide association study of Alzheimer's disease with psychotic symptoms

Author: Hollingworth, P., Sweet, R., Sims, R., Harold, D., Russo, G., Abraham, R., Stretton, A., Jones, N., Gerrish, A., Chapman, J., Ivanov, D., Moskvina, V., Lovestone, S., Priotsi, P., Lupton, M., Brayne, C., Gill, M., Lawlor, B., Lynch, A., Craig, D., McGuinness, B., Johnston, J., Holmes, C., Livingston, G., Bass, N. J., Gurling, H., McQuillin, A., GERAD Consortium, National Institute on Aging Late-Onset Alzheimer's Disease Family Study Group, Holmans, P., Devlin, B., Klei, L., Barmada, M. M., Demirci, F. Y., DeKosky, S. T., Lopez, O. L., Passmore, P., Owen, M. J., O'Donovan, M. C., Mayeux, R., Kamboh, M. I., Williams, J., Wiltfang, J. (Beitragende*r), Moebus, Susanne (Beitragende*r), and Jöckel, Karl-Heinz (Beitragende*r)
Subjects: Medizin
Published: 2012

234. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3

Author: Williams, NM, Franke, B, Mick, E, Anney, RJL, Freitag, CM, Gill, M, Thapar, A, O'Donovan, MC, Owen, MJ, Holmans, P, Kent, L, Middleton, F, Zhang-James, Y, Liu, L, Meyer, J, Nguyen, TT, Romanos, J, Romanos, M, Seitz, C, Renner, TJ, Walitza, S, Warnke, A, Palmason, H, Buitelaar, J, Rommelse, N, Vasquez, AA, Hawi, Z, Langley, K, Sergeant, J, Steinhausen, HC, Roeyers, Herbert, Biederman, J, Zaharieva, I, Hakonarson, H, Elia, J, Lionel, AC, Crosbie, J, Marshall, CR, Schachar, R, Scherer, SW, Todorov, A, Smalley, SL, Loo, S, Nelson, S, Shtir, C, Asherson, P, Reif, A, Lesch, KP, Faraone, SV, Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, and RS: CARIM School for Cardiovascular Diseases
Subjects: CANDIDATE GENE, Canada, Adolescent, alpha7 Nicotinic Acetylcholine Receptor, Genetics and epigenetic pathways of disease [NCMLS 6], DCN MP - Plasticity and memory, Gene Dosage, Inheritance Patterns, Social Sciences, ASSOCIATION SCAN, DCN PAC - Perception action and control, Nicotinic, MICRODUPLICATIONS, Medical and Health Sciences, Mental health [NCEBP 9], Fluorescence, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], MOLECULAR-GENETICS, SCHIZOPHRENIA, Receptors, mental disorders, ADHD, Humans, Genetic Predisposition to Disease, DCN PAC - Perception action and control NCEBP 9 - Mental health, Polymorphism, Child, Preschool, QH426, CHROMOSOMAL DELETIONS, In Situ Hybridization, Psychiatry, AUTISM SPECTRUM DISORDER, Psychology and Cognitive Sciences, Single Nucleotide, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], R1, United States, United Kingdom, NICOTINIC RECEPTOR, Causality, Segmental Duplications, Attention Deficit Disorder with Hyperactivity, Genomic, RC0321, Female, DEFICIT/HYPERACTIVITY DISORDER, Genome-Wide Association Study
Abstract: Item does not contain fulltext OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. METHOD: The authors performed a genome-wide analysis of large, rare CNVs (100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. CONCLUSIONS: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5-3.6), this locus could be an important contributor to ADHD etiology. 01 februari 2012
Published: 2012
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235. Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD

Author: Stergiakouli, E., Hamshere, M., Holmans, P., Langley, K., Zaharieva, I., Hawi, Z., Kent, L., Gill, M., Williams, N., Owen, M.J., O'Donovan, M., Thapar, A., Franke, B., Buitelaar, J.K., Arias Vasquez, A., and Sergeant, J.A.
Subjects: DCN MP - Plasticity and memory, mental disorders, DCN PAC - Perception action and control, DCN PAC - Perception action and control NCEBP 9 - Mental health, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3]
Abstract: Item does not contain fulltext OBJECTIVE: A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs. METHOD: The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD. RESULTS: No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. CONCLUSIONS: Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways. 01 februari 2012
Published: 2012

236. Genome-wide association of mood-incongruent psychotic bipolar disorder

Author: Goes, F.S., Hamshere, M.L., Holmans, P., Zandi, P.P., Bipolar Genome Study (BiGS), Craddock, N., Potash, J.B., Seiuddin, F., Pirooznia, M., Belmonte-Mahon, P., Breuer, R., Schulze, T., Nöthen, M., Cichon, S., and Rietschel, M.
Subjects: SNAP91, Nerve Tissue Proteins, Genome-wide association study, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, psychosis, Bipolar disorder, ddc:610, Antigens, Gene, Biological Psychiatry, 030304 developmental biology, bipolar disorder, Chromosomes, Human, Pair 14, Genetics, 0303 health sciences, genome-wide association study, Membrane Proteins, TRANK1, medicine.disease, Phenotype, schizophrenia, Psychiatry and Mental health, Polygene, Schizophrenia, Case-Control Studies, Monomeric Clathrin Assembly Proteins, Behavioral medicine, Etiology, Original Article, Chromosomes, Human, Pair 6, Chromosomes, Human, Pair 3, Serine Proteases, 030217 neurology & neurosurgery
Abstract: Mood-incongruent psychotic features (MICP) are familial symptoms of bipolar disorder (BP) that also occur in schizophrenia (SZ), and may represent manifestations of shared etiology between the major psychoses. In this study we have analyzed three large samples of BP with imputed genome-wide association data and have performed a meta-analysis of 2196 cases with MICP and 8148 controls. We found several regions with suggestive evidence of association (P
Published: 2012
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237. Genome-wide Association Study Of Recurrent Early-onset Major Depressive Disorder

Author: Shi, J, Potash, J B, Knowles, J A, Weissman, Myrna M., Coryell, W, Scheftner, W A, Lawson, W B, DePaulo, J R, Gejman, P V, Sanders, A R, Johnson, J K, Adams, P, Chaudhury, S, Jancic, D, Evgrafov, O, Zvinyatskovskiy, A, Ertman, N, Gladis, M, Neimanas, K, Goodell, M, Hale, N, Ney, N, Verma, R, Mirel, D, Holmans, P, and Levinson, D F
Published: 2011
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238. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

Author: Sullivan, P, Lencz, T, Kendler, K S, Williams, H J, Corvin, A, Nimgaonkar, V L, Ikeda, M, Morris, D W, Nikolov, I, Purcell, S, Maher, B S, Norton, N, Wood, J, Sklar, P, Hultman, C, Moskvina, V, Gill, M, Thiselton, D, Quinn, E M, Kirov, G, Owen, M J, Riley, B, Malhotra, A K, Holmans, P, Giegling, I, Dwyer, S, Rujescu, D, Carroll, L, Lichtenstein, P, Craddock, N, Williams, N M, and Georgieva, L
Subjects: mental disorders
Abstract: A recent genome wide association study reported evidence for association between rs1344706 within ZNF804A (encoding zinc finger protein 804A) and schizophrenia (P=1.61 ×10−7), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 ×10−9). Here we provide additional evidence for association through meta-analysis of a larger dataset (schizophrenia/schizoaffective disorder N = 18945, schizophrenia plus bipolar disorder N =21274, controls N =38675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high density LD mapping. Meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 ×10−11, OR=1.10, 95% CI 1.07–1.14) and schizophrenia and bipolar disorder combined (P=4.1 ×10−13, OR=1.11, 95% CI 1.07–1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.
Published: 2011
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239. Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder

Author: Williams, H.J., Norton, N., Dwyer, S., Moskvina, V., Nikolov, I., Carroll, L., Georgieva, L., Williams, N.M., Morris, D.W., Quinn, E.M., Giegling, I., Ikeda, M., Wood, J., Lencz, T., Hultman, C., Lichtenstein, P., Thiselton, D., Maher, B.S., Malhotra, A.K., Riley, B., Kendler, K.S., Gill, M., Sullivan, P., Sklar, P., Purcell, S., Nimgaonkar, V.L., Kirov, G., Holmans, P., Corvin, A., Rujescu, D., Craddock, N., Owen, M.J., O'Donovan, M.C., GROUP investigators, [No Value], and Science in Healthy Ageing & healthcaRE (SHARE)
Subjects: mental disorders
Abstract: A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P = 1.61 x 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P = 9.96 x 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N = 18 945, schizophrenia plus bipolar disorder N = 21 274 and controls N = 38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P = 2.5 x 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P = 4.1 x 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder. Molecular Psychiatry (2011) 16, 429-441; doi:10.1038/mp.2010.36; published online 6 April 2010
Published: 2011

240. Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Author: Jones, L, Holmans, P, Hamshere, M, Harold, D, Moskvina, V, Ivanov, D, Pocklington, A, Abraham, R, Hollingworth, P, Sims, R, Gerrish, A, Pahwa, J, Jones, N, Stretton, A, Morgan, A, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Morgan, K, Brown, K, Passmore, P, Craig, D, McGuinness, B, Todd, S, Holmes, C, Mann, D, Smith, D, Love, S, Kehoe, P, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Peters, O, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Hüll, M, Rujescu, D, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Livingston, G, Bass, N, Gurling, H, McQuillin, A, Gwilliam, R, Deloukas, P, Al-Chalabi, A, Shaw, C, Singleton, AB, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Rüther, E, Carrasquillo, M, Pankratz, V, Younkin, S, Hardy, J, O'Donovan, M, Owen, M, Williams, J, Neurology, NCA - Neurodegeneration, and El Khoury, Joseph
Subjects: Apolipoprotein E, endocrine system diseases, Medizin, Genome-wide association study, Disease, Bioinformatics, 0302 clinical medicine, Genetics and Genomics/Genetics of Disease, Genetic Evidence, Immune System, Cholesterol Metabolism, Aetiology, Alzheimer’s Disease, Medicine(all), 0303 health sciences, education.field_of_study, Multidisciplinary, Agricultural and Biological Sciences(all), Chromosome Mapping, Genetics and Genomics/Bioinformatics, 3. Good health, Cholesterol, Medicine, Alzheimer's disease, Neurological Disorders/Alzheimer Disease, Research Article, musculoskeletal diseases, Science, Population, Single-nucleotide polymorphism, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Apolipoproteins E, Alzheimer Disease, medicine, Humans, Dementia, Genetic Predisposition to Disease, education, 030304 developmental biology, Genetic association, GENOME-WIDE ASSOCIATION, IDENTIFIES VARIANTS, APOLIPOPROTEIN-E, DEMENTIA, RISK, BETA, INFLAMMATION, POPULATION, MICROGLIA, PATHWAYS, Genome, Human, Biochemistry, Genetics and Molecular Biology(all), nutritional and metabolic diseases, medicine.disease, R1, RC0321, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BackgroundLate Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.MethodologyWe applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.Principal FindingsWe found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.SignificanceProcesses related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
Published: 2010
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241. Common alleles contribute to schizophrenia in CNV carriers

Author: Tansey, K E, primary, Rees, E, additional, Linden, D E, additional, Ripke, S, additional, Chambert, K D, additional, Moran, J L, additional, McCarroll, S A, additional, Holmans, P, additional, Kirov, G, additional, Walters, J, additional, Owen, M J, additional, and O'Donovan, M C, additional
Published: 2015
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242. Fine mapping of ZNF804A and genome wide significant evidence for its involvement in schizophrenia and bipolar disorder

Author: Williams, H.J., Norton, N., Dwyer, S., Moskivina, V., Nikolov, I., Carroll, L., Georgieva, L., Williams, N.M., Morris, D.W., Quinn, E.M., Giegling, I., Ikeda, M., Wood, J., Lencz, T., Hultman, C., Lichtenstein, P., Thiselton, D., Mahler, B.S., Bruggeman, R., Cahn, W., de Haan, L., Kahn, R., Krabbendam, L., Linzen, D., Myin-Germeys, I., van Os, J, Wiersma, D., Malhotra, A.K., Riley, B., Kendler, K.S., Gill, M., Sklar, P., Purcell, S., Nimgaonkar, V.L., Kirov, G., Holmans, P., Corvin, A., Rujescu, D., Craddock, N., Educational Neuroscience, Clinical Child and Family Studies, LEARN! - Brain, learning and development, ANS - Amsterdam Neuroscience, Adult Psychiatry, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: Adult, Male, Linkage disequilibrium, Bipolar Disorder, Genotype, Quantitative Trait Loci, Kruppel-Like Transcription Factors, Schizoaffective disorder, Genome-wide association study, Locus (genetics), Bioinformatics, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Gene Frequency, Meta-Analysis as Topic, mental disorders, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, Bipolar disorder, Allele, Molecular Biology, 030304 developmental biology, Genetic association, Aged, Genetics, 0303 health sciences, biology, association, Chromosome Mapping, Exons, Middle Aged, medicine.disease, meta-analysis, Europe, Psychiatry and Mental health, biology.protein, Schizophrenia, Female, 030217 neurology & neurosurgery, Zinc finger protein 804A, ZNF804A, Genome-Wide Association Study
Abstract: A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 ? 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 ? 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18?945, schizophrenia plus bipolar disorder N=21?274 and controls N=38?675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 ? 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 ? 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.
Published: 2010
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243. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Author: Escott-Price, V, Bellenguez, C, Wang, LS, Choi, SH, Harold, D, Jones, L, Holmans, P, Gerrish, A, Vedernikov, A, Richards, A, DeStefano, AL, Lambert, JC, Ibrahim-Verbaas, CA, Naj, AC, Sims, R, Jun, G, Bis, JC, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Denning, N, Smith, AV, Chouraki, V, Thomas, C, Arfan Ikram, M, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Schmidt, H, Kunkle, B, Dunstan, ML, Vronskaya, M, Johnson, AD, Ruiz, A, Bihoreau, MT, Reitz, C, Pasquier, F, Hollingworth, P, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Becker, CBT, Gudnason, V, Cruchaga, C, Craig, D, Amin, N, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letenneur, L, Hernández, I, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K, Goate, AM, Fiévet, N, Huentelman, MJ, Gill, M, Brown, K, Kamboh, MI, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleo, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossù, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Sanchez Garcia, F, Fox, NC, Hardy, J, Naranjo, MCD, Bosco, P, Clarke, R, Brayne, C, Galimberti, D, Scarpini, E, Escott-Price, V, Bellenguez, C, Wang, LS, Choi, SH, Harold, D, Jones, L, Holmans, P, Gerrish, A, Vedernikov, A, Richards, A, DeStefano, AL, Lambert, JC, Ibrahim-Verbaas, CA, Naj, AC, Sims, R, Jun, G, Bis, JC, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Denning, N, Smith, AV, Chouraki, V, Thomas, C, Arfan Ikram, M, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Schmidt, H, Kunkle, B, Dunstan, ML, Vronskaya, M, Johnson, AD, Ruiz, A, Bihoreau, MT, Reitz, C, Pasquier, F, Hollingworth, P, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Becker, CBT, Gudnason, V, Cruchaga, C, Craig, D, Amin, N, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letenneur, L, Hernández, I, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K, Goate, AM, Fiévet, N, Huentelman, MJ, Gill, M, Brown, K, Kamboh, MI, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleo, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossù, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Sanchez Garcia, F, Fox, NC, Hardy, J, Naranjo, MCD, Bosco, P, Clarke, R, Brayne, C, Galimberti, D, and Scarpini, E
Abstract: Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Published: 2014

244. Increased expression of the dnaA gene has no effect on DNA replication in a dnaA + strain of Escherichia coli

Author: Churchward, G., Holmans, P., and Bremer, H.
Published: 1983
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245. Genetic variants of uncertain significance (VUS) in familial hypercholesterolaemia (FH): Can family based association studies help determine pathogenicity?

Author: Haralambos, K., primary, Whatley, S.D., additional, Edwards, R., additional, Gingell, R., additional, Townsend, D., additional, Holmans, P., additional, Clarke, A., additional, Datta, B.N., additional, and McDowell, I.F.W., additional
Published: 2014
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246. High loading of polygenic risk for ADHD in children with comorbid aggression

Author: Hamshere, M.L., Langley, K., Martin, J., Agha, S.S., Stergiakouli, E., Anney, R.J., Buitelaar, J.K., Faraone, S.V., Lesch, K.P., Neale, B.M., Franke, B., Sonuga-Barke, E., Asherson, P., Merwood, A., Kuntsi, J., Medland, S.E., Ripke, S., Steinhausen, H.C., Freitag, C., Reif, A., Renner, T.J., Romanos, M., Romanos, J., Warnke, A., Meyer, J., Palmason, H., Vasquez, A.A., Lambregts-Rommelse, N.N.J., Roeyers, H., Biederman, J., Doyle, A.E., Hakonarson, H., Rothenberger, A., Banaschewski, T., Oades, R.D., McGough, J.J., Kent, L., Williams, N., Owen, M.J., Holmans, P., O'Donovan, M.C., Thapar, A., Hamshere, M.L., Langley, K., Martin, J., Agha, S.S., Stergiakouli, E., Anney, R.J., Buitelaar, J.K., Faraone, S.V., Lesch, K.P., Neale, B.M., Franke, B., Sonuga-Barke, E., Asherson, P., Merwood, A., Kuntsi, J., Medland, S.E., Ripke, S., Steinhausen, H.C., Freitag, C., Reif, A., Renner, T.J., Romanos, M., Romanos, J., Warnke, A., Meyer, J., Palmason, H., Vasquez, A.A., Lambregts-Rommelse, N.N.J., Roeyers, H., Biederman, J., Doyle, A.E., Hakonarson, H., Rothenberger, A., Banaschewski, T., Oades, R.D., McGough, J.J., Kent, L., Williams, N., Owen, M.J., Holmans, P., O'Donovan, M.C., and Thapar, A.
Abstract: Contains fulltext : 155657.pdf (publisher's version ) (Closed access), OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.
Published: 2013

247. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease

Author: Holmans, P., Moskvina, V., Jones, L., Sharma, M., Vedernikov, A., Buchel, F., Sadd, M., Bras, J.M., Bettella, F., Nicolaou, N., Simon-Sanchez, J., Mittag, F., Gibbs, J.R., Schulte, C., Durr, A., Guerreiro, R., Hernandez, D., Brice, A., Stefansson, H., Majamaa, K., Gasser, T., Heutink, P., Wood, N.W., Martinez, M., Singleton, A.B., Nalls, M.A., Hardy, J., Morris, H.R., Williams, N.M., Bloem, B., Post, B., Warrenburg, B.P.C. van de, Ravina, B., Shoulson, I., et al., Holmans, P., Moskvina, V., Jones, L., Sharma, M., Vedernikov, A., Buchel, F., Sadd, M., Bras, J.M., Bettella, F., Nicolaou, N., Simon-Sanchez, J., Mittag, F., Gibbs, J.R., Schulte, C., Durr, A., Guerreiro, R., Hernandez, D., Brice, A., Stefansson, H., Majamaa, K., Gasser, T., Heutink, P., Wood, N.W., Martinez, M., Singleton, A.B., Nalls, M.A., Hardy, J., Morris, H.R., Williams, N.M., Bloem, B., Post, B., Warrenburg, B.P.C. van de, Ravina, B., Shoulson, I., and et al.
Abstract: Item does not contain fulltext, Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 x 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
Published: 2013

248. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

Author: Hamshere, M L, Walters, J T R, Smith, R, Richards, Alan, Green, E, Grozeva, D, Jones, Ian, Forty, L, Jones, Leigh Robert, Gordon-Smith, K, Riley, B, O'Neill, T, Kendler, K S, Sklar, P, Purcell, S, Kranz, J, Morris, David Jackson, Gill, M, Holmans, P, Craddock, N, Corvin, A, Owen, M J, O'Donovan, M C, Hansen, Thomas, Olsen, Line, Ingason, Andrés, Schmock, Henriette, Skjødt, Celina, Rosengren, Anders, Høffding, Louise.K.Enggaard, Thygesen, Johan Hilge, Werge, Thomas Mears, Hamshere, M L, Walters, J T R, Smith, R, Richards, Alan, Green, E, Grozeva, D, Jones, Ian, Forty, L, Jones, Leigh Robert, Gordon-Smith, K, Riley, B, O'Neill, T, Kendler, K S, Sklar, P, Purcell, S, Kranz, J, Morris, David Jackson, Gill, M, Holmans, P, Craddock, N, Corvin, A, Owen, M J, O'Donovan, M C, Hansen, Thomas, Olsen, Line, Ingason, Andrés, Schmock, Henriette, Skjødt, Celina, Rosengren, Anders, Høffding, Louise.K.Enggaard, Thygesen, Johan Hilge, and Werge, Thomas Mears
Abstract: The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.Molecular Psychiatry advance online publication, 22 May 2012; doi:10.1038/mp.2012.67.
Published: 2013

249. Association of Elevated Urinary miR-126, miR-155, and miR-29b with Diabetic Kidney Disease

Author: Beltrami, Cristina, Simpson, Kate, Jesky, Mark, Wonnacott, Alexa, Carrington, Christopher, Holmans, Peter, Newbury, Lucy, Jenkins, Robert, Ashdown, Thomas, Dayan, Colin, Satchell, Simon, Corish, Peter, Cockwell, Paul, Fraser, Donald, and Bowen, Timothy
Abstract: Effective diabetic kidney disease (DKD) biomarkers remain elusive, and urinary miRNAs represent a potential source of novel noninvasive disease sentinels. We profiled 754 miRNAs in pooled urine samples from DKD patients (n = 20), detecting significantly increased miR-126, miR-155, and miR-29b compared with controls (n = 20). These results were confirmed in an independent cohort of 89 DKD patients, 62 diabetic patients without DKD, and 41 controls: miR-126 (2.8-fold increase; P< 0.0001), miR-155 (1.8-fold increase; P < 0.001), and miR-29b (4.6-fold increase; P = 0.024). Combined receiver operating characteristic curve analysis resulted in an area under the curve of 0.8. A relative quantification threshold equivalent to 80% sensitivity for each miRNA gave a positive signal for 48% of DKD patients compared with 3.6% of diabetic patients without DKD. Laser-capture microdissection of renal biopsy specimens, followed by quantitative RT-PCR, detected miR-155 in glomeruli and proximal and distal tubules, whereas miR-126 and miR-29b were most abundant in glomerular extracts. Subsequent experiments showed miR-126 and miR-29b enrichment in glomerular endothelial cells (GEnCs) compared with podocytes, proximal tubular epithelial cells, and fibroblasts. Significantly increased miR-126 and miR-29b were detected in GEnC conditioned medium in response to tumor necrosis factor-α and transforming growth factor-β1, respectively. Our data reveal an altered urinary miRNA profile associated with DKD and link these variations to miRNA release from GEnCs.
Published: 2018
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250. Reduced Cancer Incidence in Huntington’s Disease: Analysis in the Registry Study

Author: McNulty, Paul, Pilcher, Richard, Ramesh, Raviram, Necuiniate, Renata, Hughes, Alis, Farewell, Daniel, Holmans, Peter, and Jones, Lesley
Abstract: People with Huntington’s disease (HD) have been observed to have lower rates of cancers. To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Data were obtained from the European Huntington’s disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22–0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis.
Published: 2018
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