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Identification of common genetic risk variants for autism spectrum disorder
- Source :
- NATURE GENETICS, Nature Genetics, 51(3), 431-444. Nature Publishing Group, 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, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Christensen, J H, Churchhouse, C, Dellenvall, K, Demontis, D, De Rubeis, S, 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, Pedersen, C B, Davey Smith, G, Pourcain, B S & the 23 and Me Research Team 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8, Nature genetics, 51(3), 431-444. Nature Publishing Group, Maller, J, Martin, J, Martin, A, Moran, J, Nyegaard, M, Naerland, T, Palmer, D, Palotie, A, Bocker Perdersen, C, Giortz Pedersen, M, dPoterba, T, Buchhave Poulsen, J, St Poucain, 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, 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 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-+ . https://doi.org/10.1038/s41588-019-0344-8, Digibug. Repositorio Institucional de la Universidad de Granada, instname, Grove, J, Abdellaoui, A, Derks, E M, Dolan, C V, Hottenga, J J, Jansen, R, Mbarek, H, Middeldorp, C M, Milaneschi, Y, Nivard, M G, Posthuma, D, Willemsen, G, Boomsma, D I, de Geus, E J C, Penninx, B W J H, Børglum, A D, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium & 23Andme Research Team 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8, Nature Genetics, Nature Genetics, 51(3), 431-+. Nature Publishing Group, 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, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Christensen, J H, Churchhouse, C, Dellenvall, K, Demontis, D, de Rubeis, S, Devlin, B, Djurovic, S, Dumont, A L, Goldstein, J I, Hansen, C S, Hauberg, M E, Hollegaard, M V, Beekman, A T F, Jansen, R, Middeldorp, C M, Milaneschi, Y, Peyrot, W J, Posthuma, D, Schoevers, R, Smit, J H, de Geus, E J C, Smit, J H, de Geus, E J C, Penninx, B W J H, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, Stefansson, K, Geschwind, D H, Nordentoft, M, Hougaard, D M, Werge, T, Mors, O, Bo Mortensen, P, Neale, B M, Daly, M J & Børglum, A D 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8, Nature Genetics, 51(3), 431-+. NATURE PUBLISHING GROUP, 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, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Christensen, J H, Churchhouse, C, Dellenvall, K, Demontis, D, De Rubeis, S, 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, Nærland, T, Palmer, D S, Palotie, A, Pedersen, C B, Pedersen, M G, dPoterba, T, Poulsen, J B, Pourcain, B S, Qvist, P, Rehnström, 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, Sullivan, P F, Turley, P, Walters, G B, Xu, X, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Stefansson, K, Geschwind, D H, Nordentoft, M, Hougaard, D M, Werge, T, Mors, O, Mortensen, P B, Neale, B M, Daly, M J & Børglum, A D 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8
- Publication Year :
- 2019
-
Abstract
- Published in final edited form as: Nat Genet. 2019 March ; 51(3): 431–444. doi:10.1038/s41588-019-0344-8.<br />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.<br />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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 10614036
- Database :
- OpenAIRE
- Journal :
- NATURE GENETICS, Nature Genetics, 51(3), 431-444. Nature Publishing Group, 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, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Christensen, J H, Churchhouse, C, Dellenvall, K, Demontis, D, De Rubeis, S, 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, Pedersen, C B, Davey Smith, G, Pourcain, B S & the 23 and Me Research Team 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8, Nature genetics, 51(3), 431-444. Nature Publishing Group, Maller, J, Martin, J, Martin, A, Moran, J, Nyegaard, M, Naerland, T, Palmer, D, Palotie, A, Bocker Perdersen, C, Giortz Pedersen, M, dPoterba, T, Buchhave Poulsen, J, St Poucain, 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, 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 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-+ . https://doi.org/10.1038/s41588-019-0344-8, Digibug. Repositorio Institucional de la Universidad de Granada, instname, Grove, J, Abdellaoui, A, Derks, E M, Dolan, C V, Hottenga, J J, Jansen, R, Mbarek, H, Middeldorp, C M, Milaneschi, Y, Nivard, M G, Posthuma, D, Willemsen, G, Boomsma, D I, de Geus, E J C, Penninx, B W J H, Børglum, A D, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium & 23Andme Research Team 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8, Nature Genetics, Nature Genetics, 51(3), 431-+. Nature Publishing Group, 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, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Christensen, J H, Churchhouse, C, Dellenvall, K, Demontis, D, de Rubeis, S, Devlin, B, Djurovic, S, Dumont, A L, Goldstein, J I, Hansen, C S, Hauberg, M E, Hollegaard, M V, Beekman, A T F, Jansen, R, Middeldorp, C M, Milaneschi, Y, Peyrot, W J, Posthuma, D, Schoevers, R, Smit, J H, de Geus, E J C, Smit, J H, de Geus, E J C, Penninx, B W J H, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, Stefansson, K, Geschwind, D H, Nordentoft, M, Hougaard, D M, Werge, T, Mors, O, Bo Mortensen, P, Neale, B M, Daly, M J & Børglum, A D 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8, Nature Genetics, 51(3), 431-+. NATURE PUBLISHING GROUP, 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, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Christensen, J H, Churchhouse, C, Dellenvall, K, Demontis, D, De Rubeis, S, 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, Nærland, T, Palmer, D S, Palotie, A, Pedersen, C B, Pedersen, M G, dPoterba, T, Poulsen, J B, Pourcain, B S, Qvist, P, Rehnström, 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, Sullivan, P F, Turley, P, Walters, G B, Xu, X, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Stefansson, K, Geschwind, D H, Nordentoft, M, Hougaard, D M, Werge, T, Mors, O, Mortensen, P B, Neale, B M, Daly, M J & Børglum, A D 2019, ' Identification of common genetic risk variants for autism spectrum disorder ', Nature Genetics, vol. 51, no. 3, pp. 431-444 . https://doi.org/10.1038/s41588-019-0344-8
- Accession number :
- edsair.doi.dedup.....89c44d1833f2fd2c00737f8057983ac2