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1. A genome-wide association study of autism using the Simons simplex collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author

Chaste, P, Klei, L, Sanders, SJ, Hus, V, Murtha, MT, Lowe, JK, Willsey, AJ, Moreno-De-Luca, D, Yu, TW, Fombonne, E, Geschwind, D, Grice, DE, Ledbetter, DH, Mane, SM, Martin, DM, Morrow, EM, Walsh, CA, Sutcliffe, JS, Lese Martin, C, Beaudet, AL, Lord, C, State, MW, Cook, EH, and Devlin, B

Subjects
Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Published
2015

2. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment

Author

State, Matthew, Sanders, Stephan, Cotney, J, Muhle, RA, Sanders, SJ, Liu, L, Willsey, AJ, Niu, W, Liu, W, Klei, L, Lei, J, and Yin, J

Abstract

© 2015 Macmillan Publishers Limited.Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human

Published
2015

3. DAWN: A framework to identify autism genes and subnetworks using gene expression and genetics

Author

State, Matthew, Sanders, Stephan, Liu, L, Lei, J, Sanders, SJ, Willsey, AJ, Kou, Y, Cicek, AE, Klei, L, Lu, C, He, X, and Li, M

Abstract

Background: De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provid

Published
2014

4. Most genetic risk for autism resides with common variation

Author

Sanders, Stephan, Gaugler, T, Klei, L, Sanders, SJ, Bodea, CA, Goldberg, AP, Lee, AB, Mahajan, M, Manaa, D, Pawitan, Y, and Reichert, J

Abstract

A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from

Published
2014

6. Common genetic variants, acting additively, are a major source of risk for autism

Author

State, Matthew, Sanders, Stephan, Klei, L, Sanders, SJ, Murtha, MT, Hus, V, Lowe, JK, Willsey, AJ, Moreno-De-Luca, D, Yu, TW, Fombonne, E, and Geschwind, D

Abstract

Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genet

Published
2012

8. BLOCKING THE BCL10-MALT1 INTERACTION IN DIFFUSE LARGE B-CELL LYMPHOMA

Author

Maurer, L., primary, Kang, H., additional, Smyers, M., additional, Klei, L., additional, Cheng, J., additional, Trotta, M., additional, Hu, D., additional, Ekambaram, P., additional, Murai, M., additional, Nikolovska-Coleska, Z., additional, Chen, B., additional, Lucas, P., additional, and McAllister-Lucas, L., additional

Published
2022
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10. Handreiking redden van mens en dier tijdens overstromingen

Author

Klei, L. van der and Klei, L. van der

Abstract

Hulp, advies - Zodra Nederland te maken krijgt met een overstroming is het belangrijk dat crisisbeheersingsorganisaties een plan hebben voor de reddingsoperaties. Deze handreiking geeft veiligheidsregio’s en hun crisispartners handvatten om inzicht te krijgen in de opgeschaalde crisisbeheersingsorganisatie bij overstromingen, de relevantste partijen, bijstandsvraagstukken en informatie-uitwisseling bij ‘redden’ en handelingsperspectieven.

Published
2022

11. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Author

J. M., Fu, Satterstrom, F. K., Peng, M., Brand, H., Collins, R. L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S. P., Stevens, C. R., Cusick, C., Babadi, M., Banks, E., Collins, B., Dodge, S., Gabriel, S. B., Gauthier, L., Lee, S. K., Liang, L., Ljungdahl, A., Mahjani, B., Sloofman, L., Smirnov, A. N., Barbosa, M., Betancur, C., Brusco, A., Chung, B. H. Y., Cook, E. H., Cuccaro, M. L., Domenici, E., Ferrero, G. B., Gargus, J. J., Herman, G. E., Hertz-Picciotto, I., Maciel, P., Manoach, D. S., Passos-Bueno, M. R., Persico, A., Renieri, A., Sutcliffe, J. S., Tassone, F., Trabetti, E., Campos, G., Cardaropoli, S., Carli, D., Chan, M. C. Y., Fallerini, C., Giorgio, E., Girardi, A. C., Hansen-Kiss, E., Lee, S. L., Lintas, C., Ludena, Y., Nguyen, R., Pavinato, L., Pericak-Vance, M., Pessah, I. N., Schmidt, R. J., Smith, M., Costa, C. I. S., Trajkova, S., Wang, J. Y. T., M. H. C., Yu, Aleksic, B., Artomov, M., Benetti, E., Biscaldi-Schafer, M., Borglum, A. D., Carracedo, A., Chiocchetti, A. G., Coon, H., Doan, R. N., Fernandez-Prieto, M., Freitag, C. M., Gerges, S., Guter, S., Hougaard, D. M., Hultman, C. M., Jacob, S., Kaartinen, M., Kolevzon, A., Kushima, I., Lehtimaki, T., Rizzo, C. L., Maltman, N., Manara, M., Meiri, G., Menashe, I., Miller, J., Minshew, N., Mosconi, M., Ozaki, N., Palotie, A., Parellada, M., Puura, K., Reichenberg, A., Sandin, S., Scherer, S. W., Schlitt, S., Schmitt, L., Schneider-Momm, K., Siper, P. M., Suren, P., Sweeney, J. A., Teufel, K., del Pilar Trelles, M., Weiss, L. A., Yuen, R., Cutler, D. J., De Rubeis, S., Buxbaum, J. D., Daly, M. J., Devlin, B., Roeder, K., Sanders, S. J., Talkowski, M. E., Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Carnegie Mellon University [Pittsburgh] (CMU), Harvard Medical School [Boston] (HMS), University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Los Angeles] (UCLA), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, The University of Hong Kong (HKU), University of Illinois [Chicago] (UIC), University of Illinois System, University of Miami Leonard M. Miller School of Medicine (UMMSM), University of Trento [Trento], University of California [Irvine] (UC Irvine), Nationwide Children's Hospital, University of California [Davis] (UC Davis), Universidade do Minho = University of Minho [Braga], Massachusetts General Hospital [Boston, MA, USA], Escola Politecnica da Universidade de Sao Paulo [Sao Paulo], Università degli Studi di Messina = University of Messina (UniMe), Università degli Studi di Siena = University of Siena (UNISI), Azienda Ospedaliera Universitaria Senese, Vanderbilt University [Nashville], Vanderbilt University School of Medicine [Nashville], Università degli studi di Verona = University of Verona (UNIVR), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), Emory University School of Medicine, Emory University [Atlanta, GA], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Autism Sequencing Consortium (ASC), Broad Institute Center for Common Disease Genomics (Broad-CCDG), iPSYCH-BROAD Consortium : Branko Aleksic, Mykyta Artomov, Elisa Benetti, Monica Biscaldi-Schafer, Anders D Børglum, Angel Carracedo, Andreas G Chiocchetti, Hilary Coon, Ryan N Doan, Montserrat Fernández-Prieto, Christine M Freitag, Sherif Gerges, Stephen Guter, David M Hougaard, Christina M Hultman, Suma Jacob, Miia Kaartinen, Alexander Kolevzon, Itaru Kushima, Terho Lehtimäki, Caterina Lo Rizzo, Nell Maltman, Marianna Manara, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Matthew Mosconi, Norio Ozaki, Aarno Palotie, Mara Parellada, Kaija Puura, Abraham Reichenberg, Sven Sandin, Stephen W Scherer, Sabine Schlitt, Lauren Schmitt, Katja Schneider-Momm, Paige M Siper, Pål Suren, John A Sweeney, Karoline Teufel, Maria Del Pilar Trelles, Lauren A Weiss, Ryan Yuen., and Betancur, Catalina

Subjects
Broad Institute Center for Common Disease Genomics, Autism Sequencing Consortium, DNA Copy Number Variations, Autism Spectrum Disorder, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Autism, Intellectual and Developmental Disabilities (IDD), iPSYCH-BROAD Consortium, autism spectrum disorders, disease gene, copy number variants, neuropsychiatric disorders, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, GENOMAS, Medical and Health Sciences, Article, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Autistic Disorder, Aetiology, Genetic association study, Pediatric, Human Genome, Neurodevelopmental disorders, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biological Sciences, Autism spectrum disorders, Brain Disorders, Mental Health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Gene expression, Biotechnology, Developmental Biology
Abstract

International audience; Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

Published
2022

12. Linkage analysis of schizophrenia in African-American families

Author

Wiener, H.W., Klei, L., Irvin, M.D., Perry, R.T., Aliyu, M.H., Allen, T.B., Bradford, L.D, Calkins, M.E., Devlin, B., Edwards, N., Gur, R.E., Gur, R.C., Kwentus, J., Lyons, P.D., McEvoy, J.P., Nasrallah, H.A., Nimgaonkar, V.L., O'Jile, J., Santos, A.B., Savage, R.M., and Go, R.C.P.

Published
2009
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13. Genome-wide association study of Alzheimer's disease with psychotic symptoms

Author

Hollingworth, P, Sweet, R, Sims, R, Harold, D, Russo, G, Abraham, R, Stretton, A, Jones, N, Gerrish, A, Chapman, J, Ivanov, D, Moskvina, V, Lovestone, S, Priotsi, P, Lupton, M, Brayne, C, Gill, M, Lawlor, B, Lynch, A, Craig, D, McGuinness, B, Johnston, J, Holmes, C, Livingston, G, Bass, N J, Gurling, H, McQuillin, A, Holmans, P, Jones, L, Devlin, B, Klei, L, Barmada, M M, Demirci, F Y, DeKosky, S T, Lopez, O L, Passmore, P, Owen, M J, O'Donovan, M C, Mayeux, R, Kamboh, M I, and Williams, J

Published
2012
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14. Prevalence of polydipsia in dogs with pericardial effusion and cardiac tamponade

Author

Klei, L. van der, Santarelli, G. (Thesis Advisor), Klei, L. van der, and Santarelli, G. (Thesis Advisor)

Abstract

Pericardial effusion is an abnormal accumulation of fluid in the pericardial sac, which may eventually lead to a significant increase in intrapericardial pressure and cardiac tamponade, a life-threatening condition characterized by collapse of the cardiac chambers and heart failure. A variety of clinical signs can be reported by the owner of dogs presenting with pericardial effusion and cardiac tamponade; most of these are non-specific, including polydipsia. This research project consisted of a retrospective and a prospective study. Clinical signs reported by the owner of dogs presenting with cardiac tamponade due to pericardial effusion and physical examination findings at presentation were evaluated. The prevalence of polydipsia was calculated, next to that of other clinical signs and physical examination findings. The presence of a mass on echocardiography and the amount of fluid drained from the pericardium were also assessed, and their correlation with the presence of polydipsia was investigated. A total prevalence of 35% for polydipsia was found. There was no significant association between this and the presence of a mass or ascites. The amount of fluid drained from the pericardium did not seem correlated with the presence of polydipsia. The prevalence of polydipsia in this study is higher than previously reported and can occur at first presentation or relapse. Therefore, it could potentially be useful as a sign of recurrence that owners can monitor at home.

Published
2021

18. Persistent infection with neurotropic herpes viruses and cognitive impairment

Author

Watson, A. M. M., Prasad, K. M., Klei, L., Wood, J. A., Yolken, R. H., Gur, R. C., Bradford, L. D., Calkins, M. E., Richard, J., Edwards, N., Savage, R. M., Allen, T. B., Kwentus, J., McEvoy, J. P., Santos, A. B., Wiener, H. W., Go, R. C. P., Perry, R. T., Nasrallah, H. A., Gur, R. E., Devlin, B., and Nimgaonkar, V. L.

Published
2013

19. Identification of common genetic risk variants for autism spectrum disorder

Author

Grove, J., Ripke, S., Als, T.D., Mattheisen, M., Walters, R.K., Won, H., Pallesen, J., Agerbo, E., Andreassen, O.A., Anney, R., Awashti, S., Belliveau, R., Bettella, F., Buxbaum, J.D., Bybjerg-Grauholm, J., Baekvad-Hansen, M., Cerrato, F., Chambert, K., Christensen, J.H., Churchhouse, C., Dellenvall, K., Demontis, D., Rubeis, S. de, Devlin, B., Djurovic, S., Dumont, A.L., Goldstein, J.I., Hansen, C.S., Hauberg, M.E., Hollegaard, M.V., Hope, S., Howrigan, D.P., Huang, H., Hultman, C.M., Klei, L., Maller, J., Martin, J., Martin, A.R., Moran, J.L., Nyegaard, M., Naeland, T., Palmer, D.S., Palotie, A., Pedersen, C.B., Pedersen, M.G., dPoterba, T., Poulsen, J.B., St Pourcain, B., Qvist, P., Rehnstrom, K., Reichenberg, A., Reichert, J., Robinson, E.B., Roeder, K., Roussos, P., Saemundsen, E., Sandin, S., Satterstrom, F.K., Smith, G.D., Stefansson, H., Steinberg, S., Stevens, C.R., Sullivan, P.F., Turley, P., Walters, G.B., Xu, X.Y., Stefansson, K., Geschwind, D.H., Nordentoft, M., Hougaard, D.M., Werge, T., Mors, O., Mortensen, P.B., Neale, B.M., Daly, M.J., Borglum, A.D., Wray, N.R., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Air, T.M., Andlauer, T.F.M., Bacanu, S.A., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Cai, N., Castelao, E., Clarke, T.K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Hall, L.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Ising, M., Jansen, R., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y.P., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F.T., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Muller-Myhsok, B., Nothen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Tiemeier, H., Uher, R., Volzke, H., Weissman, M.M., Lewis, C.M., Levinson, D.F., Breen, G., Agee, M., Alipanahi, B., Auton, A., Bell, R.K., Bryc, K., Elson, S.L., Fontanillas, P., Furlotte, N.A., Hromatka, B.S., Huber, K.E., Kleinman, A., Litterman, N.K., McIntyre, M.H., Mountain, J.L., Noblin, E.S., Northover, C.A.M., Pitts, S.J., Sathirapongsasuti, J.F., Sazonova, O.V., Shelton, J.F., Shringarpure, S., Tung, J.Y., Vacic, V., Wilson, C.H., Psychiat Genomics Consortium, BUPGEN, 23andMe Re, Biological Psychology, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Adult Psychiatry, Psychiatry, Human genetics, Amsterdam Reproduction & Development (AR&D), VU University medical center, APH - Digital Health, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Me Research Team, Epidemiology, and Child and Adolescent Psychiatry / Psychology

Subjects
Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Autism Spectrum Disorder, Denmark, LD SCORE REGRESSION, LOCI, Genome-wide association study, DE-NOVO, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, SYNAPTIC PLASTICITY, CELL-SURFACE, Child, Genetics, 0303 health sciences, HERITABILITY, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Polymorphism, Single Nucleotide/genetics, Phenotype, 3. Good health, Schizophrenia, Autism spectrum disorder, Child, Preschool, Genome-Wide Association Study/methods, Female, SIMONS SIMPLEX COLLECTION, Adolescent, Biology, NEURITE OUTGROWTH, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, SDG 2 - Zero Hunger, Multifactorial Inheritance/genetics, METAANALYSIS, 030304 developmental biology, Case-control study, Heritability, medicine.disease, Autism Spectrum Disorder/genetics, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Published in final edited form as: Nat Genet. 2019 March ; 51(3): 431–444. doi:10.1038/s41588-019-0344-8., Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture, we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD., The iPSYCH project is funded by the Lundbeck Foundation (grant numbers R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432–02 to MJD). The Danish National Biobank resource was supported by the Novo Nordisk Foundation. Data handling and analysis on the GenomeDK HPC facility was supported by NIMH (1U01MH109514–01 to M O’Donovan and ADB). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). Drs. S De Rubeis and JD Buxbaum were supported by NIH grants MH097849 (to JDB) and MH111661 (to JDB), and by the Seaver Foundation (to SDR and JDB). Dr J Martin was supported by the Wellcome Trust (grant no: 106047). O. Andreassen received funding from Research Council of Norway (#213694, #223273, #248980, #248778), Stiftelsen KG Jebsen and South-East Norway Health Authority. We thank the research participants and employees of 23andMe for making this work possible.

Published
2019

23. Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease

Author

DeMichele-Sweet, M. A. A., primary, Weamer, E. A., additional, Klei, L., additional, Vrana, D. T., additional, Hollingshead, D. J., additional, Seltman, H. J., additional, Sims, R., additional, Foroud, T., additional, Hernandez, I., additional, Moreno-Grau, S., additional, Tárraga, L., additional, Boada, M., additional, Ruiz, A., additional, Williams, J., additional, Mayeux, R., additional, Lopez, O. L., additional, Sibille, E. L., additional, Kamboh, M. I., additional, Devlin, B., additional, and Sweet, R. A., additional

Published
2019
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24. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Author

Anney, RJL, Ripke, S, Anttila, V, Grove, J, Holmans, P, Huang, H, Klei, L, Lee, PH, Medland, SE, Neale, B, Robinson, E, Weiss, LA, Zwaigenbaum, L, Yu, TW, Wittemeyer, K, Willsey, AJ, Wijsman, EM, Werge, T, Wassink, TH, Waltes, R, Walsh, CA, Wallace, S, Vorstman, JAS, Vieland, VJ, Vicente, AM, Vanengeland, H, Tsang, K, Thompson, AP, Szatmari, P, Svantesson, O, Steinberg, S, Stefansson, K, Stefansson, H, State, MW, Soorya, L, Silagadze, T, Scherer, SW, Schellenberg, GD, Sandin, S, Sanders, SJ, Saemundsen, E, Rouleau, GA, Rogé, B, Roeder, K, Roberts, W, Reichert, J, Reichenberg, A, Rehnström, K, Regan, R, Poustka, F, Poultney, CS, Piven, J, Pinto, D, Pericak-Vance, MA, Pejovic-Milovancevic, M, Pedersen, MG, Pedersen, CB, Paterson, AD, and Parr, JR

Subjects
mental disorders
Abstract

© 2017 The Author(s). Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR)

Published
2017

25. Genetic risk for schizophrenia and psychosis in Alzheimer disease

Author

DeMichele-Sweet, M A A, primary, Weamer, E A, additional, Klei, L, additional, Vrana, D T, additional, Hollingshead, D J, additional, Seltman, H J, additional, Sims, R, additional, Foroud, T, additional, Hernandez, I, additional, Moreno-Grau, S, additional, Tárraga, L, additional, Boada, M, additional, Ruiz, A, additional, Williams, J, additional, Mayeux, R, additional, Lopez, O L, additional, Sibille, E L, additional, Kamboh, M I, additional, Devlin, B, additional, and Sweet, R A, additional

Published
2017
Full Text
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26. The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Author

Hadley, D., Wu, Z.L., Kao, C., Kini, A., Mohamed-Hadley, A., Thomas, K., Vazquez, L., Qiu, H., Mentch, F., Pellegrino, R., Kim, C., Connolly, J., Glessner, J., Hakonarson, H., Pinto, D., Merikangas, A., Klei, L., Vorstman, J.A., Thompson, A., Regan, R., Pagnamenta, A.T., Oliveira, B., Magalhaes, T.R., Gilbert, J., Duketis, E., De Jonge, M.V., Cuccaro, M., Correia, C.T., Conroy, J., Conceição, I.C., Chiocchetti, A.G., Casey, J.P., Bolshakova, N., Bacchelli, E., Anney, R., Zwaigenbaum, L., Wittemeyer, K., Wallace, S., Engeland, Hv, Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McGrew, S.G., Lord, C., Leboyer, M., Le Couteur, A.S., Kolevzon, A., Jacob, S., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B.A., Duque, F., Delorme, R., Dawson, G., Café, C., Brennan, S., Bourgeron, T., Bolton, P.F., Bölte, S., Bernier, R., Baird, G., Bailey, A.J., Anagnostou, E., Almeida, J., Wijsman, E.M., Vieland, V.J., Vicente, A.M., Schellenberg, G.D., Pericak-Vance, M., Paterson, A.D., Parr, J.R., Oliveira, G., Correia, C., Nurnberger, J.I., Monaco, A.P., Maestrini, E., Klauck, S.M., Haines, J.L., Geschwind, D.H., Freitag, C.M., Folstein, S.E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J.S., Hallmayer, J., Gill, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Gallagher, L., Betancur, C., and Scherer, S.W.

Subjects
Autism, Perturbações do Desenvolvimento Infantil e Saúde Mental
Abstract

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

Published
2014

27. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Author

Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L, Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., Vorstman, J.A., Thompson, A., Regan, R., Pilorge, M., Pellecchia, G., Pagnamenta, A.T., Oliveira, B., Marshall, C.R., Magalhães, T.R., Lowe, J.K., Howe, J.L., Griswold, A.J., Gilbert, J., Duketis, E., Dombroski, B.A., De Jonge, M.V., Cuccaro, M., Crawford, E.L., Correia, C.T., Conroy, J., Conceição, I.C, Chiocchetti, A.G., Casey, J.P., Cai, G., Cabrol, C., Bolshakova, N., Bacchelli, E., Anney, R., Gallinger, S., Cotterchio, M., Casey, G., Zwaigenbaum, L., Wittemeyer, K., Wing, K., Wallace, S., van Engeland, H., Tryfon, A., Thomson, S., Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McInnes, L.A., McGrew, S.G., Lord, C., Leboyer, M., Le Couteur, A.S., Kolevzon, A., Jiménez González, P., Jacob, S., Holt, R., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B.A., Duque, F., Delorme, R., Dawson, G., Chaste, P., Café, C., Brennan, S., Bourgeron, T., Bolton, P.F., Bölte, S., Bernier, R., Baird, G., Bailey, A.J., Anagnostou, E., Almeida, J., Wijsman, E.M., Vieland, V.J., Vicente, A.M., Schellenberg, G.D., Pericak-Vance, M., Paterson, A.D., Parr, J.R., Oliveira, G., Nurnberger, J.I., Monaco, A.P., Maestrini, E., Klauck, S.M., Hakonarson, H., Haines, J.L., Geschwind, D.H., Freitag, C.M., Folstein, S.E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J.S., Hallmayer, J., Gill, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Gallagher, L., and Betancur, C.

Subjects
Autism Spectrum Disorders, Rare copy-number variation, Autism, mental disorders, Perturbações do Desenvolvimento Infantil e Saúde Mental
Abstract

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Published
2014

28. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Author

Whitcomb, DC, LaRusch, J, Krasinskas, AM, Klei, L, Smith, JP, Brand, RE, Neoptolemos, JP, Lerch, MM, Tector, M, Sandhu, BS, Guda, NM, Orlichenko, L, Alkaade, S, Amann, ST, Anderson, MA, Baillie, J, Banks, PA, Conwell, D, Coté, GA, Cotton, PB, DiSario, J, Farrer, LA, Forsmark, CE, Johnstone, M, Gardner, TB, Gelrud, A, Greenhalf, W, Haines, JL, Hartman, DJ, Hawes, RA, Lawrence, C, Lewis, M, Mayerle, J, Mayeux, R, Melhem, NM, Money, ME, Muniraj, T, Papachristou, GI, Pericak-Vance, MA, Romagnuolo, J, Schellenberg, GD, Sherman, S, Simon, P, Singh, VP, Slivka, A, Stolz, D, Sutton, R, Weiss, FU, Wilcox, CM, Zarnescu, NO, Wisniewski, SR, O'Connell, MR, Kienholz, ML, Roeder, K, Barmada, MM, Yadav, D, Devlin, B, Albert, MS, Albin, RL, Apostolova, LG, Arnold, SE, Baldwin, CT, Barber, R, Barnes, LL, Beach, TG, Beecham, GW, Beekly, D, Bennett, DA, Bigio, EH, Bird, TD, Blacker, D, Boxer, A, Burke, JR, Buxbaum, JD, Cairns, NJ, Cantwell, LB, Cao, C, Carney, RM, Carroll, SL, Chui, HC, Clark, DG, Cribbs, DH, Crocco, EA, and Cruchaga, C

Abstract

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10-12) and X-linked CLDN2 (P < 1 × 10-21) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07). © 2012 Nature America, Inc. All rights reserved.

Published
2012

29. Genome-wide association study of Alzheimer's disease with psychotic symptoms

Author

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

Subjects
Medizin
Published
2012

30. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Author

Höglinger, GU, Melhem, NM, Dickson, DW, Sleiman, PMA, Wang, LS, Klei, L, Rademakers, R, De Silva, R, Litvan, I, Riley, DE, Van Swieten, JC, Heutink, P, Wszolek, ZK, Uitti, RJ, Vandrovcova, J, Hurtig, HI, Gross, RG, Maetzler, W, Goldwurm, S, Tolosa, E, Borroni, B, Pastor, P, Cantwell, LB, Han, MR, Dillman, A, Van Der Brug, MP, Gibbs, JR, Cookson, MR, Hernandez, DG, Singleton, AB, Farrer, MJ, Yu, CE, Golbe, LI, Revesz, T, Hardy, J, Lees, AJ, Devlin, B, Hakonarson, H, Müller, U, Schellenberg, GD, Albin, RL, Alonso, E, Antonini, A, Apfelbacher, M, Arnold, SE, Avila, J, Beach, TG, Beecher, S, Berg, D, Bird, TD, Bogdanovic, N, Boon, AJW, Bordelon, Y, Brice, A, Budka, H, Canesi, M, Chiu, WZ, Cilia, R, Colosimo, C, De Deyn, PP, De Yebenes, JG, Kaat, LD, Duara, R, Durr, A, Engelborghs, S, Fabbrini, G, Finch, NA, Flook, R, Frosch, MP, Gaig, C, Galasko, DR, Gasser, T, Gearing, M, Geller, ET, Ghetti, B, Graff-Radford, NR, Grossman, M, Hall, DA, Hazrati, LN, Höllerhage, M, Jankovic, J, Juncos, JL, Karydas, A, Kretzschmar, HA, and Leber, I

Subjects
eye diseases
Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals (P < 5 × 10-8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. © 2011 Nature America, Inc. All rights reserved.

Published
2011

31. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author

Anney, R.J., Kenny, E.M., O'Dushlaine, C., Parkhomenka, E., Buxbaum, J.D., Sutcliffe, J., Gill, M., Gallagher, L., Bailey, A.J., Fernandez, B.A., Szatmari, P., Nurnberger Jr, J.I., McDougle, C.J., Posey, D.J., Lord, C., Corsello, C., Hus, V., Kolevzon, A., Soorya, L., Parkhomenko, E., Scherer, S.W., Leventhal, B.L., Dawson, G., Vieland, V.J., Hakonarson, H., Glessner, J.T., Kim, C., Wang, K., Schellenberg, G.D., Devlin, B., Klei, L., Patterson, A., Minshew, N., Sutcliffe, J.S., Haines, J.L., Lund, S.C., Thomson, S., Yaspan, B.L., Coon, H., Miller, J., McMahon, W.M., Munson, J., Marshall, C.R., Estes, A., Wijsman, EM., The Autism Genome Project, Pinto, D., Vincent, J.B., Fombonne, E., Betancur, C., Delorme, R., Leboyer, M., Bourgeron, T., Mantoulan, C., Roge, B., Tauber, M., Freitag, C.M., Poustka, F., Duketis, E., Klauck, S.M., Poustka, A., Papanikolaou, K., Tsiantis, J., Anney, R., Bolshakova, N., Brennan, S., Hughes, G., McGrath, J., Merikangas, A., Ennis, S., Green, A., Casey, J.P., Conroy, J.M., Regan, R., Shah, N., Maestrini, E., Bacchelli, E., Minopoli, F., Stoppioni, V., Battaglia, A., Igliozzi, R., Parrini, B., Tancredi, R., Oliveira, G., Almeida, J., Duque, F., Vicente, A.M., Correia, C., Magalhaes, T.R., Gillberg, C., Nygren, G., Jonge, M.D., Van Engeland, H., Vorstman, J.A., Wittemeyer, K., Baird, G., Bolton, P.F, Rutter, M.L., Green, J., Lamb, J.A., Pickles, A., Parr, J.R., Couteur, A.L., Berney, T., McConachie, H., Wallace, S., Coutanche, M., Foley, S., White, K., Monaco, A.P., Holt, R., Farrar, P., Pagnamenta, A.T., Mirza, G.K., Ragoussis, J., Sousa, I., Sykes, N., Wing, K., Hallmayer, J., Cantor, R.M., Nelson, S.F., Geschwind, D.H., Abrahams, B.S., Volkmar, F., Pericak-Vance, M.A., Cuccaro, M.L., Gilbert, J., Cook, E.H., Guter, S.J., and Jacob, S.

Subjects
Pathway analysis, Autism, Perturbações do Desenvolvimento Infantil e Saúde Mental, Gene ontology, Genome-wide association analysis, Family-based association test
Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.

Published
2011

33. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author

Anney, R.J.L. Kenny, E.M. O'Dushlaine, C. Yaspan, B.L. Parkhomenka, E. Buxbaum, J.D. Sutcliffe, J. Gill, M. Gallagher, L. Bailey, A.J. Fernandez, B.A. Szatmari, P. Scherer, S.W. Patterson, A. Marshall, C.R. Pinto, D. Vincent, J.B. Fombonne, E. Betancur, C. Delorme, R. Leboyer, M. Bourgeron, T. Mantoulan, C. Roge, B. Tauber, M. Freitag, C.M. Poustka, F. Duketis, E. Klauck, S.M. Poustka, A. Papanikolaou, K. Tsiantis, J. Bolshakova, N. Brennan, S. Hughes, G. McGrath, J. Merikangas, A. Ennis, S. Green, A. Casey, J.P. Conroy, J.M. Regan, R. Shah, N. Maestrini, E. Bacchelli, E. Minopoli, F. Stoppioni, V. Battaglia, A. Igliozzi, R. Parrini, B. Tancredi, R. Oliveira, G. Almeida, J. Duque, F. Vicente, A. Correia, C. Magalhaes, T.R. Gillberg, C. Nygren, G. De Jonge, M. Van Engeland, H. Vorstman, J.A.S. Wittemeyer, K. Baird, G. Bolton, P.F. Rutter, M.L. Green, J. Lamb, J.A. Pickles, A. Parr, J.R. Le Couteur, A. Berney, T. McConachie, H. Wallace, S. Coutanche, M. Foley, S. White, K. Monaco, A.P. Holt, R. Farrar, P. Pagnamenta, A.T. Mirza, G.K. Ragoussis, J. Sousa, I. Sykes, N. Wing, K. Hallmayer, J. Cantor, R.M. Nelson, S.F. Geschwind, D.H. Abrahams, B.S. Volkmar, F. Pericak-Vance, M.A. Cuccaro, M.L. Gilbert, J. Cook, E.H. Guter, S.J. Jacob, S. Nurnberger, J.I., Jr. McDougle, C.J. Posey, D.J. Lord, C. Corsello, C. Hus, V. Kolevzon, A. Soorya, L. Parkhomenko, E. Leventhal, B.L. Dawson, G. Vieland, V.J. Hakonarson, H. Glessner, J.T. Kim, C. Wang, K. Schellenberg, G.D. Devlin, B. Klei, L. Minshew, N. Sutcliffe, J.S. Haines, J.L. Lund, S.C. Thomson, S. Coon, H. Miller, J. McMahon, W.M. Munson, J. Estes, A. Wijsman, E.M. Autism Genome Project

Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings. © 2011 Macmillan Publishers Limited All rights reserved.

Published
2011

34. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Devlin, B. Ennis, S. Hallmayer, J.

Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 3 10-28. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10-28 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C. © The Author 2010. Published by Oxford University Press. All rights reserved.

Published
2010

35. A genome-wide scan for common alleles affecting risk for autism

Author

Bacchelli, E., Berney, T., Brian, J., Baird, G., Brennan, S., Bailey, A. J., Anney, R., Bolshakova, N., Battaglia, A., Chu, S. H., Casey, J., Bourgeron, T., Magalhaes, T. R., Bolte, S., Carson, A. R., Casallo, G., Almeida, J., Klei, L., Conroy, J., de Jonge, M., Sykes, N., Crossett, A., Cochrane, L., Abrahams, B. S., Pinto, D., Regan, R., Correia, C., Crawford, E. L., Pagnamenta, A. T., Bolton, P. F., Dawson, G., and Corsello, C.

Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Published
2010
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36. Functional impact of global rare copy number variation in autism spectrum disorders

Author

Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.

Subjects
mental disorders
Abstract

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (

Published
2010

37. Synaptic, transcriptional and chromatin genes disrupted in autism.

Author

De Rubeis, S, He, X, Goldberg, AP, Poultney, CS, Samocha, K, Cicek, AE, Kou, Y, Liu, L, Fromer, M, Walker, S, Singh, T, Klei, L, Kosmicki, J, Shih-Chen, F, Aleksic, B, Biscaldi, M, Bolton, PF, Brownfeld, JM, Cai, J, Campbell, NG, Carracedo, A, Chahrour, MH, Chiocchetti, AG, Coon, H, Crawford, EL, Curran, SR, Dawson, G, Duketis, E, Fernandez, BA, Gallagher, L, Geller, E, Guter, SJ, Hill, RS, Ionita-Laza, J, Jimenz Gonzalez, P, Kilpinen, H, Klauck, SM, Kolevzon, A, Lee, I, Lei, I, Lei, J, Lehtimäki, T, Lin, C-F, Ma'ayan, A, Marshall, CR, McInnes, AL, Neale, B, Owen, MJ, Ozaki, N, Parellada, M, Parr, JR, Purcell, S, Puura, K, Rajagopalan, D, Rehnström, K, Reichenberg, A, Sabo, A, Sachse, M, Sanders, SJ, Schafer, C, Schulte-Rüther, M, Skuse, D, Stevens, C, Szatmari, P, Tammimies, K, Valladares, O, Voran, A, Li-San, W, Weiss, LA, Willsey, AJ, Yu, TW, Yuen, RKC, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook, EH, Freitag, CM, Gill, M, Hultman, CM, Lehner, T, Palotie, A, Schellenberg, GD, Sklar, P, State, MW, Sutcliffe, JS, Walsh, CA, Scherer, SW, Zwick, ME, Barett, JC, Cutler, DJ, Roeder, K, Devlin, B, Daly, MJ, Buxbaum, JD, De Rubeis, S, He, X, Goldberg, AP, Poultney, CS, Samocha, K, Cicek, AE, Kou, Y, Liu, L, Fromer, M, Walker, S, Singh, T, Klei, L, Kosmicki, J, Shih-Chen, F, Aleksic, B, Biscaldi, M, Bolton, PF, Brownfeld, JM, Cai, J, Campbell, NG, Carracedo, A, Chahrour, MH, Chiocchetti, AG, Coon, H, Crawford, EL, Curran, SR, Dawson, G, Duketis, E, Fernandez, BA, Gallagher, L, Geller, E, Guter, SJ, Hill, RS, Ionita-Laza, J, Jimenz Gonzalez, P, Kilpinen, H, Klauck, SM, Kolevzon, A, Lee, I, Lei, I, Lei, J, Lehtimäki, T, Lin, C-F, Ma'ayan, A, Marshall, CR, McInnes, AL, Neale, B, Owen, MJ, Ozaki, N, Parellada, M, Parr, JR, Purcell, S, Puura, K, Rajagopalan, D, Rehnström, K, Reichenberg, A, Sabo, A, Sachse, M, Sanders, SJ, Schafer, C, Schulte-Rüther, M, Skuse, D, Stevens, C, Szatmari, P, Tammimies, K, Valladares, O, Voran, A, Li-San, W, Weiss, LA, Willsey, AJ, Yu, TW, Yuen, RKC, DDD Study, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, Cook, EH, Freitag, CM, Gill, M, Hultman, CM, Lehner, T, Palotie, A, Schellenberg, GD, Sklar, P, State, MW, Sutcliffe, JS, Walsh, CA, Scherer, SW, Zwick, ME, Barett, JC, Cutler, DJ, Roeder, K, Devlin, B, Daly, MJ, and Buxbaum, JD

Abstract

The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

Published
2014

38. DAWN: A framework to identify autism genes and subnetworks using gene expression and genetics

Author

Liu, L, Lei, J, Sanders, SJ, Willsey, AJ, Kou, Y, Cicek, AE, Klei, L, Lu, C, He, X, Li, M, Muhle, RA, Ma'Ayan, A, Noonan, JP, Šestan, N, McFadden, KA, State, MW, Buxbaum, JD, Devlin, B, Roeder, K, Liu, L, Lei, J, Sanders, SJ, Willsey, AJ, Kou, Y, Cicek, AE, Klei, L, Lu, C, He, X, Li, M, Muhle, RA, Ma'Ayan, A, Noonan, JP, Šestan, N, McFadden, KA, State, MW, Buxbaum, JD, Devlin, B, and Roeder, K

Abstract

Background: De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. Methods. To accelerate the search for ASD genes, we developed a novel algorithm, DAWN, to model two kinds of data: rare variations from exome sequencing and gene co-expression in the mid-fetal prefrontal and motor-somatosensory neocortex, a critical nexus for risk. The algorithm casts the ensemble data as a hidden Markov random field in which the graph structure is determined by gene co-expression and it combines these interrelationships with node-specific observations, namely gene identity, expression, genetic data and the estimated effect on risk. Results: Using currently available genetic data and a specific developmental time period for gene co-expression, DAWN identified 127 genes that plausibly affect risk, and a set of likely ASD subnetworks. Validation experiments making use of published targeted resequencing results demonstrate its efficacy in reliably predicting ASD genes. DAWN also successfully predicts known ASD genes, not included in the genetic data used to create the model. Conclusions: Validation studies demonstrate that DAWN is effective in predicting ASD genes and subnetworks by leveraging genetic and gene expression data. The findings reported here implicate neurite extension and neuronal arborization as risks for ASD. Using DAWN on emerging ASD sequence data and gene expression data from other brain regions and tissues would likely identify novel ASD genes. DAWN can also be used for other complex disorders to identify genes and subnetworks in those disorders. © 2014 Liu et al.; licensee BioMed Central Ltd.

Published
2014

39. Rare deleterious mutations of the gene EFR3A in autism spectrum disorders

Author

Gupta, AR, Pirruccello, M, Cheng, F, Kang, HJ, Fernandez, TV, Baskin, JM, Choi, M, Liu, L, Ercan-Sencicek, AG, Murdoch, JD, Klei, L, Neale, BM, Franjic, D, Daly, MJ, Lifton, RP, De Camilli, P, Zhao, H, Šestan, N, State, MW, Gupta, AR, Pirruccello, M, Cheng, F, Kang, HJ, Fernandez, TV, Baskin, JM, Choi, M, Liu, L, Ercan-Sencicek, AG, Murdoch, JD, Klei, L, Neale, BM, Franjic, D, Daly, MJ, Lifton, RP, De Camilli, P, Zhao, H, Šestan, N, and State, MW

Abstract

Background: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD. Methods. We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue. Results: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10-16, Wilcoxon test) with a module of genes significantly associated with ASD. Conclusions: Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism has been strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism. © 2014 Gupta et al.; licensee BioMed Ce

Published
2014

40. Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Author

Szatmari, P, Paterson, AD, Zwaigenbaum, L, Roberts, W, Brian, J, Liu, XQ, Vincent, JB, Skaug, JL, Thompson, AP, Senman, L, Feuk, L, Qian, C, Bryson, SE, Jones, MB, Marshall, CR, Scherer, SW, Vieland, VJ, Bartlett, C, Mangin, LV, Goedken, R, Segre, A, Pericak-Vance, MA, Cuccaro, ML, Gilbert, JR, Wright, HH, Abramson, RK, Betancur, C, Bourgeron, T, Gillberg, C, Leboyer, M, Buxbaum, JD, Davis, KL, Hollander, E, Silverman, JM, Hallmayer, J, Lotspeich, L, Sutcliffe, JS, Haines, JL, Folstein, SE, Piven, J, Wassink, TH, Sheffield, V, Geschwind, DH, Bucan, M, Brown, WT, Cantor, RM, Constantino, JN, Gilliam, TC, Herbert, M, LaJonchere, C, Ledbetter, DH, Lese-Martin, C, Miller, J, Nelson, S, Samango-Sprouse, CA, Spence, S, State, M, Tanzi, RE, Coon, H, Dawson, G, Devlin, B, Estes, A, Flodman, P, Klei, L, McMahon, WM, Minshew, N, Munson, J, Korvatska, E, Rodier, PM, Schellenberg, GD, Smith, M, Spence, MA, Stodgell, C, Tepper, PG, Wijsman, EM, Yu, CE, Rogé, B, Mantoulan, C, Wittemeyer, K, Poustka, A, Felder, B, Klauck, SM, Schuster, C, Poustka, F, Bölte, S, Feineis-Matthews, S, Herbrecht, E, Schmötzer, G, Tsiantis, J, Papanikolaou, K, Maestrini, E, and Bacchelli, E

Subjects
mental disorders
Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs. © 2007 Nature Publishing Group.

Published
2007

41. Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Author

Szatmari, P. Paterson, A.D. Zwaigenbaum, L. Roberts, W. Brian, J. Liu, X.-Q. Vincent, J.B. Skaug, J.L. Thompson, A.P. Senman, L. Feuk, L. Qian, C. Bryson, S.E. Jones, M.B. Marshall, C.R. Scherer, S.W. Vieland, V.J. Bartlett, C. Mangin, L.V. Goedken, R. Segre, A. Pericak-Vance, M.A. Cuccaro, M.L. Gilbert, J.R. Wright, H.H. Abramson, R.K. Betancur, C. Bourgeron, T. Gillberg, C. Leboyer, M. Buxbaum, J.D. Davis, K.L. Hollander, E. Silverman, J.M. Hallmayer, J. Lotspeich, L. Sutcliffe, J.S. Haines, J.L. Folstein, S.E. Piven, J. Wassink, T.H. Sheffield, V. Geschwind, D.H. Bucan, M. Brown, W.T. Cantor, R.M. Constantino, J.N. Gilliam, T.C. Herbert, M. LaJonchere, C. Ledbetter, D.H. Lese-Martin, C. Miller, J. Nelson, S. Samango-Sprouse, C.A. Spence, S. State, M. Tanzi, R.E. Coon, H. Dawson, G. Devlin, B. Estes, A. Flodman, P. Klei, L. McMahon, W.M. Minshew, N. Munson, J. Korvatska, E. Rodier, P.M. Schellenberg, G.D. Smith, M. Spence, M.A. Stodgell, C. Tepper, P.G. Wijsman, E.M. Yu, C.-E. Rogé, B. Mantoulan, C. Wittemeyer, K. Poustka, A. Felder, B. Klauck, S.M. Schuster, C. Poustka, F. Bölte, S. Feineis-Matthews, S. Herbrecht, E. Schmötzer, G. Tsiantis, J. Papanikolaou, K. Maestrini, E. Bacchelli, E. Blasi, F. Carone, S. Toma, C. Van Engeland, H. De Jonge, M. Kemner, C. Koop, F. Langemeijer, M. Hijimans, C. Staal, W.G. Baird, G. Bolton, P.F. Rutter, M.L. Weisblatt, E. Green, J. Aldred, C. Wilkinson, J.-A. Pickles, A. Le Couteur, A. Berney, T. McConachie, H. Bailey, A.J. Francis, K. Honeyman, G. Hutchinson, A. Parr, J.R. Wallace, S. Monaco, A.P. Barnby, G. Kobayashi, K. Lamb, J.A. Sousa, I. Sykes, N. Cook, E.H. Guter, S.J. Leventhal, B.L. Salt, J. Lord, C. Corsello, C. Hus, V. Weeks, D.E. Volkmar, F. Tauber, M. Fombonne, E. Shih, A.

Subjects
mental disorders
Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs. © 2007 Nature Publishing Group.

Published
2007

42. Common genetic variants, acting additively, are a major source of risk for autism

Author

Klei, L, Sanders, SJ, Murtha, MT, Hus, V, Lowe, JK, Willsey, AJ, Moreno-De-Luca, D, Yu, TW, Fombonne, E, Geschwind, D, Grice, DE, Ledbetter, DH, Lord, C, Mane, SM, Martin, CL, Martin, DM, Morrow, EM, Walsh, CA, Melhem, NM, Chaste, P, Sutcliffe, JS, State, MW, Cook, EH, Roeder, K, Devlin, B, Klei, L, Sanders, SJ, Murtha, MT, Hus, V, Lowe, JK, Willsey, AJ, Moreno-De-Luca, D, Yu, TW, Fombonne, E, Geschwind, D, Grice, DE, Ledbetter, DH, Lord, C, Mane, SM, Martin, CL, Martin, DM, Morrow, EM, Walsh, CA, Melhem, NM, Chaste, P, Sutcliffe, JS, State, MW, Cook, EH, Roeder, K, and Devlin, B

Abstract

Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods. By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions: Our results, when viewed in the context of results from genome-wi

Published
2012

43. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author

Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., Vorstman, J., Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., and Vorstman, J.

Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm < 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

44. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Author

Hoglinger, G. (Gunter), Melhem, N.M. (Nadine), Dickson, D. (Dennis), Sleiman, P.M.A. (Patrick), Wang, L.S. (Li-San), Klei, L. (Lambertus), Rademakers, R. (Rosa), Silva, R. (Rohan) de, Litvan, I. (Irene), Riley, D.E. (David), Swieten, J.C. (John) van, Heutink, P. (Peter), Wszolek, Z.K. (Zbigniew), Uitti, R.J. (Ryan), Vandrovcova, J. (Jana), Hurtig, H.I. (Howard), Gross, R.G. (Rachel), Maetzler, W. (Walter), Goldwurm, S. (Stefano), Tolosa, E., Borroni, B. (Barbara), Pastor, P. (Pau), Cantwell, L.B. (Laura), Han, M.R., Dillman, A. (Allissa), Brug, M.P. (Marcel) van der, Gibbs, J. (Raphael), Cookson, M.R. (Mark), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Farrer, M.J. (Matthew), Yu, C.-E. (Changen), Golbe, L.I. (Lawrence), Revesz, T. (Tamas), Hardy, J. (John), Lees, A.J. (Andrew), Devlin, B. (Bernie), Hakonarson, H. (Hakon), Müller, U. (Ulrich), Schellenberg, G.D. (Gerard), Albin, R.L. (Roger), Alonso, E. (Elena), Apfelbacher, M. (Manuela), Arnold, S.E. (Steven), Avila, J. (Jesús), Beach, T.G. (Thomas), Beecher, S. (Sherry), Berg, D. (Daniela), Bird, T.D. (Thomas), Bogdanović, N. (Nenad), Boon, A.J.W. (Andrea), Bordelon, Y. (Yvette), Brice, A. (Alexis), Budka, H. (Herbert), Canesi, M. (Margherita), Chiu, W.Z. (Wang Zheng), Cilia, R. (Roberto), Colosimo, C. (Carlo), Deyn, P.P. (Peter) de, Yebenes, J.G. de, Donker Kaat, L. (Laura), Duara, R. (Ranjan), Durr, A., Engelborghs, S. (Sebastiaan), Fabbrini, G. (Giovanni), Finch, N.A. (Nicole), Flook, R. (Robyn), Frosch, M.P. (Matthew), Gaig, C., Galasko, D. (Douglas), Gasser, T. (Thomas), Gearing, M. (Marla), Geller, E.T. (Evan), Ghetti, B. (Bernardino), Graff-Radford, N.R. (Neill), Grossman, M. (Murray), Hall, D.A. (Deborah), Hazrati, L.-N., Höllerhage, M. (Matthias), Jankovic, J. (Joseph), Juncos, J.L. (Jorge), Karydas, A. (Anna), Kretzschmar, H.A. (Hans), Leber, I. (Isabelle), Lee, V.M.Y. (Virginia), Lieberman, A.P. (Andrew), Lyons, K.E. (Kelly), Mariani, C. (Claudio), Masliah, E. (Eliezer), Massey, L.A. (Luke), McLean, C.A. (Catriona), Meucci, N. (Nicoletta), Miller, B.L. (Bruce), Mollenhauer, B. (Brit), Möller, J.C. (Jens), Morris, H. (Huw), O'Sullivan, S.S. (Sean), Oertel, W., Ottaviani, D. (Donatella), Padovani, A. (Alessandro), Pahwa, R. (Rajesh), Pezzoli, G. (Gianni), Pickering-Brown, S. (Stuart), Poewe, W. (Werner), Rabano, A. (Alberto), Rajput, A. (Alex), Reich, S.G. (Stephen), Respondek, G. (Gesine), Roeber, S. (Sigrun), Rohrer, J.D. (Jonathan), Ross, O.A. (Owen), Rossor, M. (Martin), Sacilotto, G. (Giorgio), Seeley, W.W. (William), Seppi, K. (Klaus), Silveira-Moriyama, L. (Laura), Spina, S. (Salvatore), Srulijes, K. (Karin), St. George-Hyslop, P. (Peter), Stamelou, M. (Maria), Standaert, D.G. (David), Tesei, S. (Silvana), Tourtellotte, W.W. (Wallace), Trenkwalder, C. (Claudia), Troakes, C. (Claire), Trojanowski, J.Q. (John), Troncoso, J.C. (Juan), Deerlin, V.M. (Vivianna), Vonsattel, J.P.G., Wenning, G.K. (Gregor), White III, C.L. (Charles), Winter, P. (Pia), Zarow, C. (Chris), Zecchinelli, A.L. (Anna), Antonini, A. (Angelo), Hoglinger, G. (Gunter), Melhem, N.M. (Nadine), Dickson, D. (Dennis), Sleiman, P.M.A. (Patrick), Wang, L.S. (Li-San), Klei, L. (Lambertus), Rademakers, R. (Rosa), Silva, R. (Rohan) de, Litvan, I. (Irene), Riley, D.E. (David), Swieten, J.C. (John) van, Heutink, P. (Peter), Wszolek, Z.K. (Zbigniew), Uitti, R.J. (Ryan), Vandrovcova, J. (Jana), Hurtig, H.I. (Howard), Gross, R.G. (Rachel), Maetzler, W. (Walter), Goldwurm, S. (Stefano), Tolosa, E., Borroni, B. (Barbara), Pastor, P. (Pau), Cantwell, L.B. (Laura), Han, M.R., Dillman, A. (Allissa), Brug, M.P. (Marcel) van der, Gibbs, J. (Raphael), Cookson, M.R. (Mark), Hernandez, D.G. (Dena), Singleton, A. (Andrew), Farrer, M.J. (Matthew), Yu, C.-E. (Changen), Golbe, L.I. (Lawrence), Revesz, T. (Tamas), Hardy, J. (John), Lees, A.J. (Andrew), Devlin, B. (Bernie), Hakonarson, H. (Hakon), Müller, U. (Ulrich), Schellenberg, G.D. (Gerard), Albin, R.L. (Roger), Alonso, E. (Elena), Apfelbacher, M. (Manuela), Arnold, S.E. (Steven), Avila, J. (Jesús), Beach, T.G. (Thomas), Beecher, S. (Sherry), Berg, D. (Daniela), Bird, T.D. (Thomas), Bogdanović, N. (Nenad), Boon, A.J.W. (Andrea), Bordelon, Y. (Yvette), Brice, A. (Alexis), Budka, H. (Herbert), Canesi, M. (Margherita), Chiu, W.Z. (Wang Zheng), Cilia, R. (Roberto), Colosimo, C. (Carlo), Deyn, P.P. (Peter) de, Yebenes, J.G. de, Donker Kaat, L. (Laura), Duara, R. (Ranjan), Durr, A., Engelborghs, S. (Sebastiaan), Fabbrini, G. (Giovanni), Finch, N.A. (Nicole), Flook, R. (Robyn), Frosch, M.P. (Matthew), Gaig, C., Galasko, D. (Douglas), Gasser, T. (Thomas), Gearing, M. (Marla), Geller, E.T. (Evan), Ghetti, B. (Bernardino), Graff-Radford, N.R. (Neill), Grossman, M. (Murray), Hall, D.A. (Deborah), Hazrati, L.-N., Höllerhage, M. (Matthias), Jankovic, J. (Joseph), Juncos, J.L. (Jorge), Karydas, A. (Anna), Kretzschmar, H.A. (Hans), Leber, I. (Isabelle), Lee, V.M.Y. (Virginia), Lieberman, A.P. (Andrew), Lyons, K.E. (Kelly), Mariani, C. (Claudio), Masliah, E. (Eliezer), Massey, L.A. (Luke), McLean, C.A. (Catriona), Meucci, N. (Nicoletta), Miller, B.L. (Bruce), Mollenhauer, B. (Brit), Möller, J.C. (Jens), Morris, H. (Huw), O'Sullivan, S.S. (Sean), Oertel, W., Ottaviani, D. (Donatella), Padovani, A. (Alessandro), Pahwa, R. (Rajesh), Pezzoli, G. (Gianni), Pickering-Brown, S. (Stuart), Poewe, W. (Werner), Rabano, A. (Alberto), Rajput, A. (Alex), Reich, S.G. (Stephen), Respondek, G. (Gesine), Roeber, S. (Sigrun), Rohrer, J.D. (Jonathan), Ross, O.A. (Owen), Rossor, M. (Martin), Sacilotto, G. (Giorgio), Seeley, W.W. (William), Seppi, K. (Klaus), Silveira-Moriyama, L. (Laura), Spina, S. (Salvatore), Srulijes, K. (Karin), St. George-Hyslop, P. (Peter), Stamelou, M. (Maria), Standaert, D.G. (David), Tesei, S. (Silvana), Tourtellotte, W.W. (Wallace), Trenkwalder, C. (Claudia), Troakes, C. (Claire), Trojanowski, J.Q. (John), Troncoso, J.C. (Juan), Deerlin, V.M. (Vivianna), Vonsattel, J.P.G., Wenning, G.K. (Gregor), White III, C.L. (Charles), Winter, P. (Pia), Zarow, C. (Chris), Zecchinelli, A.L. (Anna), and Antonini, A. (Angelo)

Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopath

Published
2011
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45. Persistent infection with neurotropic herpes viruses and cognitive impairment

Author

Watson, A. M. M., primary, Prasad, K. M., additional, Klei, L., additional, Wood, J. A., additional, Yolken, R. H., additional, Gur, R. C., additional, Bradford, L. D., additional, Calkins, M. E., additional, Richard, J., additional, Edwards, N., additional, Savage, R. M., additional, Allen, T. B., additional, Kwentus, J., additional, McEvoy, J. P., additional, Santos, A. B., additional, Wiener, H. W., additional, Go, R. C. P., additional, Perry, R. T., additional, Nasrallah, H. A., additional, Gur, R. E., additional, Devlin, B., additional, and Nimgaonkar, V. L., additional

Published
2012
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46. Amino acid position 11 of HLA-DRβ1 is a major determinant of chromosome 6p association with ulcerative colitis

Author

Achkar, J-P, primary, Klei, L, additional, Bakker, P I W de, additional, Bellone, G, additional, Rebert, N, additional, Scott, R, additional, Lu, Y, additional, Regueiro, M, additional, Brzezinski, A, additional, Kamboh, M I, additional, Fiocchi, C, additional, Devlin, B, additional, Trucco, M, additional, Ringquist, S, additional, Roeder, K, additional, and Duerr, R H, additional

Published
2011
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47. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, R., primary, Klei, L., additional, Pinto, D., additional, Regan, R., additional, Conroy, J., additional, Magalhaes, T. R., additional, Correia, C., additional, Abrahams, B. S., additional, Sykes, N., additional, Pagnamenta, A. T., additional, Almeida, J., additional, Bacchelli, E., additional, Bailey, A. J., additional, Baird, G., additional, Battaglia, A., additional, Berney, T., additional, Bolshakova, N., additional, Bolte, S., additional, Bolton, P. F., additional, Bourgeron, T., additional, Brennan, S., additional, Brian, J., additional, Carson, A. R., additional, Casallo, G., additional, Casey, J., additional, Chu, S. H., additional, Cochrane, L., additional, Corsello, C., additional, Crawford, E. L., additional, Crossett, A., additional, Dawson, G., additional, de Jonge, M., additional, Delorme, R., additional, Drmic, I., additional, Duketis, E., additional, Duque, F., additional, Estes, A., additional, Farrar, P., additional, Fernandez, B. A., additional, Folstein, S. E., additional, Fombonne, E., additional, Freitag, C. M., additional, Gilbert, J., additional, Gillberg, C., additional, Glessner, J. T., additional, Goldberg, J., additional, Green, J., additional, Guter, S. J., additional, Hakonarson, H., additional, Heron, E. A., additional, Hill, M., additional, Holt, R., additional, Howe, J. L., additional, Hughes, G., additional, Hus, V., additional, Igliozzi, R., additional, Kim, C., additional, Klauck, S. M., additional, Kolevzon, A., additional, Korvatska, O., additional, Kustanovich, V., additional, Lajonchere, C. M., additional, Lamb, J. A., additional, Laskawiec, M., additional, Leboyer, M., additional, Le Couteur, A., additional, Leventhal, B. L., additional, Lionel, A. C., additional, Liu, X.-Q., additional, Lord, C., additional, Lotspeich, L., additional, Lund, S. C., additional, Maestrini, E., additional, Mahoney, W., additional, Mantoulan, C., additional, Marshall, C. R., additional, McConachie, H., additional, McDougle, C. J., additional, McGrath, J., additional, McMahon, W. M., additional, Melhem, N. M., additional, Merikangas, A., additional, Migita, O., additional, Minshew, N. J., additional, Mirza, G. K., additional, Munson, J., additional, Nelson, S. F., additional, Noakes, C., additional, Noor, A., additional, Nygren, G., additional, Oliveira, G., additional, Papanikolaou, K., additional, Parr, J. R., additional, Parrini, B., additional, Paton, T., additional, Pickles, A., additional, Piven, J., additional, Posey, D. J., additional, Poustka, A., additional, Poustka, F., additional, Prasad, A., additional, Ragoussis, J., additional, Renshaw, K., additional, Rickaby, J., additional, Roberts, W., additional, Roeder, K., additional, Roge, B., additional, Rutter, M. L., additional, Bierut, L. J., additional, Rice, J. P., additional, Salt, J., additional, Sansom, K., additional, Sato, D., additional, Segurado, R., additional, Senman, L., additional, Shah, N., additional, Sheffield, V. C., additional, Soorya, L., additional, Sousa, I., additional, Stoppioni, V., additional, Strawbridge, C., additional, Tancredi, R., additional, Tansey, K., additional, Thiruvahindrapduram, B., additional, Thompson, A. P., additional, Thomson, S., additional, Tryfon, A., additional, Tsiantis, J., additional, Van Engeland, H., additional, Vincent, J. B., additional, Volkmar, F., additional, Wallace, S., additional, Wang, K., additional, Wang, Z., additional, Wassink, T. H., additional, Wing, K., additional, Wittemeyer, K., additional, Wood, S., additional, Yaspan, B. L., additional, Zurawiecki, D., additional, Zwaigenbaum, L., additional, Betancur, C., additional, Buxbaum, J. D., additional, Cantor, R. M., additional, Cook, E. H., additional, Coon, H., additional, Cuccaro, M. L., additional, Gallagher, L., additional, Geschwind, D. H., additional, Gill, M., additional, Haines, J. L., additional, Miller, J., additional, Monaco, A. P., additional, Nurnberger, J. I., additional, Paterson, A. D., additional, Pericak-Vance, M. A., additional, Schellenberg, G. D., additional, Scherer, S. W., additional, Sutcliffe, J. S., additional, Szatmari, P., additional, Vicente, A. M., additional, Vieland, V. J., additional, Wijsman, E. M., additional, Devlin, B., additional, Ennis, S., additional, and Hallmayer, J., additional

Published
2010
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