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101. TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome

Author: Forde, J.N., Kanaan, A.S., Widomska, J.M., Padmanabhuni, S.S., Nespoli, E., Alexander, J., Rodriguez Arranz, J.I., Fan, S., Houssari, R., Nawaz, M.S., Rizzo, F., Pagliaroli, L., Zilhao, N.R., Aranyi, T., Barta, C., Boeckers, T.M., Boomsma, D.I., Buisman, W.R., Buitelaar, J.K., Cath, D., Dietrich, A., Driessen, N., Drineas, P., Dunlap, M., Gerasch, S., Glennon, J.C., Hengerer, B., Heuvel, O.A. van den, Jespersgaard, C., Moller, H.E., Muller-Vahl, K.R., Openneer, T.J., Poelmans, G.J.V., Pouwels, P.J., Scharf, J.M., Stefansson, H., Tumer, Z., Veltman, D.J., Werf, Y.D. van der, Hoekstra, P.J., Ludolph, A., Paschou, P., Forde, J.N., Kanaan, A.S., Widomska, J.M., Padmanabhuni, S.S., Nespoli, E., Alexander, J., Rodriguez Arranz, J.I., Fan, S., Houssari, R., Nawaz, M.S., Rizzo, F., Pagliaroli, L., Zilhao, N.R., Aranyi, T., Barta, C., Boeckers, T.M., Boomsma, D.I., Buisman, W.R., Buitelaar, J.K., Cath, D., Dietrich, A., Driessen, N., Drineas, P., Dunlap, M., Gerasch, S., Glennon, J.C., Hengerer, B., Heuvel, O.A. van den, Jespersgaard, C., Moller, H.E., Muller-Vahl, K.R., Openneer, T.J., Poelmans, G.J.V., Pouwels, P.J., Scharf, J.M., Stefansson, H., Tumer, Z., Veltman, D.J., Werf, Y.D. van der, Hoekstra, P.J., Ludolph, A., and Paschou, P.
Abstract: Contains fulltext : 168171.pdf (publisher's version ) (Open Access), Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network (http://ts-eurotrain.eu) that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders.
Published: 2016

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

Author: Bertelsen, B., Stefansson, H., Jensen, L., Melchior, L., Debes, N. Mol, Groth, C., Skov, L., Werge, T., Karagiannidis, I., Tarnok, Z., Barta, C., Nagy, P., Farkas, L., Brondum-Nielsen, K., Rizzo, R., Gulisano, M., Rujescu, D., Kiemeney, L.A.L.M., Tosato, S., Nawaz, M.S., Ingason, A., Unnsteinsdottir, U., Steinberg, S., Ludvigsson, P., Stefansson, K., Kuss, A.W., Paschou, P., Cath, D., Hoekstra, P.J., Muller-Vahl, K., Stuhrmann, M., Silahtaroglu, A., Pfundt, R.P., Tumer, Z., Bertelsen, B., Stefansson, H., Jensen, L., Melchior, L., Debes, N. Mol, Groth, C., Skov, L., Werge, T., Karagiannidis, I., Tarnok, Z., Barta, C., Nagy, P., Farkas, L., Brondum-Nielsen, K., Rizzo, R., Gulisano, M., Rujescu, D., Kiemeney, L.A.L.M., Tosato, S., Nawaz, M.S., Ingason, A., Unnsteinsdottir, U., Steinberg, S., Ludvigsson, P., Stefansson, K., Kuss, A.W., Paschou, P., Cath, D., Hoekstra, P.J., Muller-Vahl, K., Stuhrmann, M., Silahtaroglu, A., Pfundt, R.P., and Tumer, Z.
Abstract: Item does not contain fulltext, BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 x 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.
Published: 2016

103. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Author: Gormley, A.M., Stefansson, H. (Hreinn), Winsvold, B.S. (Bendik), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), Mcmahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela), Todt, U. (Unda), Müller-Myhsok, B. (Bertram), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Göbel, H. (Hartmut), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H.H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie E.), Schürks, M. (Markus), Ridker, P.M. (Paul), Hrafnsdottir, M.G. (Maria Gudlaug), Ring, S.M. (Susan), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Hämäläinen, E. (Eija), Lucae, S. (Susanne), Malik, R. (Rainer), Heath, A.C. (Andrew C.), Madden, P.A. (Pamela), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M.I. (Mitja I.), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jian), Stergiakouli, E. (Evangelia), Lee, P.H. (Phil), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Christensen, A.F. (Anne Francke), Hansen, T.F. (Thomas Folkmann), Werge, T.M. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (Arfan), Ikram, M.K. (Kamran), Jarvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Strachan, D.P. (David), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), Maagdenberg, A.M.J.M. (Arn), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Smith, G.D. (George Davey), Stefansson, K. (Kari), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), Palotie, A. (Aarno), Gormley, A.M., Stefansson, H. (Hreinn), Winsvold, B.S. (Bendik), Palta, P. (Priit), Esko, T. (Tõnu), Pers, T.H. (Tune), Farh, K.-H. (Kai-How), Cuenca-Leon, E. (Ester), Muona, M. (Mikko), Furlotte, N.A. (Nicholas A.), Kurth, T. (Tobias), Ingason, A. (Andres), Mcmahon, G. (George), Ligthart, L. (Lannie), Terwindt, G.M. (Gisela), Todt, U. (Unda), Müller-Myhsok, B. (Bertram), Ran, C. (Caroline), Gordon, S.G. (Scott G.), Stam, A.H. (Anine), Steinberg, S. (Stacy), Göbel, H. (Hartmut), Koiranen, M. (Markku), Quaye, L. (Lydia), Adams, H.H.H. (Hieab H.H.), Lehtimäki, T. (Terho), Sarin, A.-P., Wedenoja, J. (Juho), Hinds, D.A. (David A.), Buring, J.E. (Julie E.), Schürks, M. (Markus), Ridker, P.M. (Paul), Hrafnsdottir, M.G. (Maria Gudlaug), Ring, S.M. (Susan), Hottenga, J.J. (Jouke Jan), Penninx, B.W.J.H. (Brenda), Färkkilä, M. (Markus), Artto, V. (Ville), Hämäläinen, E. (Eija), Lucae, S. (Susanne), Malik, R. (Rainer), Heath, A.C. (Andrew C.), Madden, P.A. (Pamela), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant), Kurki, M.I. (Mitja I.), Kals, M. (Mart), Mägi, R. (Reedik), Pärn, K. (Kalle), Huang, H. (Hailiang), Byrnes, A.E. (Andrea E.), Franke, L. (Lude), Huang, J. (Jian), Stergiakouli, E. (Evangelia), Lee, P.H. (Phil), Sandor, C. (Cynthia), Webber, C. (Caleb), Cader, Z. (Zameel), Müller-Myhsok, B. (B.), Schreiber, S. (Stefan), Meitinger, T. (Thomas), Hagen, K. (Knut), Salomaa, V. (Veikko), Heikkilä, K. (Kauko), Loehrer, E. (Elizabeth), Uitterlinden, A.G. (André), Hofman, A. (Albert), Duijn, C.M. (Cornelia) van, Cherkas, L. (Lynn), Pedersen, L.M. (Linda M.), Stubhaug, A. (Audun), Nielsen, C.S. (Christopher S.), Männikkö, M. (Minna), Mihailov, E. (Evelin), Milani, L. (Lili), Esserlind, A.-L. (Ann-Louise), Christensen, A.F. (Anne Francke), Hansen, T.F. (Thomas Folkmann), Werge, T.M. (Thomas), Kaprio, J. (Jaakko), Aromaa, A. (Arpo), Raitakari, O. (Olli), Ikram, M.A. (Arfan), Ikram, M.K. (Kamran), Jarvelin, M.-R. (Marjo-Riitta), Metspalu, A. (Andres), Kubisch, C. (Christian), Strachan, D.P. (David), Ferrari, M.D. (Michel), Belin, A.C. (Andrea C.), Wessman, M. (Maija), Maagdenberg, A.M.J.M. (Arn), Zwart, J-A. (John-Anker), Boomsma, D.I. (Dorret), Smith, G.D. (George Davey), Stefansson, K. (Kari), Eriksson, N. (Nicholas), Daly, M.J. (Mark), Neale, B.M. (Benjamin), Olesen, J. (Jes), Chasman, D.I. (Daniel), Nyholt, D.R. (Dale), and Palotie, A. (Aarno)
Abstract: Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10-8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
Published: 2016
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104. A Susceptibility Gene for Late-Onset Idiopathic Parkinsons Disease Successfully Mapped

Author: Hicks, A., Petursson, H., Jonsson, T., Stefansson, H., Johannsdottir, H., Sainz, J., Frigge, M.L., Kong, A., Gulcher, J.R., Stefansson, K., and Sveinbjornsdottir, S.
Subjects: Human genetics -- Research, Genetic disorders -- Research, Parkinson's disease -- Genetic aspects, Chromosome mapping -- Genetic aspects, Biological sciences
Published: 2001

105. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Author: Nalls, M.A. Pankratz, N. Lill, C.M. Do, C.B. Hernandez, D.G. Saad, M. Destefano, A.L. Kara, E. Bras, J. Sharma, M. Schulte, C. Keller, M.F. Arepalli, S. Letson, C. Edsall, C. Stefansson, H. Liu, X. Pliner, H. Lee, J.H. Cheng, R. Ikram, M.A. Ioannidis, J.P.A. Hadjigeorgiou, G.M. Bis, J.C. Martinez, M. Perlmutter, J.S. Goate, A. Marder, K. Fiske, B. Sutherland, M. Xiromerisiou, G. Myers, R.H. Clark, L.N. Stefansson, K. Hardy, J.A. Heutink, P. Chen, H. Wood, N.W. Houlden, H. Payami, H. Brice, A. Scott, W.K. Gasser, T. Bertram, L. Eriksson, N. Foroud, T. Singleton, A.B. Plagnol, V. Sheerin, U.-M. Simón-Sánchez, J. Lesage, S. Sveinbjörnsdóttir, S. Barker, R. Ben-Shlomo, Y. Berendse, H.W. Berg, D. Bhatia, K. de Bie, R.M.A. Biffi, A. Bloem, B. Bochdanovits, Z. Bonin, M. Bras, J.M. Brockmann, K. Brooks, J. Burn, D.J. Charlesworth, G. Chinnery, P.F. Chong, S. Clarke, C.E. Cookson, M.R. Cooper, J.M. Corvol, J.C. Counsell, C. Damier, P. Dartigues, J.-F. Deloukas, P. Deuschl, G. Dexter, D.T. van Dijk, K.D. Dillman, A. Durif, F. Dürr, A. Edkins, S. Evans, J.R. Foltynie, T. Dong, J. Gardner, M. Gibbs, J.R. Gray, E. Guerreiro, R. Harris, C. van Hilten, J.J. Hofman, A. Hollenbeck, A. Holton, J. Hu, M. Huang, X. Wurster, I. Mätzler, W. Hudson, G. Hunt, S.E. Huttenlocher, J. Illig, T. Jónsson, P.V. Lambert, J.-C. Langford, C. Lees, A. Lichtner, P. Limousin, P. Lopez, G. Lorenz, D. McNeill, A. Moorby, C. Moore, M. Morris, H.R. Morrison, K.E. Mudanohwo, E. O’sullivan, S.S. Pearson, J. Pétursson, H. Pollak, P. Post, B. Potter, S. Ravina, B. Revesz, T. Riess, O. Rivadeneira, F. Rizzu, P. Ryten, M. Sawcer, S. Schapira, A. Scheffer, H. Shaw, K. Shoulson, I. Sidransky, E. Smith, C. Spencer, C.C.A. Stefánsson, H. Bettella, F. Stockton, J.D. Strange, A. Talbot, K. Tanner, C.M. Tashakkori-Ghanbaria, A. Tison, F. Trabzuni, D. Traynor, B.J. Uitterlinden, A.G. Velseboer, D. Vidailhet, M. Walker, R. van de Warrenburg, B. Wickremaratchi, M. Williams, N. Williams-Gray, C.H. Winder-Rhodes, S. Stefánsson, K. Hardy, J. Factor, S. Higgins, D. Evans, S. Shill, H. Stacy, M. Danielson, J. Marlor, L. Williamson, K. Jankovic, J. Hunter, C. Simon, D. Ryan, P. Scollins, L. Saunders-Pullman, R. Boyar, K. Costan-Toth, C. Ohmann, E. Sudarsky, L. Joubert, C. Friedman, J. Chou, K. Fernandez, H. Lannon, M. Galvez-Jimenez, N. Podichetty, A. Thompson, K. Lewitt, P. Deangelis, M. O'brien, C. Seeberger, L. Dingmann, C. Judd, D. Marder, K. Fraser, J. Harris, J. Bertoni, J. Peterson, C. Rezak, M. Medalle, G. Chouinard, S. Panisset, M. Hall, J. Poiffaut, H. Calabrese, V. Roberge, P. Wojcieszek, J. Belden, J. Jennings, D. Marek, K. Mendick, S. Reich, S. Dunlop, B. Jog, M. Horn, C. Uitti, R. Turk, M. Ajax, T. Mannetter, J. Sethi, K. Carpenter, J. Dill, B. Hatch, L. Ligon, K. Narayan, S. Blindauer, K. Abou-Samra, K. Petit, J. Elmer, L. Aiken, E. Davis, K. Schell, C. Wilson, S. Velickovic, M. Koller, W. Phipps, S. Feigin, A. Gordon, M. Hamann, J. Licari, E. Marotta-Kollarus, M. Shannon, B. Winnick, R. Simuni, T. Videnovic, A. Kaczmarek, A. Williams, K. Wolff, M. Rao, J. Cook, M. Fernandez, M. Kostyk, S. Hubble, J. Campbell, A. Reider, C. Seward, A. Camicioli, R. Carter, J. Nutt, J. Andrews, P. Morehouse, S. Stone, C. Mendis, T. Grimes, D. Alcorn-Costa, C. Gray, P. Haas, K. Vendette, J. Sutton, J. Hutchinson, B. Young, J. Rajput, A. Klassen, L. Shirley, T. Manyam, B. Simpson, P. Whetteckey, J. Wulbrecht, B. Truong, D. Pathak, M. Frei, K. Luong, N. Tra, T. Tran, A. Vo, J. Lang, A. Kleiner-Fisman, G. Nieves, A. Johnston, L. So, J. Podskalny, G. Giffin, L. Atchison, P. Allen, C. Martin, W. Wieler, M. Suchowersky, O. Furtado, S. Klimek, M. Hermanowicz, N. Niswonger, S. Shults, C. Fontaine, D. Aminoff, M. Christine, C. Diminno, M. Hevezi, J. Dalvi, A. Kang, U. Richman, J. Uy, S. Sahay, A. Gartner, M. Schwieterman, D. Hall, D. Leehey, M. Culver, S. Derian, T. Demarcaida, T. Thurlow, S. Rodnitzky, R. Dobson, J. Lyons, K. Pahwa, R. Gales, T. Thomas, S. Shulman, L. Weiner, W. Dustin, K. Singer, C. Zelaya, L. Tuite, P. Hagen, V. Rolandelli, S. Schacherer, R. Kosowicz, J. Gordon, P. Werner, J. Serrano, C. Roque, S. Kurlan, R. Berry, D. Gardiner, I. Hauser, R. Sanchez-Ramos, J. Zesiewicz, T. Delgado, H. Price, K. Rodriguez, P. Wolfrath, S. Pfeiffer, R. Davis, L. Pfeiffer, B. Dewey, R. Hayward, B. Johnson, A. Meacham, M. Estes, B. Walker, F. Hunt, V. O'neill, C. Racette, B. Swisher, L. Dijamco, C. Conley, E.D. Dorfman, E. Tung, J.Y. Hinds, D.A. Mountain, J.L. Wojcicki, A. Lew, M. Klein, C. Golbe, L. Growdon, J. Wooten, G.F. Watts, R. Guttman, M. Goldwurm, S. Saint-Hilaire, M.H. Baker, K. Litvan, I. Nicholson, G. Nance, M. Drasby, E. Isaacson, S. Burn, D. Pramstaller, P. Al-Hinti, J. Moller, A. Sherman, S. Roxburgh, R. Slevin, J. Perlmutter, J. Mark, M.H. Huggins, N. Pezzoli, G. Massood, T. Itin, I. Corbett, A. Chinnery, P. Ostergaard, K. Snow, B. Cambi, F. Kay, D. Samii, A. Agarwal, P. Roberts, J.W. Higgins, D.S. Molho, E. Rosen, A. Montimurro, J. Martinez, E. Griffith, A. Kusel, V. Yearout, D. Factor, S. Zabetian, C. Clark, L.N. Liu, X. Lee, J.H. Cheng Taub, R. Louis, E.D. Cote, L.J. Waters, C. Ford, B. Fahn, S. Vance, J.M. Beecham, G.W. Martin, E.R. Nuytemans, K. Pericak-Vance, M.A. Haines, J.L. Destefano, A. Seshadri, S. Choi, S.H. Frank, S. Bis, J.C. Psaty, B.M. Rice, K. Longstreth, W.T., Jr. Ton, T.G.N. Jain, S. van Duijn, C.M. Uitterlinden, A.G. Verlinden, V.J. Koudstaal, P.J. Singleton, A. Cookson, M. Gibbs, J.R. Hernandez, D. Nalls, M. Zonderman, A. Ferrucci, L. Johnson, R. Longo, D. O'brien, R. Traynor, B. Troncoso, J. van der Brug, M. Zielke, R. Weale, M. Ramasamy, A. Dardiotis, E. Tsimourtou, V. Spanaki, C. Plaitakis, A. Bozi, M. Stefanis, L. Vassilatis, D. Koutsis, G. Panas, M. Hadjigeorgiou, G.M. Lunnon, K. Lupton, M. Powell, J. Parkkinen, L. Ansorge, O. International Parkinson's Disease Genomics Consortium (IPDGC) Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI) 23andMe GenePD NeuroGenetics Research Consortium (NGRC) Hussman Institute of Human Genomics (HIHG) The Ashkenazi Jewish Dataset Investigator Cohorts for Health Aging Research in Genetic Epidemiology (CHARGE) North American Brain Expression Consortium (NABEC) United Kingdom Brain Expression Consortium (UKBEC) Greek Parkinson's Disease Consortium Alzheimer Genetic Analysis Group
Abstract: We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10-16). We also show six risk loci associated with proximal gene expression or DNA methylation. © 2014 Nature America, Inc. All rights reserved.
Published: 2014

106. Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Author: Luo, XJ, Li, M, Huang, L, Steinberg, S, Mattheisen, M, Liang, G, Donohoe, G, Shi, Y, Chen, C, Yue, W, Alkelai, A, Lerer, B, Li, Z, Yi, Q, Rietschel, M, Cichon, S, Collier, DA, Tosato, S, Suvisaari, J, Rujescu, D, Golimbet, V, Silagadze, T, Durmishi, N, Milovancevic, MP, Stefansson, H, Schulze, TG, Nöthen, MM, Lyne, R, Morris, DW, Gill, M, Corvin, A, Zhang, D, Dong, Q, Moyzis, RK, Stefansson, K, Sigurdsson, E, Hu, F, SCZ Consortium36, Su, B, Gan, L, and College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China [2] Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY, USA. 2Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. 31] Nanchang University, Nanchang, China [2] Gannan Medical University, Ganzhou, China [3] Jiangxi Provincial People's Hospital, Nanchang, China. 4deCODE Genetics, Reykjavik, Iceland. 5Department of Biomedicine, Aarhus University, Aarhus C, Denmark. 6College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China. 7Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland. 8Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. 9Department of Psychology and Social Behavior, University of California, Irvine, CA, USA. 101] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China. 11Department of Psychiatry, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 12Department of Psychiatry, the First Teaching Hospital of Xinjiang Medical University, Urumqi, China. 13Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Mannheim, Mannheim, Germany. 14Department of Genomics, Life and Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany. 151] Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London, UK [2] Eli Lilly and Co. Ltd, Erl Wood Manor, Surrey, UK. 16Section of Psychiatry, University of Verona, Verona, Italy. 17Mental Health and Substance Abuse Services, National Institute for Health and Welfare THL, Helsinki, Finland. 181] Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany. 19Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia. 20Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia. 21Department of Child and Adolescent Psychiatry, University of Skopje, Skopje, Macedonia. 22Medical Faculty, University of Belgrade, Belgrade, Serbia. 23Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, Goettingen, Germany. 24State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China. 25Department of Biological Chemistry, University of California, Irvine, CA, USA. 261] deCODE Genetics, Reykjavik, Iceland [2] School of Medicine, University of Iceland, Reykjavik, Iceland. 271] School of Medicine, University of Iceland, Reykjavik, Iceland [2] Department of Psychiatry, National University Hospital, Reykjavik, Iceland. 28Affiliated Eye Hospital of Nanchang University, Nanchang, China. 29State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Subjects: Pathogenesis, protein-protein interaction, 0302 clinical medicine, Cognition, Gene expression, Genamengi, Databases, Genetic, Protein Interaction Maps, European Continental Ancestry Group/genetics, Psychotic Disorders/genetics, CAMKK2, Schizophrenic Psychology, Genetics, 0303 health sciences, Brain, Chromosome Mapping, Polymorphism, Single Nucleotide/genetics, Psychiatry and Mental health, Geðsjúkdómar, Personality, Genotype, Schizophrenia (object-oriented programming), Down-Regulation, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Single-nucleotide polymorphism, Calcium-Calmodulin-Dependent Protein Kinase, Biology, eQTL, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Cellular and Molecular Neuroscience, Asian People, Geðklofi, Personality/genetics, Kinase/metabolism, expression, SNP, Brain/metabolism, Humans, Genetic Predisposition to Disease, Asian Continental Ancestry Group/genetics, Allele, Molecular Biology, Gene, association, schizophrenia, Alleles, 030304 developmental biology, Arfgengi, Kinase/genetics, Schizophrenia/genetics, Case-Control Studies, Protein Interaction Maps/genetics, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility. National Natural Science Foundation of China/81271006/ 81060081 Hangzhou City Health Science Foundation/20120633B01 Jiangxi Provincial Natural Science Foundation/2010GZY0089/20114BAB215006 Natural Science Foundation of China/U1202225/81130022/ 81272302/31000553 863 Program 2012AA02A515 EU/HEALTH-2011-286213 HEALTH-F2-2009-223423 111 Project of the Ministry of Education of China/B07008 Israel Science Foundation info:eu-repo/grantAgreement/EC/FP7/286213
Published: 2014

107. Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus

Author: Desikan, R.S. (R. S.), Schork, A.J. (A. J.), Wang, Y. (Y.), Witoelar, A. (Aree), Sharma, M. (M.), McEvoy, L.K. (L. K.), Holland, D. (D.), Brewer, J.B. (J. B.), Chen, C.-H. (C. H.), Thompson, W.K. (W. K.), Harold, D. (Denise), Williams, J. (J.), Owen, M.J. (Michael), O'donovan, M.C. (Michael), Pericak-Vance, M.A. (Margaret), Mayeux, R. (R.), Haines, J.L. (Jonathan), Farrer, L.A. (Lindsay), Schellenberg, G.D. (G. D.), Heutink, P. (Peter), Singleton, A.B. (A. B.), Brice, A. (A.), Wood, N.W. (N. W.), Hardy, J. (J.), Martinez, M. (M.), Choi, S.-H. (Seung-Hoan), Destefano, A. (A.), Ikram, M.A. (M. A.), Bis, J.C. (Joshua), Smith, A. (A.), Fitzpatrick, A.L. (Annette), Launer, L.J. (Lenore), Van Duijn, C. (C.), Seshadri, S. (S.), Ulstein, I. (Ingun), Aarsland, D. (D.), Fladby, T. (T.), Djurovic, S. (Srdjan), Hyman, B.T. (Bradley), SnÆdal, J. (Jon), Stefansson, H. (Hreinn), Stefansson, K. (K.), Gasser, T. (T.), Andreassen, O.A. (O. A.), Dale, A.M. (A. M.), Desikan, R.S. (R. S.), Schork, A.J. (A. J.), Wang, Y. (Y.), Witoelar, A. (Aree), Sharma, M. (M.), McEvoy, L.K. (L. K.), Holland, D. (D.), Brewer, J.B. (J. B.), Chen, C.-H. (C. H.), Thompson, W.K. (W. K.), Harold, D. (Denise), Williams, J. (J.), Owen, M.J. (Michael), O'donovan, M.C. (Michael), Pericak-Vance, M.A. (Margaret), Mayeux, R. (R.), Haines, J.L. (Jonathan), Farrer, L.A. (Lindsay), Schellenberg, G.D. (G. D.), Heutink, P. (Peter), Singleton, A.B. (A. B.), Brice, A. (A.), Wood, N.W. (N. W.), Hardy, J. (J.), Martinez, M. (M.), Choi, S.-H. (Seung-Hoan), Destefano, A. (A.), Ikram, M.A. (M. A.), Bis, J.C. (Joshua), Smith, A. (A.), Fitzpatrick, A.L. (Annette), Launer, L.J. (Lenore), Van Duijn, C. (C.), Seshadri, S. (S.), Ulstein, I. (Ingun), Aarsland, D. (D.), Fladby, T. (T.), Djurovic, S. (Srdjan), Hyman, B.T. (Bradley), SnÆdal, J. (Jon), Stefansson, H. (Hreinn), Stefansson, K. (K.), Gasser, T. (T.), Andreassen, O.A. (O. A.), and Dale, A.M. (A. M.)
Abstract: We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10 -7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.
Published: 2015
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108. Polygenic risk scores for schizophrenia and bipolar disorder predict creativity

Author: Power, R.A., Steinberg, S., Bjornsdottir, G., Rietveld, C.A., Abdellaoui, A., Nivard, M.M., Johannesson, M., Galesloot, T.E., Hottenga, J.J., Willemsen, G., Cesarini, D., Benjamin, D.J., Magnusson, P.K., Ullen, F., Tiemeier, H., Hofman, A., Rooij, F.J. van, Walters, G.B., Sigurdsson, E., Thorgeirsson, T.E., Ingason, A., Helgason, A., Kong, A., Kiemeney, B., Koellinger, P., Boomsma, D.I., Gudbjartsson, D., Stefansson, H., Stefansson, K., Power, R.A., Steinberg, S., Bjornsdottir, G., Rietveld, C.A., Abdellaoui, A., Nivard, M.M., Johannesson, M., Galesloot, T.E., Hottenga, J.J., Willemsen, G., Cesarini, D., Benjamin, D.J., Magnusson, P.K., Ullen, F., Tiemeier, H., Hofman, A., Rooij, F.J. van, Walters, G.B., Sigurdsson, E., Thorgeirsson, T.E., Ingason, A., Helgason, A., Kong, A., Kiemeney, B., Koellinger, P., Boomsma, D.I., Gudbjartsson, D., Stefansson, H., and Stefansson, K.
Abstract: Item does not contain fulltext, We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 x 10(-6) and 3.8 x 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.
Published: 2015

109. All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs

Author: Aj, Schork, Wk, Thompson, Pham P, Torkamani A, Jc, Roddey, Pf, Sullivan, Jr, Kelsoe, Donovan Mc, O., Furberg H, Tobacco and Genetics Consortium, Bipolar Disorder Psychiatric Genomics Consortium, Schizophrenia Psychiatric Genomics Consortium, Nj, Schork, Oa, Andreassen, Am, Dale, Absher D, Agudo A, Almgren P, Ardissino D, Tl, Assimes, Bandinelli S, Barzan L, Bencko V, Benhamou S, Ej, Benjamin, Bernardinelli L, Bis J, Boehnke M, Boerwinkle E, Di, Boomsma, Brennan P, Canova C, Castellsagué X, Chanock S, Chasman D, Di, Conway, Dackor J, Ej, Geus, Duan J, Elosua R, Everett B, Fabianova E, Ferrucci L, Foretova L, Sp, Fortmann, Franceschini N, Frayling T, Furberg C, Pv, Gejman, Groop L, Gu F, Guralnik J, Se, Hankinson, Haritunians T, Healy C, Hofman A, Holcátová I, Dj, Hunter, Sj, Hwang, Jp, Ioannidis, Iribarren C, Au, Jackson, Janout V, Kaprio J, Kim Y, Kjaerheim K, Jw, Knowles, Kraft P, Ladenvall C, Lagiou P, Lanthrop M, Lerman C, Df, Levinson, Levy D, Md, Li, Dy, Lin, Eh, Lips, Lissowska J, Lowry R, Lucas G, Tv, Macfarlane, Maes H, Pm, Mannucci, Mates D, Mauri F, Ja, Mcgovern, Jd, Mckay, McKnight B, Melander O, Pa, Merlini, Milaneschi Y, Kl, Mohlke, Donnell Cj, O., Pare G, Bw, Penninx, Perry J, Posthuma D, Sr, Preis, Psaty B, Quertermous T, Vs, Ramachandran, Richiardi L, Ridker P, Rose J, Rudnai P, Salomaa V, Ar, Sanders, Sm, Schwartz, Shi J, Jh, Smit, Hm, Stringham, Szeszenia-Dabrowska N, Tanaka T, Taylor K, Thacker E, Thornton L, Tiemeier H, Tuomilehto J, Ag, Uitterlinden, Cm, Duijn, Jm, Vink, Vogelzangs N, Bf, Voight, Walter S, Willemsen G, Zaridze D, Znaor A, Akil H, Anjorin A, Backlund L, Ja, Badner, Jd, Barchas, Tb, Barrett, Bass N, Bauer M, Bellivier F, Se, Bergen, Berrettini W, Blackwood D, Cs, Bloss, Breen G, Breuer R, We, Bunner, Burmeister M, Byerley W, Caesar S, Chambert K, Cichon S, St Clair D, Da, Collier, Corvin A, Wh, Coryell, Craddock N, Dw, Craig, Daly M, Day R, Degenhardt F, Djurovic S, Dudbridge F, Hj, Edenberg, Elkin A, Etain B, Ae, Farmer, Ma, Ferreira, Ferrier I, Flickinger M, Foroud T, Frank J, Fraser C, Frisén L, Es, Gershon, Gill M, Gordon-Smith K, Ek, Green, Ta, Greenwood, Grozeva D, Guan W, Gurling H, Ó, Gustafsson, Ml, Hamshere, Hautzinger M, Herms S, Hipolito M, Pa, Holmans, Cm, Hultman, Jamain S, Eg, Jones, Jones I, Jones L, Kandaswamy R, Jl, Kennedy, Gk, Kirov, Dl, Koller, Kwan P, Landén M, Langstrom N, Lathrop M, Lawrence J, Wb, Lawson, Leboyer M, Ph, Lee, Li J, Lichtenstein P, Lin D, Liu C, Fw, Lohoff, Lucae S, Pb, Mahon, Maier W, Ng, Martin, Mattheisen M, Matthews K, Mattingsdal M, Ka, Mcghee, McGuffin P, Mg, Mcinnis, McIntosh A, McKinney R, Aw, Mclean, Fj, Mcmahon, McQuillin A, Meier S, Melle I, Meng F, Pb, Mitchell, Gw, Montgomery, Moran J, Morken G, Dw, Morris, Moskvina V, Muglia P, Tw, Mühleisen, Wj, Muir, Müller-Myhsok B, Rm, Myers, Cm, Nievergelt, Nikolov I, Nimgaonkar V, Mm, Nöthen, Ji, Nurnberger, Ea, Nwulia, O'Dushlaine C, Osby U, Óskarsson H, Mj, Owen, Petursson H, Bs, Pickard, Porgeirsson P, Jb, Potash, Propping P, Sm, Purcell, Quinn E, Raychaudhuri S, Rice J, Rietschel M, Ruderfer D, Schalling M, Af, Schatzberg, Wa, Scheftner, Pr, Schofield, Tg, Schulze, Schumacher J, Mm, Schwarz, Scolnick E, Lj, Scott, Pd, Shilling, Sigurdsson E, Sklar P, En, Smith, Stefansson H, Stefansson K, Steffens M, Steinberg S, Strauss J, Strohmaier J, Szelinger S, Rc, Thompson, Tozzi F, Treutlein J, Jb, Vincent, Sj, Watson, Tf, Wienker, Williamson R, Sh, Witt, Wright A, Xu W, Ah, Young, Pp, Zandi, Zhang P, Zöllner S, Agartz I, Albus M, Alexander M, Rl, Amdur, Amin F, Bitter I, Dw, Black, Ad, Børglum, Ma, Brown, Bruggeman R, Ng, Buccola, Wf, Byerley, Cahn W, Rm, Cantor, Vj, Carr, Sv, Catts, Choudhury K, Cloninger C, Cormican P, Pa, Danoy, Datta S, DeHert M, Demontis D, Dikeos D, Donnelly P, Donohoe G, Duong L, Dwyer S, Fanous A, Fink-Jensen A, Freedman R, Nb, Freimer, Friedl M, Georgieva L, Giegling I, Glenthøj B, Godard S, Golimbet V, de Haan L, Hansen M, Hansen T, Am, Hartmann, Fa, Henskens, Dm, Hougaard, Ingason A, Av, Jablensky, Kd, Jakobsen, Jay M, Eg, Jönsson, Jürgens G, Rs, Kahn, Mc, Keller, Ks, Kendler, Kenis G, Kenny E, Konnerth H, Konte B, Krabbendam L, Krasucki R, Vk, Lasseter, Laurent C, Lencz T, Lerer F, Ky, Liang, Ja, Lieberman, Dh, Linszen, Lönnqvist J, Cm, Loughland, Aw, Maclean, Bs, Maher, Ak, Malhotra, Mallet J, Malloy P, Jj, Mcgrath, McLean DE, Pt, Michie, Milanova V, Mors O, Pb, Mortensen, Bj, Mowry, Myin-Germeys I, Neale B, Da, Nertney, Nestadt G, Nielsen J, Nordentoft M, Norton N, O'Neill F, Olincy A, Olsen L, Ra, Ophoff, Tf, Ørntoft, van Os J, Pantelis C, Papadimitriou G, Cn, Pato, Mt, Pato, Peltonen L, Pickard B, Op, Pietiläinen, Pimm J, Ae, Pulver, Puri V, Digby Quested, Hb, Rasmussen, Jm, Réthelyi, Ribble R, Bp, Riley, Rossin L, Ruggeri M, Rujescu D, Schall U, Sg, Schwab, Rj, Scott, Jm, Silverman, Cc, Spencer, Strange A, Strengman E, Stroup T, Suvisaari J, Terenius L, Thirumalai S, Timm S, Toncheva D, Tosato S, Ej, Den Oord, Veldink J, Pm, Visscher, Walsh D, Ag, Wang, Werge T, Wiersma D, Db, Wildenauer, Hj, Williams, Nm, Williams, van Winkel R, Wormley B., Biological Psychology, Functional Genomics, Educational Neuroscience, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, ANS - Amsterdam Neuroscience, Adult Psychiatry, Psychiatry, Human genetics, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Gibson, Greg, Germeys, Inez, van Winkel, Ruud, and De Hert, Marc
Subjects: False discovery rate, Netherlands Twin Register (NTR), Cancer Research, Linkage disequilibrium, Genome-wide association study, Linkage Disequilibrium, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Genetics, 0303 health sciences, Statistics, Genomics, Single Nucleotide, Genome Scans, Tobacco and Genetics Consortium, Functional Genomics, Phenotype, complex trait, Research Article, Bipolar Disorder Psychiatric Genomics Consortium, lcsh:QH426-470, SNP, Single-nucleotide polymorphism, Computational biology, Biostatistics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, "genome-wide association study", Genome Analysis Tools, Clinical Research, Schizophrenia Psychiatric Genomics Consortium, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Statistical Methods, Polymorphism, Molecular Biology, Genetic Association Studies, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, Linkage (software), Human Genome, Computational Biology, Human Genetics, Heritability, R1, schizophrenia, lcsh:Genetics, Schizophrenia, Mathematics, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci., Author Summary Modern genome-wide association studies (GWAS) have failed to identify large portions of the genetic basis of common, complex traits. Recent work suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS. Moreover, these variants appear more abundantly in and near genes. Using genome annotations, summary statistics from several of the largest GWAS, and established statistical methods for quantifying distributions of test statistics, we show a consistency across studies. Namely, we show that, across all assessed traits, the test statistics resulting from SNPs that are related to the 5′ UTR of genes show the largest abundance of associations, while SNPs related to exons and the 3′UTR are also enriched. SNPs related to introns are only moderately enriched, and intergenic SNPs show a depletion of associations relative to the average SNP. This enrichment corresponds directly to increased replication across independent samples and can be incorporated a priori into statistical methods to improve discovery and prediction. Our results contribute to on-going debates about the functional nature of the genetic architecture of complex traits and point to avenues for leveraging existing GWAS data for discovery in future GWA and sequencing studies.
Published: 2013

110. Identification of risk loci with shared effects on five major psychiatric disorders:a genome-wide analysis

Author: Smoller, J.W., Ripke, S., Lee, P.H., Neale, B., Nurnberger, J.I., Santangelo, S., Sullivan, P.F., Perlis, R.H., Purcell, S.M., Fanous, A., Neale, M.C., Rietschel, M., Schulze, T.G., Thapar, A., Anney, R., Buitelaar, J.K., Farone, S.V., Hoogendijk, W.J.G., Levinson, D.F., Lesch, K.P., Riley, B., Schachar, R., Sonuga-Barke, E.J., Absher, D., Agartz, I., Akil, H., Amin, F., Andreassen, O.A., Anjorin, A., Arking, D., Asherson, P., Azevedo, M.H., Backlund, L., Badner, J.A., Banaschewski, T., Barchas, J.D., Barnes, M.R., Bass, N., Bauer, M.C.R., Bellivier, F., Bergen, S.E., Berrettini, W., Bettecken, T., Biederman, J, Binder, E.B., Black, D.W., Blackwood, D.H., Bloss, C.S., Boehnke, M., Boomsma, D.I., Breen, G., Breuer, R., Buccola, N.G., Bunner, W.E., Burmeister, M., Buxbaum, J.D., Byerley, W. F., Sian, C., Cantor, R.M., Chakravarti, A., Chambert, K., Chicon, S., Cloniger, C.R., Collier, D.A., Cook, E., Coon, H., Corvin, A., Coryell, W.H., Craig, D.W., Craig, I.W., Curtis, D., Czamara, D., Daly, M., Datta, S., Day, R., de Geus, E.J.C., Degenhardt, F., Devlin, B., Srdjan, D., Doyle, A.E., Duan, J., Dudbridge, F., Edenberg, H.J., Elkin, A., Etain, B., Farmer, A.E., Ferreira, M.A.R., Ferrier, I.N., Flickinger, M., Foroud, T., Frank, J., Franke, B., Fraser, C., Freedman, R., Freimer, N.B., Friedl, M., Frisén, L., Gejman, P.V., Georgieva, L., Gershon, E.S., Giegling, I., Gill, M., Gordon, S.D., Gordon-Smith, K., Green, E.K., Greenwood, T.A., Gross, M., Grozeva, D., Guan, W., Gurling, H., Gustafsson, O., Hakonarson, H., Hamilton, S.P., Hamshere, M.L., Hansen, T.F., Hartmann, A.M., Hautzinger, M., Heath, A.C., Henders, A.K., Herms, S., Hickie, I.B., Hipolito, M., Hoefels, S., Holmans, P.A., Holsboer, F., Hottenga, J.J., Hultman, C. M., Ingason, A., Ising, M., Jamain, S., Jones, E.G., Jones, L., Jones, I., Jung-Ying, T., Kahler, A., Kandaswamy, R., Keller, M.C., Kelsoe, J., Kennedy, J.L., Kenny, E., Kim, Y., Kirov, G. K., Knowles, J.A., Kohli, M.A., Koller, D.L., Konte, B., Korszun, A., Krasucki, R., Kuntsi, J., Phoenix, K., Landén, M., Langstrom, N., Lathrop, M., Lawrence, J., Lawson, W.B., Leboyer, M., Lencz, T., Lewis, C.M., Li, J., Lichtenstein, P., Lieberman, J. A., Lin, D., Liu, C., Lohoff, F.W., Loo, S.K., Lucae, S., MacIntyre, D.J., Madden, P.A.F., Magnusson, P., Mahon, P.B., Maier, W., Malhotra, A.K., Mattheisen, M., Matthews, K., Mattingsdal, M., McCarroll, S., McGhee, K.A., McGough, J.J., McGrath, P.J., McGuffin, P., McInnis, M.G., McIntosh, A., McKinney, R., McClean, A.W., McMahon, F.J., McQuillin, A., Medeiros, H., Medland, S.E., Meier, S., Melle, I., Meng, F., Middeldorp, C.M., Middleton, L., Vihra, M., Mitchell, P.B., Montgomery, G.W., Moran, J., Morken, G., Morris, D.W., Moskvina, V., Mowry, B. J., Muglia, P., Mühleisen, T.W., Muir, W.J., Müller-Myhsok, B., Myers, R.M., Nelson, S.F., Nievergelt, C.M., Nikolovq, I., Nimgaonkar, V.L., Nolen, W.A., Nöthen, M.M., Nwulia, E.A., Nyholt, DR, O'Donovan, M.C., O'Dushlaine, C., Oades, R.D., Olincy, A., Olsen, L., Ophoff, R.A., Osby, U., Óskarsson, H., Owen, M.J., Palotie, A., Pato, M.T., Pato, C.N., Penninx, B.W.J.H., Pergadia, M.L., Petursson, H., Pickard, B.S., Pimm, J., Piven, J., Porgeirsson, P., Posthuma, D., Potash, J.B., Propping, J., Puri, V., Quested, D., Quinn, E.M., Rasmussen, H.B., Raychaudhuri, S., Rehnström, K., Reif, A., Rice, J., Rossin, L., Rothenberger, A., Rouleau, G., Ruderfer, D., Rujescu, D., Sanders, A.R., Schalling, M., Schatzberg, A.F., Scheftner, W.A., Schellenberg, G.D., Schofield, P.R., Schork, N.J., Schumacher, J., Schwarz, M.M., Scolnick, E., Scott, L.J., Shi, J., Shillling, P.D., Shyn, S.I., Sigurdsson, E., Silverman, J.M., Sklar, P., Slager, S.L., Smalley, S.L., Smit, J.H., Smith, E.N., Sonuga-Barke, E., St Clair, D., State, M., Stefansson, K., Stefansson, H., Steffans, M., Steinberg, S., Steinhausen, H.C., Strauss, J., Strohmaier, J., Stroup, T.S., Sutcliffe, J., Szatmari, P., Szelinger, S., Thirumalai, S., Thompson, R.C., Tozzi, F., Treutlein, J., Uhr, M., van den Oord, E.J., Grootheest, G., Vieland, V., Vincent, J.B., Visscher, P.M., Watson, S.J., Weissman, M.M., Werge, T., Wienker, T.F., Willemsen, G., Williamson, R., Witt, S.H., Wray, N.R., Wright, A., Xu, W., Young, A.H., Zammit, S., Zandi, P.P., Zhang, P., Zitman, F.G., Zöllner, S., Kendler, K.S., Psychiatry, Human genetics, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Oades, Robert D. (Beitragende*r), and Oades, Robert D.
Subjects: Netherlands Twin Register (NTR), Adult, medicine.medical_specialty, Bipolar Disorder, Calcium Channels, L-Type, Population, Medizin, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], medicine, ddc:61, Attention deficit hyperactivity disorder, Humans, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Age of Onset, Psychiatry, education, Child, Genetics, education.field_of_study, Depressive Disorder, Major, General Medicine, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], medicine.disease, Logistic Models, Autism spectrum disorder, Schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Genetic Loci, Expression quantitative trait loci, Major depressive disorder, Genome-Wide Association Study
Abstract: Item does not contain fulltext BACKGROUND: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. METHODS: We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. FINDINGS: SNPs at four loci surpassed the cutoff for genome-wide significance (p
Published: 2013

111. A mega-analysis of genome-wide association studies for major depressive disorder

Author: Ripke, S, Wray, NR, Lewis, CM, Hamilton, SP, Weissman, MM, Breen, G, Byrne, EM, Blackwood, DHR, Boomsma, DI, Cichon, S, Heath, AC, Holsboer, F, Lucae, S, Madden, PA, Martin, NG, McGuffin, P, Muglia, P, Noethen, MM, Penninx, BP, Pergadia, ML, Potash, JB, Rietschel, M, Lin, DY, Muller-Myhsok, B, Shi, J, Steinberg, S, Grabe, HJ, Lichtenstein, P, Magnusson, P, Perlis, RH, Preisig, M, Smoller, JW, Stefansson, K, Uher, R, Kutalik, Z, Tansey, KE, Teumer, A, Viktorin, A, Barnes, MR, Bettecken, T, Binder, EB, Breuer, R, Castro, VM, Churchill, SE, Coryell, WH, Craddock, N, Craig, IW, Czamara, D, de Geus, EJC, Degenhardt, F, Farmer, AE, Fava, M, Frank, J, Gainer, VS, Gallagher, PJ, Gordon, SD, Goryachev, S, Gross, M, Guipponi, M, Henders, AK, Herms, S, Hickie, IB, Hoefels, S, Hoogendijk, Witte, Hottenga, JJ (Jouke Jan), Iosifescu, DV, Ising, M, Jones, I, Jones, L, Jung-Ying, T, Knowles, JA, Kohane, IS, Kohli, MA, Korszun, A, Landen, M, Lawson, WB, Lewis, G, MacIntyre, DJ, Maier, W, Mattheisen, M, McGrath, PJ, McIntosh, A, McLean, AW, Middeldorp, CM (Christel), Middleton, L, Montgomery, GM, Murphy, SN, Nauck, M, Nolen, WA, Nyholt, DR, O' Donovan, M, Oskarsson, H, Pedersen, N, Scheftner, WA, Schulz, TG, Shyn, SI, Sigurdsson, E, Slager, SL, Smit, JH, Stefansson, H, Steffens, M, Thorgeirsson, T, Tozzi, F, Treutlein, J, Uhr, M, van den Oord, EJCG (Edwin), Van Grootheest, G, Volzke, H, Weilburg, JB, Willemsen, G, Zitman, FG, Neale, BM, Daly, M, Levinson, DF, Sullivan, PF, Psychiatry, Epidemiology, and Child and Adolescent Psychiatry / Psychology
Published: 2013

112. 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

113. Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

Author: Terwisscha van Scheltinga, Af, Bakker, Sc, van Haren, Ne, Derks, Em, Buizer Voskamp, Je, Boos, Hb, Cahn, W, Hulshoff, Pol, Ripke, S, Ophoff, Ra, Kahn, Rs, Sanders, Ar, Kendler, Ks, Levinson, Df, Sklar, P, Holmans, Pa, Lin, Dy, Duan, J, Andreassen, Oa, Scolnick, E, Cichon, S, Clair, St, D, Corvin, A, Gurling, H, Werge, T, Rujescu, D, Blackwood, Dh, Pato, Cn, Malhotra, Ak, Purcell, S, Dudbridge, F, Neale, Bm, Rossin, L, Visscher, Pm, Posthuma, D, Ruderfer, Dm, Fanous, A, Stefansson, H, Steinberg, S, Mowry, Bj, Golimbet, V, Hert, De, M, Jonsson, Eg, Bitter, I, Pietiläinen, Op, Collier, Da, Tosato, Sarah, Agartz, I, Albus, M, Alexander, M, Amdur, Rl, Amin, F, Bass, N, Bergen, Se, Black, Dw, Børglum, Ad, Brown, Ma, Bruggeman, R, Buccola, Ng, Byerley, Wf, Cantor, Rm, Carr, Vj, Catts, Sv, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, Pa, 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, Nb, Friedl, M, Georgieva, L, Giegline, I, Gill, M, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, Am, Henskens, Fa, Hougaard, Dm, Hultman, Cm, Ingason, A, Jablensky, Av, Jakobsen, Kd, Jay, M, Jürgens, G, Keller, Mc, Kenis, G, Kenny, E, Kim, Y, Kirov, Gk, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, Vk, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, Ky, Lichtenstein, P, Lieberman, Ja, Linszen, Dh, Lönnqvist, J, Loughland, Cm, Maclean, Aw, Maher, Bs, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, Mcghee, Ka, Mcgrath, Jj, Mcintosh, A, Mclean, De, Mcquillin, A, Melle, I, Michie, Pt, Milanova, V, Morris, Dw, Mors, O, Mortensen, Pb, Moskvina, V, Muglia, P, Myin Germeys, I, Nertney, Da, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nöthen, Mm, O'Dushlaine, C, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, Tf, Owen, Mj, Pantelis, C, Papadimitriou, G, Pato, Mt, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, Ae, Puri, V, Quested, D, Quinn, Em, Rasmussen, Hb, Réthelyi, Jm, Ribble, R, Rietschel, M, Riley, Bp, Ruggeri, Mirella, Schall, U, Schulze, Tg, Schwab, Sg, Scott, Rj, Shi, J, Sigurdsson, E, Silverman, Jm, Spencer, Cc, Stefansson, K, Strange, A, Strengman, E, Stroup, Ts, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, Jh, Timm, S, Toncheva, D, van den Oord, E, van Os, J, Van, Winkel, R, Veldink, J, Walsh, D, Wang, Ag, Wiersma, D, Wildenauer, Db, Williams, Hj, Williams, Nm, Wormley, B, Zammit, S, Sullivan, Pf, O'Donovan, Mc, Daly, Mj, Gejman, Pv, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, 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, Myin-Germeys, Inez, De Hert, Marc, and van Winkel, Ruud
Subjects: Adult, Male, Psychosis, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Biology, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Article, White matter, genome-wide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, mental disorders, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Biological Psychiatry, structural MRI, Genetics, neuroimaging, Case-control study, Brain, imaging, medicine.disease, 030227 psychiatry, 3. Good health, schizophrenia, Endophenotype, Phenotype, medicine.anatomical_structure, psychiatric, Schizophrenia, Case-Control Studies, Female, endophenotype, Genome-Wide Association Study, SNPs, Atrophy, 030217 neurology & neurosurgery
Abstract: BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. METHODS: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. RESULTS: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2 = .048, p = 1.6 × 10(-4)) and white matter volume (R2 = .051, p = 8.6 × 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. CONCLUSIONS: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.
Published: 2013

114. A two-stage meta-analysis identifies several new loci for Parkinson's disease

Author: Plagnol, V., Nalls, M.A., Bras, J.M., Hernandez, D., Sharma, M., Sheerin, U.M., Saad, M., Simon-Sanchez, J., Schulte, C., Lesage, S., Sveinbjornsdottir, S., Amouyel, P., Arepalli, S., Band, G., Barker, R.A., Bellinguez, C., Ben-Shlomo, Y., Berendse, H.W., Berg, D., Bhatia, K.P., Bie, R.M. de, Biffi, A., Bloem, B.R., Bochdanovits, Z., Bonin, M., Brockmann, K., Brooks, J., Burn, D.J., Charlesworth, G., Chen, H., Chinnery, P.F., Chong, S., Clarke, C.E., Cookson, M.R., Cooper, J.M., Corvol, J.C., Counsell, J., Damier, P., Dartigues, J.F., Deloukas, P., Deuschl, G., Dexter, D.T., Dijk, K.D. van, Dillman, A., Durif, F., Durr, A., Edkins, S., Evans, J.R., Foltynie, T., Freeman, C., Gao, J., Gardner, M., Gibbs, J.R., Goate, A., Gray, E., Guerreiro, R., Gustafsson, O., Harris, C., Hellenthal, G., Hilten, J.J. van, Hofman, A., Hollenbeck, A., Holton, J.L., Hu, M., Huang, X., Huber, H, Hudson, G., Hunt, S.E., Huttenlocher, J., Illig, T., Jonsson, P.V., Langford, C., Lees, A.J., Lichtner, P., Limousin, P., Lopez, G., McNeill, A., Moorby, C., Moore, M., Morris, H.A., Morrison, K.E., Mudanohwo, E., O'Sullivan, S.S, Pearson, J., Pearson, R., Perlmutter, J., Petursson, H., Pirinen, M., Polnak, P., Post, B., Potter, S.C., Ravina, B., Revesz, T., Riess, O., Rivadeneira, F., Rizzu, P., Ryten, M., Sawcer, S.J., Schapira, A., Scheffer, H., Shaw, K., Shoulson, I., Sidransky, E., Silva, R. de, Smith, C., Spencer, C.C., Stefansson, H., Steinberg, S., Stockton, J.D., Strange, A., Su, Z., Talbot, K., Tanner, C.M., Tashakkori-Ghanbaria, A., Tison, F., Trabzuni, D., Traynor, B.J., Uitterlinden, A.G., Vandrovcova, J., Velseboer, D., Vidailhet, M., Vukcevic, D., Walker, R., Warrenburg, B.P.C. van de, Weale, M.E., Wickremaratchi, M., Williams, N., Williams-Gray, C.H., Winder-Rhodes, S., Stefansson, K., Martinez, M., Donnelly, P., Singleton, A.B., Hardy, J., Heutink, P., Brice, A., Gasser, T., and Wood, N.W.
Subjects: Functional Neurogenomics Human Movement & Fatigue [DCN 2], Genomic disorders and inherited multi-system disorders Functional Neurogenomics [IGMD 3], Functional Neurogenomics [DCN 2]
Abstract: Contains fulltext : 97597.pdf (Publisher’s version ) (Open Access) A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p
Published: 2011

115. Genome-wide association study identifies five new schizophrenia loci

Author: Ripke, S. Sanders, A.R. Kendler, K.S. Levinson, D.F. Sklar, P. Holmans, P.A. Lin, D.-Y. Duan, J. Ophoff, R.A. Andreassen, O.A. Scolnick, E. Cichon, S. St. Clair, D. Corvin, A. Gurling, H. Werge, T. Rujescu, D. Blackwood, D.H.R. Pato, C.N. Malhotra, A.K. Purcell, S. Dudbridge, F. Neale, B.M. Rossin, L. Visscher, P.M. Posthuma, D. Ruderfer, D.M. Fanous, A. Stefansson, H. Steinberg, S. Mowry, B.J. Golimbet, V. De Hert, M. Jönsson, E.G. Bitter, I. Pietiläinen, O.P.H. Collier, D.A. Tosato, S. Agartz, I. Albus, M. Alexander, M. Amdur, R.L. Amin, F. Bass, N. Bergen, S.E. Black, D.W. Børglum, A.D. Brown, M.A. Bruggeman, R. Buccola, N.G. Byerley, W.F. Cahn, W. Cantor, R.M. Carr, V.J. Catts, S.V. Choudhury, K. Cloninger, C.R. Cormican, P. Craddock, N. Danoy, P.A. Datta, S. De Haan, L. Demontis, D. Dikeos, D. Djurovic, S. Donnelly, P. Donohoe, G. Duong, L. Dwyer, S. Fink-Jensen, A. Freedman, R. Freimer, N.B. Friedl, M. Georgieva, L. Giegling, I. Gill, M. Glenthøj, B. Godard, S. Hamshere, M. Hansen, M. Hansen, T. Hartmann, A.M. Henskens, F.A. Hougaard, D.M. Hultman, C.M. Ingason, A. Jablensky, A.V. Jakobsen, K.D. Jay, M. Jürgens, G. Kahn, R.S. Keller, M.C. Kenis, G. Kenny, E. Kim, Y. Kirov, G.K. Konnerth, H. Konte, B. Krabbendam, L. Krasucki, R. Lasseter, V.K. Laurent, C. Lawrence, J. Lencz, T. Lerer, F.B. Liang, K.-Y. Lichtenstein, P. Lieberman, J.A. Linszen, D.H. Lönnqvist, J. Loughland, C.M. MacLean, A.W. Maher, B.S. Maier, W. Mallet, J. Malloy, P. Mattheisen, M. Mattingsdal, M. McGhee, K.A. McGrath, J.J. McIntosh, A. McLean, D.E. McQuillin, A. Melle, I. Michie, P.T. Milanova, V. Morris, D.W. Mors, O. Mortensen, P.B. Moskvina, V. Muglia, P. Myin-Germeys, I. Nertney, D.A. Nestadt, G. Nielsen, J. Nikolov, I. Nordentoft, M. Norton, N. Nöthen, M.M. O'Dushlaine, C.T. Olincy, A. Olsen, L. O'Neill, F.A. Ørntoft, T.F. Owen, M.J. Pantelis, C. Papadimitriou, G. Pato, M.T. Peltonen, L. Petursson, H. Pickard, B. Pimm, J. Pulver, A.E. Puri, V. Quested, D. Quinn, E.M. Rasmussen, H.B. Réthelyi, J.M. Ribble, R. Rietschel, M. Riley, B.P. Ruggeri, M. Schall, U. Schulze, T.G. Schwab, S.G. Scott, R.J. Shi, J. Sigurdsson, E. Silverman, J.M. Spencer, C.C.A. Stefansson, K. Strange, A. Strengman, E. Stroup, T.S. Suvisaari, J. Terenius, L. Thirumalai, S. Thygesen, J.H. Timm, S. Toncheva, D. Van Den Oord, E. Van Os, J. Van Winkel, R. Veldink, J. Walsh, D. Wang, A.G. Wiersma, D. Wildenauer, D.B. Williams, H.J. Williams, N.M. Wormley, B. Zammit, S. Sullivan, P.F. O'Donovan, M.C. Daly, M.J. Gejman, P.V.
Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10 -11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10 -9), ANK3 (rs10994359, P = 2.5 × 10 -8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10 -9). © 2011 Nature America, Inc. All rights reserved.
Published: 2011

116. Common variants at VRK2 and TCF4 conferring risk of schizophrenia

Author: Steinberg, S., Jong, S. d., Genomics, I. S., Andreassen, O. A., Werge, T., Børglum, A. D., Mors, O., Mortensen, P. B., Gustafsson, O., Costas, J., O. P. H., Demontis, D., Papiol, S., Huttenlocher, J., Mattheisen, M., Breuer, R., Vassos, E., Giegling, I., Fraser, G., Walker, N., Tuulio Henriksson, A., Suvisaari, J., Lönnqvist, J., Paunio, T., Agartz, I., Melle, I., Djurovic, S., Strengman, E., G. R. O., Jürgens, G., Glenthøj, B., Terenius, L., Hougaard, D. M., Orntoft, T., Wiuf, C., Didriksen, M., Hollegaard, M. V., Nordentoft, M., Winkel, R. v., Kenis, G., Abramova, L., Kaleda, V., Arrojo, M., Sanjuán, J., Arango, C., Sperling, S., Rossner, M., Ribolsi, M., Magni, V., Siracusano, A., Christiansen, C., Kiemeney, L. A., Veldink, J., Den, L. v., Ingason, A., Muglia, P., Murray, R., Nöthen, M. M., Sigurdsson, E., Petursson, H., Thorsteinsdottir, U., Kong, A., Rubino, I. A., Hert, M. D., Réthelyi, J. M., Bitter, I., Jönsson, E. G., Golimbet, V., Carracedo, A., Ehrenreich, H., Craddock, N., Owen, M. J., O'Donovan, M. C., Case, W. T., Ruggeri, Mirella, Tosato, Sarah, Peltonen, L., Ophoff, R. A., Collier, D. A., Clair, D. S., Rietschel, M., Cichon, S., Stefansson, H., Rujescu, D., Stefansson, K., Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Amsterdam Neuroscience, Adult Psychiatry, and deCODE Genetics, IS-101 Reykjavik, Iceland.
Subjects: schizophrenia, sequence variants, TCF4, Genome-wide association study, Transcription Factor 4, 0302 clinical medicine, VRK2 protein, human, Polymorphism (computer science), Genotype, genetics [Schizophrenia], Neurogranin, Genetics (clinical), Schizophrenia, Risk, Alleles, Polymorphism, Single Nucleotide, Transcription Factors, Humans, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Genetic Predisposition to Disease, Protein-Serine-Threonine Kinases, Genome-Wide Association Study, Genetics, 0303 health sciences, Association Studies Articles, Single Nucleotide, General Medicine, genetics [Transcription Factors], 3. Good health, Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], Molecular epidemiology [NCEBP 1], 03 medical and health sciences, ddc:570, Polymorphism, Allele, genetics [Basic Helix-Loop-Helix Leucine Zipper Transcription Factors], Settore MED/25 - Psichiatria, Molecular Biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Intron, Odds ratio, Molecular biology, TCF4 protein, human, 030217 neurology & neurosurgery
Abstract: To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)). European Union LSHM-CT-2006-037761 PIAP-GA-2008-218251 HEALTH-F2-2009-223423 National Genome Research Network of the German Federal Ministry of Education and Research (BMBF) 01GS08144 01GS08147 National Institute of Mental Health R01 MH078075 N01 MH900001 MH074027 Centre of Excellence for Complex Disease Genetics of the Academy of Finland 213506 129680 Biocentrum Helsinki Foundation Faculty of Medicine, University of Helsinki Stanley Medical Research Institute Danish Council for Strategic Research 2101-07-0059 H. Lundbeck A/S Research Council of Norway 163070/V50 South-East Norway Health Authority 2004-123 Medical Research Council Ministerio de Sanidad y Consumo, Spain PI081522 Xunta de Galicia 08CSA005208PR Swedish Research Council Wellcome Trust 083948/Z/07/Z Max Planck Society Eli Lilly and Company info:eu-repo/grantAgreement/EC/FP7/218251
Published: 2011

117. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Author: Anttila, V., Stefansson, H., Kallela, M., Todt, U., Terwindt, G.M., Calafato, M.S., Nyholt, D.R., Dimas, A.S., Freilinger, T., Muller-Myhsok, B., Artto, V., Inouye, M., Alakurtti, K., Kaunisto, M.A., Hamalainen, E., Vries, B. de, Stam, A.H., Weller, C.M., Heinze, A., Heinze-Kuhn, K., Goebel, I., Borck, G., Gobel, H., Steinberg, S., Wolf, C., Bjornsson, A., Gudmundsson, G., Kirchmann, M., Hauge, A., Werge, T., Schoenen, J., Eriksson, J.G., Hagen, K., Stovner, L., Wichmann, E., Meitinger, T., Alexander, M., Moebus, S., Schreiber, S., Aulchenko, Y.S., Breteler, M.M.B., Uitterlinden, A.G., Hofman, A., Duijn, C.M. van, Tikka-Kleemola, P., Vepsalainen, Lucae, S., Tozzi, F., Muglia, P., Barrett, J., Kaprio, J., Farkkila, M., Peltonen, L., Stefansson, K., Zwart, J.A., Ferrari, M.D., Olesen, J., Daly, M., Wessman, M., Maagdenberg, A.M.J.M. van den, Dichgans, M., Kubisch, C., Dermitzakis, E.T., Frants, R.R., Palotie, A., and Int Headache Genetics Consortium
Subjects: familial hemiplegic migraine lymphoblastoid cell-lines gene-expression episodic ataxia spreading depression confers risk mutation type-2 involvement mechanisms
Abstract: Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-11) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-5), permuted threshold for genome-wide significance 7.7 x 10(-5)). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.
Published: 2010

118. How Can Pharmacogenomics Biomarkers Be Translated into Patient Benefit

Author: Collier, D., primary, Achilla, E., additional, Breen, G., additional, Curran, S., additional, Dima, D., additional, Flanagan, R., additional, Frank, J., additional, Frangou, S., additional, Gasse, C., additional, Giegling, I., additional, Rietschel, M., additional, Rujescu, D., additional, Maccabe, J., additional, McCrone, P., additional, Mill, J., additional, Sigurdsson, E., additional, Stefansson, H., additional, Walters, J., additional, Verbelen, M., additional, and Helthuis, M., additional
Published: 2015
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119. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm

Author: Gretarsdottir, S, Baas, AF, Thorleifsson, G, Holm, H, den Heijer, M, de Vries, JPPM, Kranendonk, SE, Zeebregts, CJAM, van Sterkenburg, SM, Geelkerken, RH, van Rij, AM, Williams, MJA, Boll, APM, Kostic, JP, Jonasdottir, A, Walters, GB, Masson, G, Sulem, P, Saemundsdottir, J, Mouy, M, Magnusson, KP, Tromp, G, Elmore, JR, Sakalihasan, N, Limet, R, Defraigne, JO, Ferrell, RE, Ronkainen, A, Ruigrok, YM, Wijmenga, C, Grobbee, DE, Shah, SH, Granger, CB, Quyyumi, AA, Vaccarino, V, Patel, RS, Zafari, AM, Levey, AI, Austin, H, Girelli, D, Pignatti, PF, Olivieri, O, Martinelli, N, Malerba, G, Trabetti, E, Becker, LC, Becker, DM, Reilly, MP, Rader, DJ, Mueller, T, Dieplinger, B, Haltmayer, M, Urbonavicius, S, Lindblad, B, Gottsater, A, Gaetani, E, Pola, R, Wells, P, Rodger, M, Forgie, M, Langlois, N, Corral, J, Vicente, V, Fontcuberta, J, Espana, F, Grarup, N, Jorgensen, T, Witte, DR, Hansen, T, Pedersen, O, Aben, KK, de Graaf, J, Holewijn, S, Folkersen, L, Franco-Cereceda, A, Eriksson, P, Collier, DA, Stefansson, H, Steinthorsdottir, V, Rafnar, T, Valdimarsson, EM, Magnadottir, HB, Sveinbjornsdottir, S, Olafsson, I, Magnusson, MK, Palmason, R, Haraldsdottir, V, Andersen, K, Onundarson, PT, Thorgeirsson, G, Kiemeney, LA, Powell, JT, Carey, DJ, Kuivaniemi, H, Lindholt, JS, Jones, GT, Kong, A, Blankensteijn, JD, Matthiasson, SE, Thorsteinsdottir, U, and Stefansson, K
Abstract: We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
Published: 2010

120. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.

Author: Nalls, M.A., Pankratz, N., Lill, C.M., Do, C.B., Hernandez, D.G., Saad, M., DeStefano, A.L., Kara, E., Bras, J., Sharma, M., Schulte, C., Keller, M.F., Arepalli, S., Letson, C., Edsall, C., Stefansson, H., Liu, X., Pliner, H., Lee, J.H. van der, Cheng, R., Ikram, M.A., Ioannidis, J.P., Hadjigeorgiou, G.M., Bis, J.C., Martinez, M., Perlmutter, J.S., Goate, A., Marder, K., Fiske, B., Sutherland, M., Xiromerisiou, G., Myers, R.H., Clark, L.N., Stefansson, K., Hardy, J.A., Heutink, P., Chen, H., Wood, N.W., Houlden, H., Payami, H., Brice, A., Scott, W.K., Gasser, T., Bertram, L., Eriksson, N., Foroud, T., Singleton, A.B., Scheffer, H., Warrenburg, B.P.C. van de, et al., Nalls, M.A., Pankratz, N., Lill, C.M., Do, C.B., Hernandez, D.G., Saad, M., DeStefano, A.L., Kara, E., Bras, J., Sharma, M., Schulte, C., Keller, M.F., Arepalli, S., Letson, C., Edsall, C., Stefansson, H., Liu, X., Pliner, H., Lee, J.H. van der, Cheng, R., Ikram, M.A., Ioannidis, J.P., Hadjigeorgiou, G.M., Bis, J.C., Martinez, M., Perlmutter, J.S., Goate, A., Marder, K., Fiske, B., Sutherland, M., Xiromerisiou, G., Myers, R.H., Clark, L.N., Stefansson, K., Hardy, J.A., Heutink, P., Chen, H., Wood, N.W., Houlden, H., Payami, H., Brice, A., Scott, W.K., Gasser, T., Bertram, L., Eriksson, N., Foroud, T., Singleton, A.B., Scheffer, H., Warrenburg, B.P.C. van de, and et al.
Abstract: 1 september 2014, Item does not contain fulltext, We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 x 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
Published: 2014

121. Biological insights from 108 schizophrenia-associated genetic loci

Author: Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Keong, JLC, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Mueller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Borglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Noethen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, O'Donovan, MC, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Keong, JLC, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Mueller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Borglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Noethen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, and O'Donovan, MC
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
Published: 2014

122. Disruption of the neurexin 1 gene is associated with schizophrenia

Author: Toulopoulou, T, Wiersma, D, Murray, R, Ruggeri, M, Tosato, S, Bonetto, C, Steinberg, S, Sigurdsson, E, Sigmundsson, T, Petursson, H, Gylfason, A, Olason, PI, Hardarsson, G, Jonsdottir, GA, Cahn, W, de Haan, L, Krabbendam, L, MyinGermeys, I, Werge, T, Kiemeney, LA, Franke, B, Pietiläinen, OPH, Picchioni, M, Vassos, E, Ettinger, U, Rietschel, M, Gustafsson, O, BuizerVoskamp, JE, Fossdal, R, Giegling, I, Sabatti, C, Ophoff, RA, Möller, HJ, Hartmann, AM, Hoffmann, P, Crombie, C, Rujescu, D, Veltman, J, Fraser, G, St Clair, D, Peltonen, L, Stefansson, K, Barnes, MR, Ingason, A, Stefansson, H, Nöthen, MM, Walker, N, Lonnqvist, J, Suvisaari, J, TuulioHenriksson, A, Djurovic, S, Collier, DA, Kahn, RS, Melle, I, Andreassen, OA, Hansen, T, Linszen, D, von Os, J, Bramon, E, Cichon, S, Bruggeman, R, ANS - Amsterdam Neuroscience, Adult Psychiatry, Germeys, Inez, Clinical Child and Family Studies, LEARN! - Brain, learning and development, and Faculteit Medische Wetenschappen/UMCG
Subjects: Male, Genetics and epigenetic pathways of disease [NCMLS 6], Gene Dosage, Aetiology, screening and detection [ONCOL 5], CARDIO-FACIAL SYNDROME, 0302 clinical medicine, Gene Duplication, Gene duplication, Perception and Action [DCN 1], HUMAN GENOME, Copy-number variation, European Continental Ancestry Group/genetics, Neural Cell Adhesion Molecules, POPULATION, Genetics (clinical), RISK, Genetics, 0303 health sciences, education.field_of_study, Schizophrenia/*genetics, REARRANGEMENTS, General Medicine, Exons, Nerve Tissue Proteins/*genetics, Penetrance, 3. Good health, Female, Molecular Sequence Numbers, Functional Neurogenomics [DCN 2], Adult, Psychosis, Adolescent, Cell Adhesion Molecules, Neuronal, Population, European Continental Ancestry Group, Nerve Tissue Proteins, COPY-NUMBER VARIATION, Biology, Gene dosage, Article, White People, STRUCTURAL VARIANTS, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Young Adult, Translational research [ONCOL 3], mental disorders, medicine, Humans, MICRODELETION, Genetic Predisposition to Disease, Gene Silencing, education, Molecular Biology, 030304 developmental biology, Genetic association, Hereditary cancer and cancer-related syndromes [ONCOL 1], AUTISM SPECTRUM DISORDER, Calcium-Binding Proteins, Case-Control Studies, Gene Deletion, Breakpoint, ADVANCING PATERNAL AGE, medicine.disease, Schizophrenia, 030217 neurology & neurosurgery
Abstract: Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia. © The Author 2008. Published by Oxford University Press. All rights reserved., link_to_OA_fulltext
Published: 2009

123. Common variants conferring risk of schizophrenia

Author: Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Chichon, S., Rujescu, D., Werge, T., Pietilainen, O. P., Mors, O., Mortensen, P. B., Sigurdsson, E., Gustafsson, O., Nyegaard, M., Tuulio Henriksson, A., Ingason, A., Hansen, T., Suvisaari, J., Lonnqvist, J., Paunio, T., Borglum, A. D., Hartmann, A., Fink Jensen, A., Nordentoft, M., Hougaard, D., Norgaard Petersen, B., Bottcher, J., Olesen, J., Breuer, R., Moller, H. J., Giegling, I., Rasmussen, H. B., Timm, S., Mattheisen, M., Bitter, I., Rethelyi, J. M., Magnusdottir, B. B., Sigmundsson, T., Olason, P. I., Masson, G., Gulcher, J. R., Haraldsson, M., Fossdal, R., Thorgeirsson, T. E., Thorsteinsdottir, U., Ruggeri, Mirella, Tosato, Sarah, Franke, B., Strengman, E., Kiemeney, L. A., Group, Melle, I., Djurovic, S., Abramova, I., Kaleda, V., Sanjuan, J., de Frutos, R., Bramon, E., Vassos, E., Fraser, G., Ettinger, U., Picchioni, M., Walker, N., Toulopoulou, T., Need, A. C., Ge, D., Lim Yoon, J., Shianna, K. V., Freimer, N. B., Cator, R. M., Murray, R., Kong, A., Golimbet, V., Carracedo, A., Arango, C., Costas, J., Jonsson, E. G., Terenius, L., Agartz, I., Petursson, H., Nothen, M. M., Rietschel, M., Matthews, P. M., Muglia, P., Peltonen, L., St Clair, D., Goldstein, D. B., Collier, D., Genetic, Risk, Outcome in Psychosis, Kahn, R. S., Linszen, D. H., Van Os, J., Wiersma, D., Bruggeman, R., Cahn, H., de Haan, L., Krabbendam, L., Myin Germeys, I., ANS - Amsterdam Neuroscience, Adult Psychiatry, deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland., Clinical Child and Family Studies, LEARN! - Brain, learning and development, and Germeys, Inez
Subjects: Pair 6/genetics, Genetics and epigenetic pathways of disease [NCMLS 6], Genome-wide association study, Aetiology, screening and detection [ONCOL 5], 1Q21.1, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, Transcription Factor 4, 0302 clinical medicine, Chemicals And Cas Registry Numbers, Perception and Action [DCN 1], Copy-number variation, POPULATION, Genetics, Pair 18/genetics, 0303 health sciences, education.field_of_study, Genome, Human/genetics, Multidisciplinary, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Schizophrenia/*genetics/immunology, Genetic Predisposition to Disease/*genetics, 3. Good health, DNA-Binding Proteins, Neurogranin/genetics, DISEASES, Chromosomes, Human, Pair 6, Single Nucleotide/*genetics, Functional Neurogenomics [DCN 2], Zinc finger protein 804A, Human, Genetic Markers, Psychosis, Genotype, Population, Transcription Factors/genetics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Chromosomes, Pair 11/genetics, Article, DNA-Binding Proteins/genetics, Genetic Markers/genetics, Genome-Wide Association Study, Humans, Polymorphism, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Translational research [ONCOL 3], medicine, SNP, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, 030304 developmental biology, Genetic association, Hereditary cancer and cancer-related syndromes [ONCOL 1], Genome, Human, Chromosomes, Human, Pair 11, MEMORY, medicine.disease, GENE, NEUROGRANIN, DELETIONS, Schizophrenia, biology.protein, Neurogranin, Chromosomes, Human, Pair 18, MENTAL-RETARDATION, SCAN, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ĝ€ genomic disordersĝ€™, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition. © 2009 Macmillan Publishers Limited., link_to_OA_fulltext
Published: 2009

124. Large recurrent microdeletions associated with schizophrenia

Author: Toulopoulou, T, Franke, B, Crombie, C, Fossdal, R, Sigmundsson, T, BuizerVoskamp, JE, Hansen, T, Jakobsen, KD, Muglia, P, Francks, C, Matthews, PM, Murray, R, Ruggeri, M, Sabatti, C, Gylfason, A, Halldorsson, BV, Vassos, E, Tosato, S, Walshe, M, Freimer, NB, Gulcher, JR, Gudbjartsson, D, Thorsteinsdottir, U, Kong, A, Thorgeirsson, TE, Olesen, J, Vasilescu, C, Andreassen, OA, Melle, I, Mühleisen, TW, Wang, AG, Ullum, H, Need, AC, Sigurdsson, A, Jonasdottir, A, Djurovic, S, Ophoff, RA, Georgi, A, Rietschel, M, Werge, T, Bjornsson, A, Mattiasdottir, S, Blondal, T, Haraldsson, M, Petursson, H, MyinGermeys, I, Krabbendam, L, De Haan, L, Cahn, W, Bruggeman, R, Wiersma, D, Goldstein, DB, Nöthen, MM, Peltonen, L, Van Os, J, Linszen, DH, Kahn, RS, Stefansson, K, Magnusdottir, BB, Di Forti, M, Bramon, E, Paunio, T, TuulioHenriksson, A, Giegling, I, Möller, HJ, Suvisaari, J, Hartmann, A, Shianna, KV, Ge, D, Lonnqvist, J, Collier, DA, Walker, N, Li, T, Fraser, G, Ingason, A, Steinberg, S, Sigurdsson, E, St Clair, D, Kiemeney, LA, Stefansson, H, Rujescu, D, Cichon, S, Pietiläinen, OPH, ANS - Amsterdam Neuroscience, and Adult Psychiatry
Subjects: Schizophrenia/genetics, Genetics and epigenetic pathways of disease [NCMLS 6], Loss of Heterozygosity, Aetiology, screening and detection [ONCOL 5], Bioinformatics, China, Chromosomes, Human, Pair 1/genetics, Pair 15/genetics, Europe, Gene Dosage/genetics, Genetic Predisposition to Disease/genetics, Genome, Human/genetics, Genotype, Models, Genetic, Polymorphism, Single Nucleotide/genetics, Psychotic Disorders/genetics, Sequence Deletion/genetics, Perception and Action [DCN 1], Determinants in Health and Disease [EBP 1], Copy-number variation, Molecular diagnosis, prognosis and monitoring [UMCN 1.2], Genetics, education.field_of_study, Multidisciplinary, biology, CHRNA7, Fragile X syndrome, References (31) View In Table Layout, Schizophrenia, Functional Neurogenomics [DCN 2], Psychosis, Population, Single-nucleotide polymorphism, Article, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], Cognitive neurosciences [UMCN 3.2], Translational research [ONCOL 3], mental disorders, medicine, education, Hereditary cancer and cancer-related syndromes [ONCOL 1], medicine.disease, Genetic defects of metabolism [UMCN 5.1], biology.protein, Autism
Abstract: Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. ©2008 Macmillan Publishers Limited. All rights reserved., link_to_OA_fulltext
Published: 2008

125. Large recurrent microdeletions associated with schizophrenia [Letter to Nature]

Author: Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J., Hansen, T., Jakobsen, K., Muglia, P., Francks, C., Matthews, P., Gylfason, A., Halldorsson, B., Gudbjartsson, D., Thorgeirsson, T., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B., Giegling, I., Möller, H., Hartmann, A., Shianna, K., Ge, D., Need, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T., Wang, A., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L., Franke, B., Sabatti, C., Freimer, N., Gulcher, J., Thorsteinsdottir, U., Kong, A., Andreassen, O., Ophoff, R., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D., Nothen, M., Peltonen, L., Collier, D., St. Clair, D., and Stefansson, K.
Subjects: mental disorders
Abstract: Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
Published: 2008

126. Cutaneous melanoma inIceland: changingBreslow's tumour thickness

Author: Stefansson, H., primary, Tryggvadottir, L., additional, Olafsdottir, E.J., additional, Mooney, E., additional, Olafsson, J.H., additional, Sigurgeirsson, B., additional, and Jonasson, J.G., additional
Published: 2014
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127. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration

Author: Helgason, H., Sulem, P., Duvvari, M.R., Luo, H., Thorleifsson, G., Stefansson, H., Jonsdottir, I., Masson, G., Gudbjartsson, D.F., Walters, G.B., Magnusson, O.T., Kong, A., Rafnar, T., Kiemeney, L.A.L.M., Schoenmaker-Koller, F.E., Zhao, L., Boon, C.J.F., Song, Y., Fauser, S., Pei, M., Ristau, T., Patel, S., Liakopoulos, S., Ven, J.P.H. van de, Hoyng, C.B., Ferreyra, H., Duan, Y., Bernstein, P.S., Geirsdottir, A., Helgadottir, G., Stefansson, E., Hollander, A.I. den, Zhang, K., Jonasson, F., Sigurdsson, H., Thorsteinsdottir, U., Stefansson, K., Helgason, H., Sulem, P., Duvvari, M.R., Luo, H., Thorleifsson, G., Stefansson, H., Jonsdottir, I., Masson, G., Gudbjartsson, D.F., Walters, G.B., Magnusson, O.T., Kong, A., Rafnar, T., Kiemeney, L.A.L.M., Schoenmaker-Koller, F.E., Zhao, L., Boon, C.J.F., Song, Y., Fauser, S., Pei, M., Ristau, T., Patel, S., Liakopoulos, S., Ven, J.P.H. van de, Hoyng, C.B., Ferreyra, H., Duan, Y., Bernstein, P.S., Geirsdottir, A., Helgadottir, G., Stefansson, E., Hollander, A.I. den, Zhang, K., Jonasson, F., Sigurdsson, H., Thorsteinsdottir, U., and Stefansson, K.
Abstract: Contains fulltext : 125275.pdf (publisher's version ) (Closed access), Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 x 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 x 10(-10), resulting in OR = 3.65 and P = 8.8 x 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.
Published: 2013

128. 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

129. A common biological basis of obesity and nicotine addiction

Author: Thorgeirsson, T.E. (Thorgeir), Gudbjartsson, D.F. (Daniel), Sulem, P. (Patrick), Besenbacher, S. (Søren), Styrkarsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Walters, G.B. (Bragi), Furberg, H. (Helena), Sullivan, P. (Patrick), Marchini, J. (Jonathan), McCarthy, M.I. (M.), Steinthorsdottir, V. (Valgerdur), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Surakka, I. (Ida), Vink, J.M. (Jacqueline), Amin, N. (Najaf), Geller, F. (Frank), Rafnar, T. (Thorunn), Esko, T. (Tõnu), Walter, S. (Stefan), Gieger, C. (Christian), Rawal, R. (Rajesh), Mangino, M. (Massimo), Prokopenko, I. (Inga), Mägi, R. (Reedik), Keskitalo, K. (Kaisu), Gudjonsdottir, I.H. (Iris), Gretarsdottir, S. (Solveig), Stefansson, H. (Hreinn), Aulchenko, Y.S. (Yurii), Nelis, M. (Mari), Aben, K.K.H. (Katja), Heijer, M. (Martin) den, Soranzo, N. (Nicole), Valdes, A.M. (Ana Maria), Steves, C.J. (Claire), Uitterlinden, A.G. (André), Hofman, A. (Albert), Tönjes, A. (Anke), Kovacs, P. (Peter), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Vogelzangs, N. (Nicole), Döring, A. (Angela), Dahmen, N. (N.), Nitz, B. (Barbara), Ripatti, S. (Samuli), Perola, M. (Markus), Kettunen, J. (Johannes), Hartikainen, A.L., Pouta, A. (Anneli), Laitinen, J. (Jaana), Isohanni, M.K. (Matti), Huei-Yi, S. (Shen), Allen, M. (Maxine), Krestyaninova, M. (Maria), Hall, A. (Anne), Thompson, J.R. (John), Oskarsson, H. (Hogni), Tyrfingsson, T. (Thorarinn), Kiemeney, L.A.L.M. (Bart), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Stumvoll, M. (Michael), Spector, T.D. (Timothy), Wichmann, H.E. (Heinz Erich), Metspalu, A. (Andres), Samani, N.J. (Nilesh), Penninx, B.W.J.H. (Brenda), Oostra, B.A. (Ben), Boomsma, D.I. (Dorret), Tiemeier, H.W. (Henning), Duijn, C.M. (Cornelia) van, Kaprio, J. (Jaakko), Gulcher, J.R. (Jeffrey), Kim, Y. (Yunjung), Dackor, J. (Jennifer), Boerwinkle, E.A. (Eric), Franceschini, N. (Nora), Ardissino, D. (Diego), Bernardinelli, L. (Luisa), Mannucci, P.M. (Pier), Mauri, F. (Francesco), Merlini, P.A. (Piera), Absher, D. (Devin), Assimes, T.L. (Themistocles), Fortmann, S.P. (Stephen), Iribarren, C. (Carlos), Knowles, J.W. (Joshua), Quertermous, T. (Thomas), Ferrucci, L. (Luigi), Tanaka, T. (Toshiko), Bis, J.C. (Joshua), Haritunians, T. (Talin), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Thacker, E.L. (Evan), Almgren, P. (Peter), Groop, L. (Leif), Ladenvall, C. (Claes), Boehnke, M. (Michael), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Stringham, H.M. (Heather), Tuomilehto, J. (Jaakko), Benjamin, E.J. (Emelia), Hwang, S.J., Levy, D. (Daniel), Preis, S.R., Vasan, R.S. (Ramachandran Srini), Duan, J. (Jubao), Gejman, P.V. (Pablo), Levinson, D.F. (Douglas), Sanders, A.R. (Alan), Shi, J. (Jianxin), Lips, E.H. (Esther), McKay, J.D. (James), Agudo, A. (Antonio), Barzan, L. (Luigi), Bencko, V. (Vladimir), Benhamou, S. (Simone), Castellsagué, X. (Xavier), Canova, C. (Cristina), Conway, D.I. (David), Fabianova, E. (Eleonora), Foretova, L. (Lenka), Janout, V. (Vladimir), Healy, C.M. (Claire), Holcátová, I. (Ivana), Kjaerheim, K. (Kristina), Lagiou, P., Lissowska, J. (Jolanta), Lowry, R. (Ray), MacFarlane, T.V. (Tatiana), Mates, D. (Dana), Richiardi, L. (Lorenzo), Rudnai, P. (Peter), Szeszenia-Dabrowska, N. (Neonilia), Zaridze, D., Znaor, A. (Ariana), Lathrop, M. (Mark), Brennan, P. (Paul), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Guralnik, J.M. (Jack), Milaneschi, Y. (Yuri), Perry, J.R.B. (John), Altshuler, D. (David), Elosua, R. (Roberto), Kathiresan, S. (Sekar), Lucas, G. (Gavin), Melander, O. (Olle), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Voight, B.F. (Benjamin), Smith, A.V. (Davey), Geus, E.J.C. (Eco) de, Chanock, S.J. (Stephen), Gu, F. (Fangyi), Hankinson, S.E. (Susan), Hunter, D. (David), Chasman, D.I. (Daniel), Everett, B.M. (Brendan), Paré, G. (Guillaume), Ridker, P.M. (Paul), Li, M.D. (Ming), Maes, H.H. (Hermine), Audrain-Mcgovern, J. (Janet), Posthuma, D. (Danielle), Thornton, L.M. (Laura), Lerman, C. (Caryn), Rose, J.E. (Jed), Ioannidis, J.P.A. (John), Kraft, P. (Peter), Lin, D.Y. (Dan), Liu, J. (Jason), Muglia, P. (Pierandrea), Waterworth, D. (Dawn), Pillai, A.D. (Ajay), Middleton, L. (Lefkos), Berrettini, W. (Wade), Knouff, C.W. (Christopher), Yuan, X. (Xin), Waeber, G. (Gérard), Vollenweider, P. (Peter), Preisig, M. (Martin), Wareham, N.J. (Nick), Zhao, J.H. (Jing Hua), Loos, R.J.F. (Ruth), Barroso, I.E. (Inês), Khaw, K-T. (Kay-Tee), Grundy, S.M. (Scott), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), McPherson, R. (Ruth), Vincent, J. (John), Strauss, J.S. (John S), Kennedy, J. (James), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Day, R.N. (Richard), Matthews, K. (Keith), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lucae, S. (Susanne), Ising, M. (Marcus), Brueckl, T. (Tanja), Horstmann, S. (Sonja), Heinrich, J. (Joachim), Lamina, C. (Claudia), Polasek, O. (Ozren), Zgaga, L. (Lina), Huffman, J.E. (Jennifer), Campbell, S. (Susan), Kooner, J.S. (Jaspal), Chambers, J.C. (John), Burnett, M.S., Devaney, J. (Joseph), Pichard, A.D., Kent, K.M. (Kenneth), Satler, L.F., Lindsay, J.M. (Joseph), Waksman, R. (Ron), Epstein, S.E. (Stephen), Wilson, J.F. (James), Wild, S.H. (Sarah), Campbell, H. (Harry), Vitart, V. (Veronique), Reilly, M.P. (Muredach), Li, M. (Mingyao), Qu, L. (Liming), Wilensky, A. (Asaf), Matthai, W. (William), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Franke, A. (Andre), Wittig, M. (Michael), Schäfer, A. (Arne), Uda, M. (Manuela), Terracciano, A., Xiao, X. (Xiangjun), Busonero, F., Scheet, P. (Paul), Schlessinger, D., Clair, D.S., Rujescu, D. (Dan), Abecasis, G.R. (Gonçalo), Grabe, H.J. (Hans Jörgen), Teumer, A. (Alexander), Völzke, H. (Henry), Petersmann, A. (Astrid), John, U. (Ulrich), Rudan, I. (Igor), Hayward, C. (Caroline), Wright, A.F. (Alan), Kolcic, I. (Ivana), Wright, B.J. (Benjamin), Balmforth, A.J. (Anthony), Anderson, C. (Carl), Ahmed, T. (Tariq), Mathew, J. (Joseph), Parkes, M. (Miles), Satsangi, J. (Jack), Caulfield, M. (Mark), Munroe, P. (Patricia), Farrall, M. (Martin), Dominiczak, A. (Anna), Worthington, H. (Helen), Thomson, W. (Wendy), Eyre, D.S. (Dylan Samuel), Barton, A. (Anne), Mooser, V. (Vincent), Francks, C. (Clyde), Thorgeirsson, T.E. (Thorgeir), Gudbjartsson, D.F. (Daniel), Sulem, P. (Patrick), Besenbacher, S. (Søren), Styrkarsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Walters, G.B. (Bragi), Furberg, H. (Helena), Sullivan, P. (Patrick), Marchini, J. (Jonathan), McCarthy, M.I. (M.), Steinthorsdottir, V. (Valgerdur), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Surakka, I. (Ida), Vink, J.M. (Jacqueline), Amin, N. (Najaf), Geller, F. (Frank), Rafnar, T. (Thorunn), Esko, T. (Tõnu), Walter, S. (Stefan), Gieger, C. (Christian), Rawal, R. (Rajesh), Mangino, M. (Massimo), Prokopenko, I. (Inga), Mägi, R. (Reedik), Keskitalo, K. (Kaisu), Gudjonsdottir, I.H. (Iris), Gretarsdottir, S. (Solveig), Stefansson, H. (Hreinn), Aulchenko, Y.S. (Yurii), Nelis, M. (Mari), Aben, K.K.H. (Katja), Heijer, M. (Martin) den, Soranzo, N. (Nicole), Valdes, A.M. (Ana Maria), Steves, C.J. (Claire), Uitterlinden, A.G. (André), Hofman, A. (Albert), Tönjes, A. (Anke), Kovacs, P. (Peter), Hottenga, J.J. (Jouke Jan), Willemsen, G.A.H.M. (Gonneke), Vogelzangs, N. (Nicole), Döring, A. (Angela), Dahmen, N. (N.), Nitz, B. (Barbara), Ripatti, S. (Samuli), Perola, M. (Markus), Kettunen, J. (Johannes), Hartikainen, A.L., Pouta, A. (Anneli), Laitinen, J. (Jaana), Isohanni, M.K. (Matti), Huei-Yi, S. (Shen), Allen, M. (Maxine), Krestyaninova, M. (Maria), Hall, A. (Anne), Thompson, J.R. (John), Oskarsson, H. (Hogni), Tyrfingsson, T. (Thorarinn), Kiemeney, L.A.L.M. (Bart), Jarvelin, M.-R. (Marjo-Riitta), Salomaa, V. (Veikko), Stumvoll, M. (Michael), Spector, T.D. (Timothy), Wichmann, H.E. (Heinz Erich), Metspalu, A. (Andres), Samani, N.J. (Nilesh), Penninx, B.W.J.H. (Brenda), Oostra, B.A. (Ben), Boomsma, D.I. (Dorret), Tiemeier, H.W. (Henning), Duijn, C.M. (Cornelia) van, Kaprio, J. (Jaakko), Gulcher, J.R. (Jeffrey), Kim, Y. (Yunjung), Dackor, J. (Jennifer), Boerwinkle, E.A. (Eric), Franceschini, N. (Nora), Ardissino, D. (Diego), Bernardinelli, L. (Luisa), Mannucci, P.M. (Pier), Mauri, F. (Francesco), Merlini, P.A. (Piera), Absher, D. (Devin), Assimes, T.L. (Themistocles), Fortmann, S.P. (Stephen), Iribarren, C. (Carlos), Knowles, J.W. (Joshua), Quertermous, T. (Thomas), Ferrucci, L. (Luigi), Tanaka, T. (Toshiko), Bis, J.C. (Joshua), Haritunians, T. (Talin), McKnight, B. (Barbara), Psaty, B.M. (Bruce), Taylor, K.D. (Kent), Thacker, E.L. (Evan), Almgren, P. (Peter), Groop, L. (Leif), Ladenvall, C. (Claes), Boehnke, M. (Michael), Jackson, A.U. (Anne), Mohlke, K.L. (Karen), Stringham, H.M. (Heather), Tuomilehto, J. (Jaakko), Benjamin, E.J. (Emelia), Hwang, S.J., Levy, D. (Daniel), Preis, S.R., Vasan, R.S. (Ramachandran Srini), Duan, J. (Jubao), Gejman, P.V. (Pablo), Levinson, D.F. (Douglas), Sanders, A.R. (Alan), Shi, J. (Jianxin), Lips, E.H. (Esther), McKay, J.D. (James), Agudo, A. (Antonio), Barzan, L. (Luigi), Bencko, V. (Vladimir), Benhamou, S. (Simone), Castellsagué, X. (Xavier), Canova, C. (Cristina), Conway, D.I. (David), Fabianova, E. (Eleonora), Foretova, L. (Lenka), Janout, V. (Vladimir), Healy, C.M. (Claire), Holcátová, I. (Ivana), Kjaerheim, K. (Kristina), Lagiou, P., Lissowska, J. (Jolanta), Lowry, R. (Ray), MacFarlane, T.V. (Tatiana), Mates, D. (Dana), Richiardi, L. (Lorenzo), Rudnai, P. (Peter), Szeszenia-Dabrowska, N. (Neonilia), Zaridze, D., Znaor, A. (Ariana), Lathrop, M. (Mark), Brennan, P. (Paul), Bandinelli, S. (Stefania), Frayling, T.M. (Timothy), Guralnik, J.M. (Jack), Milaneschi, Y. (Yuri), Perry, J.R.B. (John), Altshuler, D. (David), Elosua, R. (Roberto), Kathiresan, S. (Sekar), Lucas, G. (Gavin), Melander, O. (Olle), O'Donnell, C.J. (Christopher), Schwartz, S.M. (Stephen), Voight, B.F. (Benjamin), Smith, A.V. (Davey), Geus, E.J.C. (Eco) de, Chanock, S.J. (Stephen), Gu, F. (Fangyi), Hankinson, S.E. (Susan), Hunter, D. (David), Chasman, D.I. (Daniel), Everett, B.M. (Brendan), Paré, G. (Guillaume), Ridker, P.M. (Paul), Li, M.D. (Ming), Maes, H.H. (Hermine), Audrain-Mcgovern, J. (Janet), Posthuma, D. (Danielle), Thornton, L.M. (Laura), Lerman, C. (Caryn), Rose, J.E. (Jed), Ioannidis, J.P.A. (John), Kraft, P. (Peter), Lin, D.Y. (Dan), Liu, J. (Jason), Muglia, P. (Pierandrea), Waterworth, D. (Dawn), Pillai, A.D. (Ajay), Middleton, L. (Lefkos), Berrettini, W. (Wade), Knouff, C.W. (Christopher), Yuan, X. (Xin), Waeber, G. (Gérard), Vollenweider, P. (Peter), Preisig, M. (Martin), Wareham, N.J. (Nick), Zhao, J.H. (Jing Hua), Loos, R.J.F. (Ruth), Barroso, I.E. (Inês), Khaw, K-T. (Kay-Tee), Grundy, S.M. (Scott), Barter, P. (Phil), Mahley, R. (Robert), Kesaniemi, Y.A. (Antero), McPherson, R. (Ruth), Vincent, J. (John), Strauss, J.S. (John S), Kennedy, J. (James), Farmer, A.E. (Anne E), Mcguffin, P. (Peter), Day, R.N. (Richard), Matthews, K. (Keith), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lucae, S. (Susanne), Ising, M. (Marcus), Brueckl, T. (Tanja), Horstmann, S. (Sonja), Heinrich, J. (Joachim), Lamina, C. (Claudia), Polasek, O. (Ozren), Zgaga, L. (Lina), Huffman, J.E. (Jennifer), Campbell, S. (Susan), Kooner, J.S. (Jaspal), Chambers, J.C. (John), Burnett, M.S., Devaney, J. (Joseph), Pichard, A.D., Kent, K.M. (Kenneth), Satler, L.F., Lindsay, J.M. (Joseph), Waksman, R. (Ron), Epstein, S.E. (Stephen), Wilson, J.F. (James), Wild, S.H. (Sarah), Campbell, H. (Harry), Vitart, V. (Veronique), Reilly, M.P. (Muredach), Li, M. (Mingyao), Qu, L. (Liming), Wilensky, A. (Asaf), Matthai, W. (William), Hakonarson, H. (Hakon), Rader, D.J. (Daniel), Franke, A. (Andre), Wittig, M. (Michael), Schäfer, A. (Arne), Uda, M. (Manuela), Terracciano, A., Xiao, X. (Xiangjun), Busonero, F., Scheet, P. (Paul), Schlessinger, D., Clair, D.S., Rujescu, D. (Dan), Abecasis, G.R. (Gonçalo), Grabe, H.J. (Hans Jörgen), Teumer, A. (Alexander), Völzke, H. (Henry), Petersmann, A. (Astrid), John, U. (Ulrich), Rudan, I. (Igor), Hayward, C. (Caroline), Wright, A.F. (Alan), Kolcic, I. (Ivana), Wright, B.J. (Benjamin), Balmforth, A.J. (Anthony), Anderson, C. (Carl), Ahmed, T. (Tariq), Mathew, J. (Joseph), Parkes, M. (Miles), Satsangi, J. (Jack), Caulfield, M. (Mark), Munroe, P. (Patricia), Farrall, M. (Martin), Dominiczak, A. (Anna), Worthington, H. (Helen), Thomson, W. (Wendy), Eyre, D.S. (Dylan Samuel), Barton, A. (Anne), Mooser, V. (Vincent), and Francks, C. (Clyde)
Abstract: Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34 216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10-7). These findings replicate in a second large data set (N=127 274, thereof 76 242 smokers) for both SI (P=1.2 × 10-5) and CPD (P=9.3 × 10-5). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
Published: 2013
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130. The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

Author: Klebe, S. (Stephan), Golmard, L. (Lisa), Nalls, M.A. (Michael), Saad, F. (Fred), Singleton, A. (Andrew), Bras, J. (Jose), Hardy, J. (John), Simón-Sánchez, J. (Javier), Heutink, P. (Peter), Kuhlenbäumer, G. (Gregor), Charfi, R. (Rim), Klein, C. (Christoph), Hagenah, J., Gasser, T. (Thomas), Wurster, K.D. (Kathrin), Lesage, S. (Suzanne), Lorenz, D. (Delia), Deuschl, G. (Günther), Durif, F. (Franck), Pollak, M.N. (Michael), Damier, P. (Philippe), Tison, F. (François), Durr, A., Amouyel, P. (Philippe), Lambert, J.C. (Jean Charles), Tzourio, C. (Christophe), Maubaret, C. (Cécilia), Charbonnier-Beaupel, F. (Fanny), Tahiri, K. (Khadija), Vidailhet, M. (M.), Martinez, M. (Maria), Brice, A., Corvol, J.C. (Jean-Christophe), Agid, Y. (Yves), Anheim, M. (M.), Bonnet, A.-M. (A.), Borg, M. (Michael), Broussolle, E. (E.), Corvol, J.C. (Jean Christophe), Damier, Ph. (Ph), Destée, A. (A.), Durif, F. (F.), Klebe, S. (S.), Lohmann, E. (E.), Penet, C. (C.), Krack, P. (P.), Rascol, O. (O.), Tison, F. (F.), Tranchant, C. (C.), Vérin, M. (M.), Viallet, F. (F.), Vidailhet, M. (Marie), Plagnol, V. (Vincent), Bras, J.M. (Jose), Hernandez, D.G. (Dena), Sharma, M., Sheerin, U.-M. (Una-Marie), Schulte, C. (Claudia), Sveinbjörnsdóttir, S. (Sigurlaug), Arepalli, S. (Sampath), Band, G. (Gavin), Vukcevic, D. (Damjan), Barker, R.A. (Roger), Bellinguez, C. (Céline), Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Berg, D. (Daniela), Bhatia, K.P. (Kailash), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Bloem, B. (Bas), Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Brockmann, K., Brooks, J. (Janet), Burn, D.J. (David), Charlesworth, K. (Kate), Chen, H. (Honglei), Chinnery, P.F. (Patrick), Chong, S. (Sean), Clarke, C.E. (Carl), Cookson, M.R. (Mark), Cooper, J.M. (J. Mark), Counsell, C. (Carl), Dartigues, J.-F., Deloukas, P. (Panagiotis), Dexter, D.T. (David), Dijk, K.D. (Karin) van, Dillman, A. (Allissa), Durif, F. (Frank), Edkins, T. (Ted), Evans, J. (Jonathan Mark), Foltynie, T. (Thomas), Freeman, C. (Colin), Gao, J. (Jianjun), Gardner, M. (Mac), Gibbs, J. (Raphael), Goate, A.M. (Alison), Gray, E. (Emma), Guerreiro, R. (Rita), Gustafsson, O. (Omar), Harris, C. (Clare), Hellenthal, F.A., Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Huber, H. (Heiko), Hudson, G. (Gavin), Hunt, S.E. (Sarah), Huttenlocher, J. (Johanna), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Langford, C. (Cordelia), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., McNeill, N.H. (Nathan), Moorby, C. (Catriona), Moore, M. (Matt), Morris, H. (Huw), Morrison, K.E. (Karen), Mudanohwo, E. (Ese), O'Sullivan, S.S. (Sean), Pearson, J. (Justin), Pearson, R. (Ruth), Perlmutter, J.S. (Joel), Pétursson, H. (Hjörvar), Pirinen, M. (Matti), Post, B. (Bart), Ravina, B. (Bernard), Revesz, T. (Tamas), Riess, O. (Olaf), Rivadeneira Ramirez, F. (Fernando), Rizzu, P. (Patrizia), Ryten, M. (Mina), Sawcer, S.J. (Stephen), Schapira, A.H.V. (Anthony), Scheffer, H. (Hans), Shaw, K. (Karen), Shoulson, I. (Ira), Sidransky, E. (Ellen), Silva, R. (Rohan) de, Smith, C. (Colin), Spencer, C.C.A. (Chris C.), Stefansson, H. (Hreinn), Wolf, C. (Christiane), Stockton, J.D. (Joanna), Strange, A. (Amy), Su, Z. (Zhan), Talbot, D., Tanner, C.M. (Carlie), Tashakkori-Ghanbaria, A. (Avazeh), Trabzuni, D. (Danyah), Traynor, B.J. (Bryan), Uitterlinden, A.G. (André), Vandrovcova, J. (Jana), Velseboer, D. (Daan), Walker, R. (Robert), Warrenburg, B. (Bart) van de, Weale, M.E. (Michael), Wickremaratchi, M. (Mirdhu), Williams, N. (Nigel), Williams-Gray, C.H. (Caroline), Winder-Rhodes, S. (Sophie), Zwart, J-A. (John-Anker), Wood, N.W. (Nicholas), Klebe, S. (Stephan), Golmard, L. (Lisa), Nalls, M.A. (Michael), Saad, F. (Fred), Singleton, A. (Andrew), Bras, J. (Jose), Hardy, J. (John), Simón-Sánchez, J. (Javier), Heutink, P. (Peter), Kuhlenbäumer, G. (Gregor), Charfi, R. (Rim), Klein, C. (Christoph), Hagenah, J., Gasser, T. (Thomas), Wurster, K.D. (Kathrin), Lesage, S. (Suzanne), Lorenz, D. (Delia), Deuschl, G. (Günther), Durif, F. (Franck), Pollak, M.N. (Michael), Damier, P. (Philippe), Tison, F. (François), Durr, A., Amouyel, P. (Philippe), Lambert, J.C. (Jean Charles), Tzourio, C. (Christophe), Maubaret, C. (Cécilia), Charbonnier-Beaupel, F. (Fanny), Tahiri, K. (Khadija), Vidailhet, M. (M.), Martinez, M. (Maria), Brice, A., Corvol, J.C. (Jean-Christophe), Agid, Y. (Yves), Anheim, M. (M.), Bonnet, A.-M. (A.), Borg, M. (Michael), Broussolle, E. (E.), Corvol, J.C. (Jean Christophe), Damier, Ph. (Ph), Destée, A. (A.), Durif, F. (F.), Klebe, S. (S.), Lohmann, E. (E.), Penet, C. (C.), Krack, P. (P.), Rascol, O. (O.), Tison, F. (F.), Tranchant, C. (C.), Vérin, M. (M.), Viallet, F. (F.), Vidailhet, M. (Marie), Plagnol, V. (Vincent), Bras, J.M. (Jose), Hernandez, D.G. (Dena), Sharma, M., Sheerin, U.-M. (Una-Marie), Schulte, C. (Claudia), Sveinbjörnsdóttir, S. (Sigurlaug), Arepalli, S. (Sampath), Band, G. (Gavin), Vukcevic, D. (Damjan), Barker, R.A. (Roger), Bellinguez, C. (Céline), Ben-Shlomo, Y., Berendse, H.W. (Henk W.), Berg, D. (Daniela), Bhatia, K.P. (Kailash), Bie, R.M.A. (Rob) de, Biffi, A. (Alessandro), Bloem, B. (Bas), Bochdanovits, Z. (Zoltan), Bonin, M. (Malte) von, Brockmann, K., Brooks, J. (Janet), Burn, D.J. (David), Charlesworth, K. (Kate), Chen, H. (Honglei), Chinnery, P.F. (Patrick), Chong, S. (Sean), Clarke, C.E. (Carl), Cookson, M.R. (Mark), Cooper, J.M. (J. Mark), Counsell, C. (Carl), Dartigues, J.-F., Deloukas, P. (Panagiotis), Dexter, D.T. (David), Dijk, K.D. (Karin) van, Dillman, A. (Allissa), Durif, F. (Frank), Edkins, T. (Ted), Evans, J. (Jonathan Mark), Foltynie, T. (Thomas), Freeman, C. (Colin), Gao, J. (Jianjun), Gardner, M. (Mac), Gibbs, J. (Raphael), Goate, A.M. (Alison), Gray, E. (Emma), Guerreiro, R. (Rita), Gustafsson, O. (Omar), Harris, C. (Clare), Hellenthal, F.A., Hilten, J.J. (Jacobus) van, Hofman, A. (Albert), Hollenbeck, J.R. (John R.), Holton, J.L. (Janice), Hu, M. (Michele), Huang, X. (Xiaohong), Huber, H. (Heiko), Hudson, G. (Gavin), Hunt, S.E. (Sarah), Huttenlocher, J. (Johanna), Illig, T. (Thomas), Jónsson, P.V. (Pálmi), Langford, C. (Cordelia), Lees, A.J. (Andrew), Lichtner, P. (Peter), Limousin, P. (Patricia), Lopez, G., McNeill, N.H. (Nathan), Moorby, C. (Catriona), Moore, M. (Matt), Morris, H. (Huw), Morrison, K.E. (Karen), Mudanohwo, E. (Ese), O'Sullivan, S.S. (Sean), Pearson, J. (Justin), Pearson, R. (Ruth), Perlmutter, J.S. (Joel), Pétursson, H. (Hjörvar), Pirinen, M. (Matti), Post, B. (Bart), Ravina, B. (Bernard), Revesz, T. (Tamas), Riess, O. (Olaf), Rivadeneira Ramirez, F. (Fernando), Rizzu, P. (Patrizia), Ryten, M. (Mina), Sawcer, S.J. (Stephen), Schapira, A.H.V. (Anthony), Scheffer, H. (Hans), Shaw, K. (Karen), Shoulson, I. (Ira), Sidransky, E. (Ellen), Silva, R. (Rohan) de, Smith, C. (Colin), Spencer, C.C.A. (Chris C.), Stefansson, H. (Hreinn), Wolf, C. (Christiane), Stockton, J.D. (Joanna), Strange, A. (Amy), Su, Z. (Zhan), Talbot, D., Tanner, C.M. (Carlie), Tashakkori-Ghanbaria, A. (Avazeh), Trabzuni, D. (Danyah), Traynor, B.J. (Bryan), Uitterlinden, A.G. (André), Vandrovcova, J. (Jana), Velseboer, D. (Daan), Walker, R. (Robert), Warrenburg, B. (Bart) van de, Weale, M.E. (Michael), Wickremaratchi, M. (Mirdhu), Williams, N. (Nigel), Williams-Gray, C.H. (Caroline), Winder-Rhodes, S. (Sophie), Zwart, J-A. (John-Anker), and Wood, N.W. (Nicholas)
Abstract: The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson’s disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polym
Published: 2013
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131. Genome-wide meta-analysis identifies new susceptibility loci for migraine

Author: Anttila, V., Winsvold, B.S., Gormley, P., Kurth, T., Bettella, F., McMahon, G., Kallela, M., Malik, R., de Vries, B., Terwindt, G., Medland, S.E., Todt, U., McArdle, W.L., Quaye, L., Koiranen, M., Ikram, M.A., Lehtimäki, T., Stam, A.H., Ligthart, L., Wedenoja, J., Dunham, I., Neale, B. M., Palta, P., Hamalainen, E., Schürks, M., Rose, L.M., Buring, J.E., Ridker, P.M., Steinberg, S., Stefansson, H., Jakobsson, F., Lawlor, D.A., Evans, D.M., Ring, S.M., Färkkilä, M., Artto, V., Kaunisto, M.A., Freilinger, T., Schoenen, J., Frants, R.R., Pelzer, N., Weller, C.M., Zielman, R., Heath, A.C., Madden, P.A.F., Montgomery, G.W., Martin, N.G., Borck, G., Göbel, H., Heinze, A., Heinze-Kuhn, K., Williams, F.M., Hartikainen, A.-L., Pouta, A., van den Ende, J.., Uitterlinden, A.G., Hofman, A., Amin, N., Hottenga, J.J., Vink, J.M., Heikkilä, K., Alexander, M., Muller-Myhsok, B., Schreiber, S, Meitinger, T., Wichmann, H. E., Aromaa, A., Eriksson, J.G., Traynor, B.J., Trabzuni, D., Rossin, E., Lage, K., Jacobs, S.B., Gibbs, J.R., Birney, E., Kaprio, J., Penninx, B.W.J.H., Boomsma, D.I., van Duijn, C.M., Raitakari, O., Jarvelin, M.-R., Zwart, J.A., Cherkas, L., Strachan, D.P., Kubisch, C., Ferrari, M.D., van den Maagdenberg, A.M.J.M., Dichgans, M., Wessman, M., Smith, G.D., Stefansson, K., Daly, M.J., Nyholt, DR, Chasman, D.I., Palotie, A., Anttila, V., Winsvold, B.S., Gormley, P., Kurth, T., Bettella, F., McMahon, G., Kallela, M., Malik, R., de Vries, B., Terwindt, G., Medland, S.E., Todt, U., McArdle, W.L., Quaye, L., Koiranen, M., Ikram, M.A., Lehtimäki, T., Stam, A.H., Ligthart, L., Wedenoja, J., Dunham, I., Neale, B. M., Palta, P., Hamalainen, E., Schürks, M., Rose, L.M., Buring, J.E., Ridker, P.M., Steinberg, S., Stefansson, H., Jakobsson, F., Lawlor, D.A., Evans, D.M., Ring, S.M., Färkkilä, M., Artto, V., Kaunisto, M.A., Freilinger, T., Schoenen, J., Frants, R.R., Pelzer, N., Weller, C.M., Zielman, R., Heath, A.C., Madden, P.A.F., Montgomery, G.W., Martin, N.G., Borck, G., Göbel, H., Heinze, A., Heinze-Kuhn, K., Williams, F.M., Hartikainen, A.-L., Pouta, A., van den Ende, J.., Uitterlinden, A.G., Hofman, A., Amin, N., Hottenga, J.J., Vink, J.M., Heikkilä, K., Alexander, M., Muller-Myhsok, B., Schreiber, S, Meitinger, T., Wichmann, H. E., Aromaa, A., Eriksson, J.G., Traynor, B.J., Trabzuni, D., Rossin, E., Lage, K., Jacobs, S.B., Gibbs, J.R., Birney, E., Kaprio, J., Penninx, B.W.J.H., Boomsma, D.I., van Duijn, C.M., Raitakari, O., Jarvelin, M.-R., Zwart, J.A., Cherkas, L., Strachan, D.P., Kubisch, C., Ferrari, M.D., van den Maagdenberg, A.M.J.M., Dichgans, M., Wessman, M., Smith, G.D., Stefansson, K., Daly, M.J., Nyholt, DR, Chasman, D.I., and Palotie, A.
Abstract: Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10
Published: 2013
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132. Seven new loci associated with age-related macular degeneration

Author: Fritsche, LG, Chen, W, Schu, M, Yaspan, BL, Yu, Y, Thorleifsson, G, Zack, DJ, Arakawa, S, Cipriani, V, Ripke, S, Igo, RP, Buitendijk, GHS, Sim, X, Weeks, DE, Guymer, RH, Merriam, JE, Francis, PJ, Hannum, G, Agarwal, A, Armbrecht, AM, Audo, I, Aung, T, Barile, GR, Benchaboune, M, Bird, AC, Bishop, PN, Branham, KE, Brooks, M, Brucker, AJ, Cade, WH, Cain, MS, Campochiaroll, PA, Chan, C-C, Cheng, C-Y, Chew, EY, Chin, KA, Chowers, I, Clayton, DG, Cojocaru, R, Conley, YP, Cornes, BK, Daly, MJ, Dhillon, B, Edwards, A, Evangelou, E, Fagemess, J, Ferreyra, HA, Friedman, JS, Geirsdottir, A, George, RJ, Gieger, C, Gupta, N, Hagstrom, SA, Harding, SP, Haritoglou, C, Heckenlively, JR, Hoz, FG, Hughes, G, Ioannidis, JPA, Ishibashi, T, Joseph, P, Jun, G, Kamatani, Y, Katsanis, N, Keilhauer, CN, Khan, JC, Kim, IK, Kiyohara, Y, Klein, BEK, Klein, R, Kovach, JL, Kozak, I, Lee, CJ, Lee, KE, Lichtner, P, Lotery, AJ, Meitinger, T, Mitchell, P, Mohand-Saied, S, Moore, AT, Morgan, DJ, Morrison, MA, Myers, CE, Naj, AC, Nakamura, Y, Okada, Y, Orlin, A, Ortube, MC, Othman, MI, Pappas, C, Park, KH, Pauer, GJT, Peachey, NS, Poch, O, Priya, RR, Reynolds, R, Richardson, AJ, Ripp, R, Rudolph, G, Ryu, E, Sahel, J-A, Schaumberg, DA, Scholl, HPN, Schwartz, SG, Scott, WK, Shahid, H, Sigurdsson, H, Silvestri, G, Sivakumaran, TA, Smith, RT, Sobrin, L, Souied, EH, Stambolian, DE, Stefansson, H, Sturgill-Short, GM, Takahashi, A, Tosakulwong, N, Truitt, BJ, Tsironi, EE, Uitterlinden, AG, van Duijn, CM, Vijaya, L, Vingerling, JR, Vithana, EN, Webster, AR, Wichmann, H-E, Winkler, TW, Wong, TY, Wright, AF, Zelenika, D, Zhang, M, Zhao, L, Zhang, K, Klein, ML, Hageman, GS, Lathrop, GM, Stefansson, K, Allikmets, R, Baird, PN, Gorin, MB, Wang, JJ, Klaver, CCW, Seddon, JM, Pericak-Vance, MA, Iyengar, SK, Yates, JRW, Swaroop, A, Weber, BHF, Kubo, M, DeAngelis, MM, Leveillard, T, Thorsteinsdottir, U, Haines, JL, Farrer, LA, Heid, IM, Abecasis, GR, Fritsche, LG, Chen, W, Schu, M, Yaspan, BL, Yu, Y, Thorleifsson, G, Zack, DJ, Arakawa, S, Cipriani, V, Ripke, S, Igo, RP, Buitendijk, GHS, Sim, X, Weeks, DE, Guymer, RH, Merriam, JE, Francis, PJ, Hannum, G, Agarwal, A, Armbrecht, AM, Audo, I, Aung, T, Barile, GR, Benchaboune, M, Bird, AC, Bishop, PN, Branham, KE, Brooks, M, Brucker, AJ, Cade, WH, Cain, MS, Campochiaroll, PA, Chan, C-C, Cheng, C-Y, Chew, EY, Chin, KA, Chowers, I, Clayton, DG, Cojocaru, R, Conley, YP, Cornes, BK, Daly, MJ, Dhillon, B, Edwards, A, Evangelou, E, Fagemess, J, Ferreyra, HA, Friedman, JS, Geirsdottir, A, George, RJ, Gieger, C, Gupta, N, Hagstrom, SA, Harding, SP, Haritoglou, C, Heckenlively, JR, Hoz, FG, Hughes, G, Ioannidis, JPA, Ishibashi, T, Joseph, P, Jun, G, Kamatani, Y, Katsanis, N, Keilhauer, CN, Khan, JC, Kim, IK, Kiyohara, Y, Klein, BEK, Klein, R, Kovach, JL, Kozak, I, Lee, CJ, Lee, KE, Lichtner, P, Lotery, AJ, Meitinger, T, Mitchell, P, Mohand-Saied, S, Moore, AT, Morgan, DJ, Morrison, MA, Myers, CE, Naj, AC, Nakamura, Y, Okada, Y, Orlin, A, Ortube, MC, Othman, MI, Pappas, C, Park, KH, Pauer, GJT, Peachey, NS, Poch, O, Priya, RR, Reynolds, R, Richardson, AJ, Ripp, R, Rudolph, G, Ryu, E, Sahel, J-A, Schaumberg, DA, Scholl, HPN, Schwartz, SG, Scott, WK, Shahid, H, Sigurdsson, H, Silvestri, G, Sivakumaran, TA, Smith, RT, Sobrin, L, Souied, EH, Stambolian, DE, Stefansson, H, Sturgill-Short, GM, Takahashi, A, Tosakulwong, N, Truitt, BJ, Tsironi, EE, Uitterlinden, AG, van Duijn, CM, Vijaya, L, Vingerling, JR, Vithana, EN, Webster, AR, Wichmann, H-E, Winkler, TW, Wong, TY, Wright, AF, Zelenika, D, Zhang, M, Zhao, L, Zhang, K, Klein, ML, Hageman, GS, Lathrop, GM, Stefansson, K, Allikmets, R, Baird, PN, Gorin, MB, Wang, JJ, Klaver, CCW, Seddon, JM, Pericak-Vance, MA, Iyengar, SK, Yates, JRW, Swaroop, A, Weber, BHF, Kubo, M, DeAngelis, MM, Leveillard, T, Thorsteinsdottir, U, Haines, JL, Farrer, LA, Heid, IM, and Abecasis, GR
Abstract: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.
Published: 2013

133. Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine

Author: Esserlind, A-L, Christensen, A F, Le, H, Kirchmann, M, Hauge, A W, Toyserkani, N M, Hansen, Torben, Grarup, Niels, Werge, T, Steinberg, S, Bettella, F, Stefansson, H, Olesen, J, Esserlind, A-L, Christensen, A F, Le, H, Kirchmann, M, Hauge, A W, Toyserkani, N M, Hansen, Torben, Grarup, Niels, Werge, T, Steinberg, S, Bettella, F, Stefansson, H, and Olesen, J
Abstract: Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and MTA, the genetic background is still not fully established. In a population-based genome-wide association study by Chasman et al. (Nat Genet 2011: 43: 695-698), three common variants were found to confer risk of migraine at a genome-wide significant level (P <5 × 10(-8) ). We aimed to evaluate the top association single nucleotide polymorphisms (SNPs) from the discovery set by Chasman et al. in a primarily clinic-based Danish and Icelandic cohort.
Published: 2013

134. Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Author: Keller, M.F., Saad, M., Bras, J., Bettella, F., Nicolaou, N., Simon-Sanchez, J., Mittag, F., Buchel, F., Sharma, M., Gibbs, J.R., Schulte, C., Moskvina, V., Durr, A., Holmans, P., Kilarski, L.L., Guerreiro, R., Hernandez, D.G., Brice, A., Ylikotila, P., Stefansson, H., Majamaa, K., Morris, H.R., Williams, N., Gasser, T., Heutink, P., Wood, N.W., Hardy, J., Martinez, M., Singleton, A.B., Nalls, M.A., Donnelly, P., Bloem, B., et al., Keller, M.F., Saad, M., Bras, J., Bettella, F., Nicolaou, N., Simon-Sanchez, J., Mittag, F., Buchel, F., Sharma, M., Gibbs, J.R., Schulte, C., Moskvina, V., Durr, A., Holmans, P., Kilarski, L.L., Guerreiro, R., Hernandez, D.G., Brice, A., Ylikotila, P., Stefansson, H., Majamaa, K., Morris, H.R., Williams, N., Gasser, T., Heutink, P., Wood, N.W., Hardy, J., Martinez, M., Singleton, A.B., Nalls, M.A., Donnelly, P., Bloem, B., and et al.
Abstract: Item does not contain fulltext, Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
Published: 2012

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

Author: Li, R., Brockschmidt, F.F., Kiefer, A.K., Stefansson, H., Nyholt, D.R., Song, K., Vermeulen, S., Kanoni, S., Glass, D., Medland, S.E., Dimitriou, M., Waterworth, D., Tung, J.Y., Geller, F., Heilmann, S., Hillmer, A.M., Bataille, V., Eigelshoven, S., Hanneken, S., Moebus, S., Herold, C., Heijer, M. den, Montgomery, G.W., Deloukas, P., Eriksson, N., Heath, A.C., Becker, T., Sulem, P., Mangino, M., Vollenweider, P., Spector, T.D., Dedoussis, G., Martin, N.G., Kiemeney, L.A., Mooser, V., Stefansson, K., Hinds, D.A., Nothen, Markus, Richards, J.B., Li, R., Brockschmidt, F.F., Kiefer, A.K., Stefansson, H., Nyholt, D.R., Song, K., Vermeulen, S., Kanoni, S., Glass, D., Medland, S.E., Dimitriou, M., Waterworth, D., Tung, J.Y., Geller, F., Heilmann, S., Hillmer, A.M., Bataille, V., Eigelshoven, S., Hanneken, S., Moebus, S., Herold, C., Heijer, M. den, Montgomery, G.W., Deloukas, P., Eriksson, N., Heath, A.C., Becker, T., Sulem, P., Mangino, M., Vollenweider, P., Spector, T.D., Dedoussis, G., Martin, N.G., Kiemeney, L.A., Mooser, V., Stefansson, K., Hinds, D.A., Nothen, Markus, and Richards, J.B.
Abstract: Contains fulltext : 109543.pdf (publisher's version ) (Open Access), Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62x10(-)(9)-1.01x10(-)(1)(2)). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9x10(-)(3)). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4x10(-)(8)(8)]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.
Published: 2012

136. Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder

Author: Vassos, E., Steinberg, S., Cichon, S., Breen, G., Sigurdsson, E., Andreassen, O.A., Djurovic, S., Morken, G., Grigoroiu-Serbanescu, M., Diaconu, C.C., Czerski, P.M., Hauser, J., Babadjanova, G., Abramova, L.I., Muhleisen, T.W., Nothen, Markus, Rietschel, M., McGuffin, P., St Clair, D., Gustafsson, O., Melle, I., Pietilainen, O.P., Ruggeri, M., Tosato, S., Werge, T., Ophoff, R.A., Consortium, G., Rujescu, D., Borglum, A.D., Mors, O., Mortensen, P.B., Demontis, D., Hollegaard, M.V., van Winkel, R., Kenis, G., De Hert, M., Rethelyi, J.M., Bitter, I., Rubino, I.A., Golimbet, V., Kiemeney, L.A., Berg, L.H. van den, Franke, B., Jonsson, E.G., Farmer, A., Stefansson, H., Stefansson, K., Collier, D.A., Vassos, E., Steinberg, S., Cichon, S., Breen, G., Sigurdsson, E., Andreassen, O.A., Djurovic, S., Morken, G., Grigoroiu-Serbanescu, M., Diaconu, C.C., Czerski, P.M., Hauser, J., Babadjanova, G., Abramova, L.I., Muhleisen, T.W., Nothen, Markus, Rietschel, M., McGuffin, P., St Clair, D., Gustafsson, O., Melle, I., Pietilainen, O.P., Ruggeri, M., Tosato, S., Werge, T., Ophoff, R.A., Consortium, G., Rujescu, D., Borglum, A.D., Mors, O., Mortensen, P.B., Demontis, D., Hollegaard, M.V., van Winkel, R., Kenis, G., De Hert, M., Rethelyi, J.M., Bitter, I., Rubino, I.A., Golimbet, V., Kiemeney, L.A., Berg, L.H. van den, Franke, B., Jonsson, E.G., Farmer, A., Stefansson, H., Stefansson, K., and Collier, D.A.
Abstract: Item does not contain fulltext, BACKGROUND: Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia. METHODS: To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method. RESULTS: In our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 x 10(-9)). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21). CONCLUSIONS: There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.
Published: 2012

137. Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Author: Keller, M. F., Saad, M., Bras, J., Bettella, F., Nicolaou, N., Simon-Sanchez, J., Mittag, F., Buchel, F., Sharma, M., Gibbs, J. R., Schulte, C., Moskvina, V., Durr, A., Holmans, P., Kilarski, L. L., Guerreiro, R., Hernandez, D. G., Brice, A., Ylikotila, P., Stefansson, H., Majamaa, K., Morris, H. R., Williams, N., Gasser, T., Heutink, P., Wood, N. W., Hardy, J., Martinez, M., Jankowski, Janusz, Nalls, M. A., Singleton, A. B., Keller, M. F., Saad, M., Bras, J., Bettella, F., Nicolaou, N., Simon-Sanchez, J., Mittag, F., Buchel, F., Sharma, M., Gibbs, J. R., Schulte, C., Moskvina, V., Durr, A., Holmans, P., Kilarski, L. L., Guerreiro, R., Hernandez, D. G., Brice, A., Ylikotila, P., Stefansson, H., Majamaa, K., Morris, H. R., Williams, N., Gasser, T., Heutink, P., Wood, N. W., Hardy, J., Martinez, M., Jankowski, Janusz, Nalls, M. A., and Singleton, A. B.
Abstract: Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17–38, P = 8.08E − 08) phenotypic variance associated with all types of PD, 15% (95% CI −0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17–44, P = 1.34E − 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
Published: 2012

138. No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder.

Author: Curran, S., Bolton, P., Rozsnyai, K., Chiocchetti, A., Klauck, S.M., Duketis, E., Poustka, F., Schlitt, S., Freitag, C.M., Lee, I. van der, Muglia, P., Poot, M., Staal, W.G., Jonge, M.V. de, Ophoff, R.A., Lewis, C., Skuse, D., Mandy, W., Vassos, E., Fossdal, R., Magnusson, P., Hreidarsson, S., Saemundsen, E., Stefansson, H., Stefansson, K., Collier, D., Curran, S., Bolton, P., Rozsnyai, K., Chiocchetti, A., Klauck, S.M., Duketis, E., Poustka, F., Schlitt, S., Freitag, C.M., Lee, I. van der, Muglia, P., Poot, M., Staal, W.G., Jonge, M.V. de, Ophoff, R.A., Lewis, C., Skuse, D., Mandy, W., Vassos, E., Fossdal, R., Magnusson, P., Hreidarsson, S., Saemundsen, E., Stefansson, H., Stefansson, K., and Collier, D.
Abstract: 1 september 2011, Item does not contain fulltext, The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism.
Published: 2011

139. Identification of low-frequency variants associated with gout and serum uric acid levels

Author: Sulem, P., Gudbjartsson, D.F., Walters, G.B., Helgadottir, H.T., Helgason, A., Gudjonsson, S.A., Zanon, C., Besenbacher, S., Bjornsdottir, G., Magnusson, O.T., Magnusson, G., Hjartarson, E., Saemundsdottir, J., Gylfason, A, Jonasdottir, A., Holm, H., Karason, A., Rafnar, T., Stefansson, H., Andreassen, O.A., Pedersen, J.H., Pack, A.I., Visser, M.C. de, Kiemeney, L.A.L.M., Geirsson, A.J., Eyjolfsson, G.I., Olafsson, I., Kong, A., Masson, G., Jonsson, H., Thorsteinsdottir, U., Jonsdottir, I., Stefansson, K., Sulem, P., Gudbjartsson, D.F., Walters, G.B., Helgadottir, H.T., Helgason, A., Gudjonsson, S.A., Zanon, C., Besenbacher, S., Bjornsdottir, G., Magnusson, O.T., Magnusson, G., Hjartarson, E., Saemundsdottir, J., Gylfason, A, Jonasdottir, A., Holm, H., Karason, A., Rafnar, T., Stefansson, H., Andreassen, O.A., Pedersen, J.H., Pack, A.I., Visser, M.C. de, Kiemeney, L.A.L.M., Geirsson, A.J., Eyjolfsson, G.I., Olafsson, I., Kong, A., Masson, G., Jonsson, H., Thorsteinsdottir, U., Jonsdottir, I., and Stefansson, K.
Abstract: Contains fulltext : 97981.pdf (publisher's version ) (Closed access), We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 x 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 x 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 x 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.
Published: 2011

140. Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness

Author: Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A.R., Jakobsen, K.D., Kristinsson, K.T., Roux, L. le, Gustafsson, O., Craddock, N., Moller, H.J., McQuillin, A., Muglia, P., Cichon, S., Rietschel, M., Ophoff, R.A., Djurovic, S., Andreassen, O.A., Pietilainen, O.P.H., Peltonen, L., Dempster, E., Collier, D.A., St Clair, D., Rasmussen, H.B., Glenthoj, B.Y., Kiemeney, L.A.L.M., Franke, B., Tosato, S., Bonetto, C., Saemundsen, E., Hreidarsson, S.J., Nothen, Markus, Gurling, H., O'Donovan, M.C., Owen, M.J., Sigurdsson, E., Petursson, H., Stefansson, H., Rujescu, D., Stefansson, K., Werge, T., Ingason, A., Kirov, G., Giegling, I., Hansen, T., Isles, A.R., Jakobsen, K.D., Kristinsson, K.T., Roux, L. le, Gustafsson, O., Craddock, N., Moller, H.J., McQuillin, A., Muglia, P., Cichon, S., Rietschel, M., Ophoff, R.A., Djurovic, S., Andreassen, O.A., Pietilainen, O.P.H., Peltonen, L., Dempster, E., Collier, D.A., St Clair, D., Rasmussen, H.B., Glenthoj, B.Y., Kiemeney, L.A.L.M., Franke, B., Tosato, S., Bonetto, C., Saemundsen, E., Hreidarsson, S.J., Nothen, Markus, Gurling, H., O'Donovan, M.C., Owen, M.J., Sigurdsson, E., Petursson, H., Stefansson, H., Rujescu, D., Stefansson, K., and Werge, T.
Abstract: Contains fulltext : 97099.pdf (publisher's version ) (Closed access), OBJECTIVE: Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10-15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness. METHOD: The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis. RESULTS: Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome. CONCLUSIONS: These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.
Published: 2011

141. Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Author: Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O.P.H., Buizer-Voskamp, J.E., Strengman, E., Francks, C., Muglia, P., Gylfason, A, Gustafsson, O., Olason, P.I., Steinberg, S., Hansen, T., Jakobsen, K.D., Rasmussen, H.B., Giegling, I., Moller, H.J., Hartmann, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Bramon, E., Kiemeney, L.A.L.M., Franke, B., Murray, R., Vassos, E., Toulopoulou, T., Muhleisen, T.W., Tosato, S., Ruggeri, M., Djurovic, S., Andreassen, O.A., Zhang, Z., Werge, T., Ophoff, R.A., Rietschel, M., Nothen, Markus, Petursson, H., Stefansson, H., Peltonen, L., Collier, D., Stefansson, K., St Clair, D.M., Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O.P.H., Buizer-Voskamp, J.E., Strengman, E., Francks, C., Muglia, P., Gylfason, A, Gustafsson, O., Olason, P.I., Steinberg, S., Hansen, T., Jakobsen, K.D., Rasmussen, H.B., Giegling, I., Moller, H.J., Hartmann, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Bramon, E., Kiemeney, L.A.L.M., Franke, B., Murray, R., Vassos, E., Toulopoulou, T., Muhleisen, T.W., Tosato, S., Ruggeri, M., Djurovic, S., Andreassen, O.A., Zhang, Z., Werge, T., Ophoff, R.A., Rietschel, M., Nothen, Markus, Petursson, H., Stefansson, H., Peltonen, L., Collier, D., Stefansson, K., and St Clair, D.M.
Abstract: Contains fulltext : 96767.pdf (publisher's version ) (Closed access), Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
Published: 2011

142. Genome-wide analysis shows increased frequency of copy number variation deletions in dutch schizophrenia patients

Author: Buizer-Voskamp, J.E., Muntjewerff, J.W., Strengman, E., Sabatti, C., Stefansson, H., Vorstman, J.A., Ophoff, R.A., Buizer-Voskamp, J.E., Muntjewerff, J.W., Strengman, E., Sabatti, C., Stefansson, H., Vorstman, J.A., and Ophoff, R.A.
Abstract: Item does not contain fulltext, BACKGROUND: Since 2008, multiple studies have reported on copy number variations (CNVs) in schizophrenia. However, many regions are unique events with minimal overlap between studies. This makes it difficult to gain a comprehensive overview of all CNVs involved in the etiology of schizophrenia. We performed a systematic CNV study on the basis of a homogeneous genome-wide dataset aiming at all CNVs >/= 50 kilobase pair. We complemented this analysis with a review of cytogenetic and chromosomal abnormalities for schizophrenia reported in the literature with the purpose of combining classical genetic findings and our current understanding of genomic variation. METHODS: We investigated 834 Dutch schizophrenia patients and 672 Dutch control subjects. The CNVs were included if they were detected by QuantiSNP (http://www.well.ox.ac.uk/QuantiSNP/) as well as PennCNV (http://www.neurogenome.org/cnv/penncnv/) and contain known protein coding genes. The integrated identification of CNV regions and cytogenetic loci indicates regions of interest (cytogenetic regions of interest [CROIs]). RESULTS: In total, 2437 CNVs were identified with an average number of 2.1 CNVs/subject for both cases and control subjects. We observed significantly more deletions but not duplications in schizophrenia cases versus control subjects. The CNVs identified coincide with loci previously reported in the literature, confirming well-established schizophrenia CROIs 1q42 and 22q11.2 as well as indicating a potentially novel CROI on chromosome 5q35.1. CONCLUSIONS: Chromosomal deletions are more prevalent in schizophrenia patients than in healthy subjects and therefore confer a risk factor for pathogenicity. The combination of our CNV data with previously reported cytogenetic abnormalities in schizophrenia provides an overview of potentially interesting regions for positional candidate genes.
Published: 2011

143. A rare variant in MYH6 is associated with high risk of sick sinus syndrome

Author: Holm, H., Gudbjartsson, D.F., Sulem, P., Masson, G., Helgadottir, H.T., Zanon, C., Magnusson, O.T., Helgason, A., Saemundsdottir, J., Gylfason, A, Stefansdottir, H., Gretarsdottir, S., Matthiasson, S.E., Thorgeirsson, G.M., Jonasdottir, A., Sigurdsson, A., Stefansson, H., Werge, T., Rafnar, T., Kiemeney, L.A.L.M., Parvez, B., Muhammad, R., Roden, D.M., Darbar, D., Thorleifsson, G., Walters, G.B., Kong, A., Thorsteinsdottir, U., Arnar, D.O., Stefansson, K., Holm, H., Gudbjartsson, D.F., Sulem, P., Masson, G., Helgadottir, H.T., Zanon, C., Magnusson, O.T., Helgason, A., Saemundsdottir, J., Gylfason, A, Stefansdottir, H., Gretarsdottir, S., Matthiasson, S.E., Thorgeirsson, G.M., Jonasdottir, A., Sigurdsson, A., Stefansson, H., Werge, T., Rafnar, T., Kiemeney, L.A.L.M., Parvez, B., Muhammad, R., Roden, D.M., Darbar, D., Thorleifsson, G., Walters, G.B., Kong, A., Thorsteinsdottir, U., Arnar, D.O., and Stefansson, K.
Abstract: Contains fulltext : 95597.pdf (publisher's version ) (Closed access), Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 x 10(2). We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.
Published: 2011

144. Expanding the range of ZNF804A variants conferring risk of psychosis

Author: Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., Stefansson, K., Steinberg, S., Mors, O., Borglum, A.D., Gustafsson, O., Werge, T., Mortensen, P.B., Andreassen, O.A., Sigurdsson, E., Thorgeirsson, T.E., Bottcher, Y., Olason, P., Ophoff, R.A., Cichon, S., Gudjonsdottir, I.H., Pietilainen, O.P.H., Nyegaard, M., Tuulio-Henriksson, A., Ingason, A., Hansen, T., Athanasiu, L., Suvisaari, J., Lonnqvist, J., Paunio, T., Hartmann, A., Jurgens, G., Nordentoft, M., Hougaard, D., Norgaard-Pedersen, B., Breuer, R., Moller, H.J., Giegling, I., Glenthoj, B., Rasmussen, H.B., Mattheisen, M., Bitter, I., Rethelyi, J.M., Sigmundsson, T., Fossdal, R., Thorsteinsdottir, U., Ruggeri, M., Tosato, S., Strengman, E., Kiemeney, L.A.L.M., Melle, I., Djurovic, S., Abramova, L.I., Kaleda, V., Walshe, M., Bramon, E., Vassos, E., Li, T., Fraser, G., Walker, N., Toulopoulou, T., Yoon, J., Freimer, N.B., Cantor, R.M., Murray, R., Kong, A., Golimbet, V., Jonsson, E.G., Terenius, L., Agartz, I., Petursson, H., Nothen, Markus, Rietschel, M., Peltonen, L., Rujescu, D., Collier, D.A., Stefansson, H., St Clair, D., and Stefansson, K.
Abstract: Contains fulltext : 95884.pdf (publisher's version ) (Closed access), A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 x 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 x 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 x 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).
Published: 2011

145. Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Author: Ingason, A, Rujescu, D, Cichon, S, Sigurdsson, E, Sigmundsson, T, Pietiläinen, O P H, Buizer-Voskamp, J E, Strengman, E, Francks, C, Muglia, P, Gylfason, A, Gustafsson, O, Olason, P I, Steinberg, S, Hansen, Thomas Folkmann, Jakobsen, K D, Rasmussen, H B, Giegling, I, Möller, H-J, Hartmann, A, Crombie, C, Fraser, G, Walker, N, Lonnqvist, J, Suvisaari, J, Tuulio-Henriksson, A, Bramon, E, Kiemeney, L A, Franke, B, Murray, R, Vassos, E, Toulopoulou, T, Mühleisen, T W, Tosato, S, Ruggeri, M, Djurovic, S, Andreassen, O A, Zhang, Z, Werge, T, Ophoff, R A, Rietschel, M, Nöthen, M M, Petursson, H, Stefansson, H, Peltonen, L, Collier, D, Stefansson, K, St Clair, D M, Ingason, A, Rujescu, D, Cichon, S, Sigurdsson, E, Sigmundsson, T, Pietiläinen, O P H, Buizer-Voskamp, J E, Strengman, E, Francks, C, Muglia, P, Gylfason, A, Gustafsson, O, Olason, P I, Steinberg, S, Hansen, Thomas Folkmann, Jakobsen, K D, Rasmussen, H B, Giegling, I, Möller, H-J, Hartmann, A, Crombie, C, Fraser, G, Walker, N, Lonnqvist, J, Suvisaari, J, Tuulio-Henriksson, A, Bramon, E, Kiemeney, L A, Franke, B, Murray, R, Vassos, E, Toulopoulou, T, Mühleisen, T W, Tosato, S, Ruggeri, M, Djurovic, S, Andreassen, O A, Zhang, Z, Werge, T, Ophoff, R A, Rietschel, M, Nöthen, M M, Petursson, H, Stefansson, H, Peltonen, L, Collier, D, Stefansson, K, and St Clair, D M
Abstract: Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.
Published: 2011

146. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

Author: Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, J, Carrasquillo, M, Abraham, R, Hamshere, M, Pahwa, J, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Brown, K, Passmore, P, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, A, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, P, Hooper, N, Vardy, E, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Rüther, E, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Gallacher, J, Hüll, M, Rujescu, D, Giegling, I, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Sleegers, K, Bettens, K, Engelborghs, S, De Deyn, P, Van Broeckhoven, C, Livingston, G, Bass, N, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al Chalabi, A, Shaw, C, Tsolaki, M, Singleton, A, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Pankratz, V, Sando, S, Aasly, J, Barcikowska, M, Wszolek, Z, Dickson, D, Graff Radford, N, Petersen, R, van Duijn, C, Breteler, M, Ikram, M, Destefano, A, Fitzpatrick, A, Lopez, O, Launer, L, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, J, Tzourio, C, Alpérovitch, A, Lathrop, M, Feulner, T, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snædal, J, Björnsson, S, Jonsson, P, Chouraki, V, Genier Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, M, Pasquier, F, Mateo, I, Frank Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossù, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, P, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, S, Owen, M, O'Donovan, M, Amouyel, P, Williams, J, Carrasquillo, MM, Hamshere, ML, Pahwa, JS, Lupton, MK, Rubinsztein, DC, Brown, KS, Passmore, PA, McGuinness, B, Smith, AD, Kehoe, PG, Hooper, NM, Vardy, ERLC, Fox, NC, Goate, AM, Kauwe, JSK, Morris, JC, De Deyn, PP, Bass, NJ, McQuillin, A, Shaw, CE, Singleton, AB, Mühleisen, TW, Nöthen, MM, Pankratz, VS, Sando, SB, Aasly, JO, Wszolek, ZK, Dickson, DW, Graff Radford, NR, Petersen, RC, van Duijn, CM, Breteler, MMB, Ikram, MA, DeStefano, AL, Fitzpatrick, AL, Launer, LJ, Feulner, TM, Jonsson, PV, Bullido, MJ, ANNONI, GIORGIO, Holmans, PA, Younkin, SG, Owen, MJ, Williams, J., Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, J, Carrasquillo, M, Abraham, R, Hamshere, M, Pahwa, J, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Brown, K, Passmore, P, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, A, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, P, Hooper, N, Vardy, E, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Rüther, E, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Gallacher, J, Hüll, M, Rujescu, D, Giegling, I, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Sleegers, K, Bettens, K, Engelborghs, S, De Deyn, P, Van Broeckhoven, C, Livingston, G, Bass, N, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al Chalabi, A, Shaw, C, Tsolaki, M, Singleton, A, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Pankratz, V, Sando, S, Aasly, J, Barcikowska, M, Wszolek, Z, Dickson, D, Graff Radford, N, Petersen, R, van Duijn, C, Breteler, M, Ikram, M, Destefano, A, Fitzpatrick, A, Lopez, O, Launer, L, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, J, Tzourio, C, Alpérovitch, A, Lathrop, M, Feulner, T, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snædal, J, Björnsson, S, Jonsson, P, Chouraki, V, Genier Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, M, Pasquier, F, Mateo, I, Frank Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossù, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, P, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, S, Owen, M, O'Donovan, M, Amouyel, P, Williams, J, Carrasquillo, MM, Hamshere, ML, Pahwa, JS, Lupton, MK, Rubinsztein, DC, Brown, KS, Passmore, PA, McGuinness, B, Smith, AD, Kehoe, PG, Hooper, NM, Vardy, ERLC, Fox, NC, Goate, AM, Kauwe, JSK, Morris, JC, De Deyn, PP, Bass, NJ, McQuillin, A, Shaw, CE, Singleton, AB, Mühleisen, TW, Nöthen, MM, Pankratz, VS, Sando, SB, Aasly, JO, Wszolek, ZK, Dickson, DW, Graff Radford, NR, Petersen, RC, van Duijn, CM, Breteler, MMB, Ikram, MA, DeStefano, AL, Fitzpatrick, AL, Launer, LJ, Feulner, TM, Jonsson, PV, Bullido, MJ, ANNONI, GIORGIO, Holmans, PA, Younkin, SG, Owen, MJ, and Williams, J.
Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10 -5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 -17; including ADGC data, meta P = 5.0 × 10 -21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 -14; including ADGC data, meta P = 1.2 × 10 -16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 -4; including ADGC data, meta P = 8.6 × 10 -9), CD33 (GERAD+, P = 2.2 × 10 -4; including ADGC data, meta P = 1.6 × 10 -9) and EPHA1 (GERAD+, P = 3.4 × 10 -4; including ADGC data, meta P = 6.0 × 10 -10). © 2011 Nature America, Inc. All rights reserved.
Published: 2011

147. Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior.

Author: Thorgeirsson, T.E., Gudbjartsson, D.F., Surakka, I., Vink, J.M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., Mangino, M., Prokopenko, I., Magi, R., Keskitalo, K., Gudjonsdottir, I.H., Gretarsdottir, S., Stefansson, H., Thompson, J.R., Aulchenko, Y.S., Nelis, M., Aben, K.K.H., Heijer, M. den, Dirksen, A., Ashraf, H., Soranzo, N., Valdes, A.M., Steves, C., Uitterlinden, A.G., Hofman, A., Tonjes, A., Kovacs, P., Hottenga, J.J., Willemsen, G., Vogelzangs, N., Doring, A., Dahmen, N., Nitz, B., Pergadia, M.L., Saez, B., Diego, V. De, Lezcano, V., Garcia-Prats, M.D., Ripatti, S., Perola, M., Kettunen, J., Hartikainen, A.L., Pouta, A., Laitinen, J., Isohanni, M., Huei-Yi, S., Allen, M., Krestyaninova, M., Hall, A.S., Jones, G.T., Rij, A.M. van, Mueller, T., Dieplinger, B., Haltmayer, M., Jonsson, S., Matthiasson, S.E., Oskarsson, H., Tyrfingsson, T., Kiemeney, L.A.L.M., Mayordomo, J.I., Lindholt, J.S., Pedersen, J.H., Franklin, W.A., Wolf, H., Montgomery, G.W., Heath, A.C., Martin, N.G., Madden, P.A.F., Giegling, I., Rujescu, D., Jarvelin, M.R., Salomaa, V., Stumvoll, M., Spector, T.D., Wichmann, H.E., Metspalu, A., Samani, N.J., Penninx, B.W.J.H., Oostra, B.A., Boomsma, D.I., Tiemeier, H., Duijn, C.M. van, Kaprio, J., Gulcher, J.R., McCarthy, M.I., Peltonen, L., Thorsteinsdottir, U., Stefansson, K., Thorgeirsson, T.E., Gudbjartsson, D.F., Surakka, I., Vink, J.M., Amin, N., Geller, F., Sulem, P., Rafnar, T., Esko, T., Walter, S., Gieger, C., Rawal, R., Mangino, M., Prokopenko, I., Magi, R., Keskitalo, K., Gudjonsdottir, I.H., Gretarsdottir, S., Stefansson, H., Thompson, J.R., Aulchenko, Y.S., Nelis, M., Aben, K.K.H., Heijer, M. den, Dirksen, A., Ashraf, H., Soranzo, N., Valdes, A.M., Steves, C., Uitterlinden, A.G., Hofman, A., Tonjes, A., Kovacs, P., Hottenga, J.J., Willemsen, G., Vogelzangs, N., Doring, A., Dahmen, N., Nitz, B., Pergadia, M.L., Saez, B., Diego, V. De, Lezcano, V., Garcia-Prats, M.D., Ripatti, S., Perola, M., Kettunen, J., Hartikainen, A.L., Pouta, A., Laitinen, J., Isohanni, M., Huei-Yi, S., Allen, M., Krestyaninova, M., Hall, A.S., Jones, G.T., Rij, A.M. van, Mueller, T., Dieplinger, B., Haltmayer, M., Jonsson, S., Matthiasson, S.E., Oskarsson, H., Tyrfingsson, T., Kiemeney, L.A.L.M., Mayordomo, J.I., Lindholt, J.S., Pedersen, J.H., Franklin, W.A., Wolf, H., Montgomery, G.W., Heath, A.C., Martin, N.G., Madden, P.A.F., Giegling, I., Rujescu, D., Jarvelin, M.R., Salomaa, V., Stumvoll, M., Spector, T.D., Wichmann, H.E., Metspalu, A., Samani, N.J., Penninx, B.W.J.H., Oostra, B.A., Boomsma, D.I., Tiemeier, H., Duijn, C.M. van, Kaprio, J., Gulcher, J.R., McCarthy, M.I., Peltonen, L., Thorsteinsdottir, U., and Stefansson, K.
Abstract: 01 mei 2010, Contains fulltext : 89305.pdf (publisher's version ) (Closed access), Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
Published: 2010

148. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.

Author: Gretarsdottir, S., Baas, A.F., Thorleifsson, G., Holm, H., Heijer, M. den, Vries, J.P. de, Kranendonk, S.E., Zeebregts, C.J.A., Sterkenburg, S.M. van, Geelkerken, R.H., Rij, A.M. van, Williams, M.J., Boll, A.P.M., Kostic, J., Jonasdottir, A., Walters, G.B., Masson, G., Sulem, P., Saemundsdottir, J., Mouy, M., Magnusson, K.P., Tromp, G., Elmore, J.B., Sakalihasan, N., Limet, R., Defraigne, J.O., Ferrell, R.E., Ronkainen, A., Ruigrok, Y.M., Wijmenga, C., Grobbee, D.E., Shah, S.H., Granger, C.B., Quyyumi, A.A., Vaccarino, V., Patel, R., Zafari, A.M., Levey, A.I., Austin, H., Girelli, D., Pignatti, P.F., Olivieri, O., Martinelli, N., Malerba, G., Trabetti, E., Becker, L.C., Becker, D.M., Reilly, M.P., Rader, D.J., Mueller, T., Dieplinger, B., Haltmayer, M., Urbonavicius, S., Lindblad, B., Gottsäter, A., Gaetani, E., Pola, R., Wells, P., Rodger, M., Forgie, M., Langlois, N., Corral, J., Vicente, V., Fontcuberta, J., España, F., Grarup, N., Jørgensen, T., Witte, D.R., Hansen, T., Pedersen, O., Aben, K.K.H., Graaf, J. de, Holewijn, S., Folkersen, L., Franco-Cereceda, A., Eriksson, P., Collier, D.A., Stefansson, H., Steinthorsdottir, V., Rafnar, T., Valdimarsson, E.M., Magnadottir, H.B., Sveinbjornsdottir, S., Olafsson, I., Magnusson, M.K., Palmason, R., Haraldsdottir, V., Andersen, K., Onundarson, P.T., Thorgeirsson, G., Kiemeney, L.A.L.M., Powell, J.T., Carey, D.J., Kuivaniemi, H., Lindholt, J.S., Jones, G.T., Blankensteijn, J.D., Gretarsdottir, S., Baas, A.F., Thorleifsson, G., Holm, H., Heijer, M. den, Vries, J.P. de, Kranendonk, S.E., Zeebregts, C.J.A., Sterkenburg, S.M. van, Geelkerken, R.H., Rij, A.M. van, Williams, M.J., Boll, A.P.M., Kostic, J., Jonasdottir, A., Walters, G.B., Masson, G., Sulem, P., Saemundsdottir, J., Mouy, M., Magnusson, K.P., Tromp, G., Elmore, J.B., Sakalihasan, N., Limet, R., Defraigne, J.O., Ferrell, R.E., Ronkainen, A., Ruigrok, Y.M., Wijmenga, C., Grobbee, D.E., Shah, S.H., Granger, C.B., Quyyumi, A.A., Vaccarino, V., Patel, R., Zafari, A.M., Levey, A.I., Austin, H., Girelli, D., Pignatti, P.F., Olivieri, O., Martinelli, N., Malerba, G., Trabetti, E., Becker, L.C., Becker, D.M., Reilly, M.P., Rader, D.J., Mueller, T., Dieplinger, B., Haltmayer, M., Urbonavicius, S., Lindblad, B., Gottsäter, A., Gaetani, E., Pola, R., Wells, P., Rodger, M., Forgie, M., Langlois, N., Corral, J., Vicente, V., Fontcuberta, J., España, F., Grarup, N., Jørgensen, T., Witte, D.R., Hansen, T., Pedersen, O., Aben, K.K.H., Graaf, J. de, Holewijn, S., Folkersen, L., Franco-Cereceda, A., Eriksson, P., Collier, D.A., Stefansson, H., Steinthorsdottir, V., Rafnar, T., Valdimarsson, E.M., Magnadottir, H.B., Sveinbjornsdottir, S., Olafsson, I., Magnusson, M.K., Palmason, R., Haraldsdottir, V., Andersen, K., Onundarson, P.T., Thorgeirsson, G., Kiemeney, L.A.L.M., Powell, J.T., Carey, D.J., Kuivaniemi, H., Lindholt, J.S., Jones, G.T., and Blankensteijn, J.D.
Abstract: Contains fulltext : 88507.pdf (publisher's version ) (Closed access)
Published: 2010

149. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Author: Anttila, V, Stefansson, H, Kallela, M, Todt, U, Terwindt, GM, Calafato, MS, Nyholt, DR, Dimas, AS, Freilinger, T, Mueller-Myhsok, B, Artto, V, Inouye, M, Alakurtti, K, Kaunisto, MA, Haemaelaeinen, E, de Vries, B, Stam, AH, Weller, CM, Heinze, A, Heinze-Kuhn, K, Goebel, I, Borck, G, Goebel, H, Steinberg, S, Wolf, C, Bjoernsson, A, Gudmundsson, G, Kirchmann, M, Hauge, A, Werge, T, Schoenen, J, Eriksson, JG, Hagen, K, Stovner, L, Wichmann, E, Meitinger, T, Alexander, M, Moebus, S, Schreiber, S, Aulchenko, YS, Breteler, MMB, Uitterlinden, AG, Hofman, A, van Duijn, CM, Tikka-Kleemola, P, Vepsaelaeinen, S, Lucae, S, Tozzi, F, Muglia, P, Barrett, J, Kaprio, J, Faerkkilae, M, Peltonen, L, Stefansson, K, Zwart, J-A, Ferrari, MD, Olesen, J, Daly, M, Wessman, M, van den Maagdenberg, AMJM, Dichgans, M, Kubisch, C, Dermitzakis, ET, Frants, RR, Palotie, A, Anttila, V, Stefansson, H, Kallela, M, Todt, U, Terwindt, GM, Calafato, MS, Nyholt, DR, Dimas, AS, Freilinger, T, Mueller-Myhsok, B, Artto, V, Inouye, M, Alakurtti, K, Kaunisto, MA, Haemaelaeinen, E, de Vries, B, Stam, AH, Weller, CM, Heinze, A, Heinze-Kuhn, K, Goebel, I, Borck, G, Goebel, H, Steinberg, S, Wolf, C, Bjoernsson, A, Gudmundsson, G, Kirchmann, M, Hauge, A, Werge, T, Schoenen, J, Eriksson, JG, Hagen, K, Stovner, L, Wichmann, E, Meitinger, T, Alexander, M, Moebus, S, Schreiber, S, Aulchenko, YS, Breteler, MMB, Uitterlinden, AG, Hofman, A, van Duijn, CM, Tikka-Kleemola, P, Vepsaelaeinen, S, Lucae, S, Tozzi, F, Muglia, P, Barrett, J, Kaprio, J, Faerkkilae, M, Peltonen, L, Stefansson, K, Zwart, J-A, Ferrari, MD, Olesen, J, Daly, M, Wessman, M, van den Maagdenberg, AMJM, Dichgans, M, Kubisch, C, Dermitzakis, ET, Frants, RR, and Palotie, A
Abstract: Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10⁻⁹, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10⁻¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10⁻⁵, permuted threshold for genome-wide significance 7.7 × 10⁻⁵. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.
Published: 2010

150. Disruption of the neurexin 1 gene is associated with schizophrenia.

Author: Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., Collier, D.A., Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., and Collier, D.A.
Abstract: Contains fulltext : 80670.pdf (publisher's version ) (Closed access), Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.
Published: 2009

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