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      Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

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      Proceedings of the National Academy of Sciences of the United States of America
      National Academy of Sciences
      reading, language, genome-wide association study, meta-analysis

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          Significance

          Our unique capacities for spoken and written language are fundamental features of what makes us human, yet the biological bases remain largely mysterious. We present a large-scale well-powered genome-wide association study meta-analysis of individual differences in reading- and language-related skills (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in tens of thousands of participants. The findings prompt a major reevaluation of prior literature claiming candidate gene associations in much smaller samples. Moreover, we use the novel genetic data as windows into multiple aspects of the biology of these important abilities, revealing molecular links to individual differences in neuroanatomy of language-related brain areas and enriched heritability in archaic deserts of the human genome as well as in fetal brain enhancer regions.

          Abstract

          The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10 −8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

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          LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

          Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.
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            The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019

            Abstract The GWAS Catalog delivers a high-quality curated collection of all published genome-wide association studies enabling investigations to identify causal variants, understand disease mechanisms, and establish targets for novel therapies. The scope of the Catalog has also expanded to targeted and exome arrays with 1000 new associations added for these technologies. As of September 2018, the Catalog contains 5687 GWAS comprising 71673 variant-trait associations from 3567 publications. New content includes 284 full P-value summary statistics datasets for genome-wide and new targeted array studies, representing 6 × 109 individual variant-trait statistics. In the last 12 months, the Catalog's user interface was accessed by ∼90000 unique users who viewed >1 million pages. We have improved data access with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database. Summary statistics provision is supported by a new format proposed as a community standard for summary statistics data representation. This format was derived from our experience in standardizing heterogeneous submissions, mapping formats and in harmonizing content. Availability: https://www.ebi.ac.uk/gwas/.
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              Integrative analysis of 111 reference human epigenomes

              The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc Natl Acad Sci U S A
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                23 August 2022
                30 August 2022
                23 August 2022
                : 119
                : 35
                : e2202764119
                Affiliations
                [1] aLanguage and Genetics Department, Max Planck Institute for Psycholinguistics , 6525 XD Nijmegen, the Netherlands;
                [2] bInstitute of Neurogenomics, Helmholtz Zentrum Munich , 85764 Munich, Germany;
                [3] cDepartment of Biological Psychology, Vrije Universiteit Amsterdam , 1081 BT Amsterdam, the Netherlands;
                [4] dSchool of Medicine and Public Health, The University of Newcastle , Newcastle, NSW 2308, Australia;
                [5] eMothers and Babies Research Program, Hunter Medical Research Institute , Newcastle, NSW 2305, Australia;
                [6] fDepartment of Pediatrics and Genetics, Yale Medical School , New Haven, CT 06510;
                [7] gSocial, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , London SE5 8AF, United Kingdom;
                [8] hMRC Integrative Epidemiology Unit, University of Bristol , Bristol BS8 2BN, United Kingdom;
                [9] iPopulation Health Sciences, University of Bristol , Bristol BS8 2PS, United Kingdom;
                [10] jGenetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute , Brisbane, QLD 4006, Australia;
                [11] kDivision of Experimental and Translational Neuroscience, Krembil Research Institute, University Health Network , Toronto, ON M5T 0S8, Canada;
                [12] lTranslational Research in Psychiatry, Max Planck Institute of Psychiatry , 80804 Munich, Germany;
                [13] mDepartment of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed , 86077 Pozzilli, Italy;
                [14] nDepartment of Medicine and Surgery, University of Insubria , 21100 Varese, Italy;
                [15] oSchool of Medicine, University of St Andrews , KY16 9TF, St. Andrews, Scotland;
                [16] pDepartment of Psychology, Royal Holloway, University of London , Egham TW20 0EY, United Kingdom;
                [17] qDepartment of Psychology, University of Toronto , Toronto, ON M5S 3G3,Canada;
                [18] rDepartment of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center , 3000 CB Rotterdam, the Netherlands;
                [19] sDepartment of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam , Amsterdam, 1081 HV the Netherlands;
                [20] tDepartment of Human Genetics, VU Medical Center, Amsterdam University Medical Center , 1081 BT Amsterdam, the Netherlands;
                [21] uDepartment of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich , 81675 Munich, Germany;
                [22] vDepartment of Psychology, University of Edinburgh , Edinburgh EH8 9JZ, United Kingdom;
                [23] wDepartment of Physiology and Nutritional Sciences, University of Toronto , Toronto, ON M5S 1A1, Canada;
                [24] xProgram in Neuroscience and Mental Health, Hospital for Sick Children , Toronto, M5G 1X8 ON, Canada;
                [25] yDepartment of Cognitive Neuroscience and Maastricht Brain Imaging Center, Faculty of Psychology and Neuroscience, Maastricht University , 6229 ER Maastricht, the Netherlands;
                [26] zDepartment of Biomedicine, Aarhus University , 8000 Aarhus, Denmark;
                [27] aaThe Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH , 8210 Aarhus, Denmark;
                [28] bbCenter for Genomics and Personalized Medicine (CGPM) , 8000 Aarhus, Denmark;
                [29] ccHuman Genetics and Cognitive Functions, Institut Pasteur, UMR3571 Centre national de la recherche scientifique (CNRS), Université Paris Cité , Paris, 75015, France;
                [30] ddDepartment of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich , 8032 Zurich, Switzerland;
                [31] eeZurich Center for Integrative Human Physiology, University of Zurich and ETH Zurich , 8057 Zurich, Switzerland;
                [32] ffNeuroscience Center Zurich, University of Zurich and ETH Zurich , 8057 Zurich, Switzerland;
                [33] ggDepartment of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University , 68159 Mannheim, Germany;
                [34] hhDepartment of Pharmacy and Biotechnology, University of Bologna , 40126 Bologna, Italy;
                [35] iiFaculty of Health and Life Sciences, Oxford Brookes University , Oxford OX3 0BP, United Kingdom;
                [36] jjBrain Imaging Centre, Research Centre for Natural Sciences , Budapest, 1117 Hungary;
                [37] kkMultilingualism Doctoral School, Faculty of Modern Philology and Social Sciences, University of Pannonia , Veszprém, 8200 Hungary;
                [38] llDepartment of Speech & Hearing Sciences, University of New Mexico , Albuquerque, NM 87131;
                [39] mmDepartment of Child Development and Education, University of Amsterdam , 1012 WX Amsterdam, the Netherlands;
                [40] nnInstitute for Behavioral Genetics, University of Colorado , Boulder, CO 80309-0447;
                [41] ooDepartment of Psychology and Neuroscience, University of Colorado , Boulder, CO 80309-0447;
                [42] ppLeenaards Memory Centre, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), University of Lausanne , CH-1011 Lausanne, Switzerland;
                [43] qqDepartment of Psychology, Hospital for Sick Children , Toronto, ON M5G 1X8, Canada;
                [44] rrDepartment of Psychology, University of York , York YO10 5DD, United Kingdom;
                [45] ssDepartamento de Psicología, Clínica Psicobiología y Metodología , 38200, La Laguna, Santa Cruz de Tenerife, Spain;
                [46] ttDepartment of Education, University of Oxford , Oxford, Oxfordshire OX2 6PY, United Kingdom;
                [47] uuDepartment of Biosciences and Nutrition, Karolinska Institutet , 171 77 Stockholm, Sweden;
                [48] vvStem Cells and Metabolism Research Program, University of Helsinki and Folkhälsan Research Center , 00014 Helsinki, Finland;
                [49] wwDepartment of Neurology, Hospital for Sick Children , Toronto, ON M5G 1X8, Canada;
                [50] xxDepartment of Paediatrics, University of Toronto , Toronto, ON M5G 1X8, Canada;
                [51] yyDepartment of Psychiatry, University of Iowa , Iowa City, IA 52242;
                [52] zzInstitute of Psychology, University of Graz , 8010 Graz, Austria;
                [53] aaaBioTechMed-Graz , 8010 Graz, Austria;
                [54] bbbCognitive Neuroscience Neurology and Neurosurgery, McGill University , Montreal, QC H3A 1G1, Canada;
                [55] cccDepartment of Psychology, University of Jyväskylä , 40014 Jyväskylä, Finland;
                [56] dddDepartment of Psychology, The Chinese University of Hong Kong , Hong Kong, China;
                [57] eeeDepartment of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwig-Maximilians-University Hospital Munich , Munich, 80336 Germany;
                [58] fffOffice of the President, Tufts University , Medford, MA 02155;
                [59] gggSpeech and Language, Murdoch Children's Research Institute , Melbourne, VIC 3052, Australia;
                [60] hhhDepartment of Audiology and Speech Pathology, University of Melbourne , Melbourne, VIC 3052, Australia;
                [61] iiiSpeech Pathology Department, Royal Children's Hospital , Melbourne, VIC 3052, Australia;
                [62] jjjInstitute of Human Genetics, University Hospital of Bonn , 53127 Bonn, Germany;
                [63] kkkHospital for Sick Children , Toronto, ON M5G 1X8, Canada;
                [64] lllMaternity and Gynaecology, John Hunter Hospital , Newcastle, NSW 2305, Australia;
                [65] mmmDepartment of Psychology, University of Denver , Denver, CO 80210;
                [66] nnnDepartment of Physiology, University of Toronto , Toronto, ON M5S 1A8, Canada;
                [67] oooLaboratoire de Sciences Cognitives et Psycholinguistique, Ecole Normale Supérieure, Paris Sciences & Lettres University, École des Hautes Études en Sciences Sociales (EHESS), Centre National de la Recherche Scientifique (CNRS) , Paris, 75005 France;
                [68] pppDepartment of Health Sciences, Université du Québec à Chicoutimi , Chicoutimi, QC G7H 2B1, Canada;
                [69] qqqDepartment of Experimental Psychology, University of Oxford , Oxford OX2 6GG, United Kingdom;
                [70] rrrDepartment of Neurological Sciences, College of Medicine, University of Nebraska Medical Center , Omaha, NE 68198;
                [71] sssSt. John’s College, University of Oxford , Oxford OX1 3JP, United Kingdom;
                [72] tttDepartment of Physiology, Anatomy and Genetics, Oxford University , Oxford OX1 3PT, United Kingdom;
                [73] uuuDepartment of Statistical Sciences and Computer Science and Division of Biostatistics, University of Toronto , Toronto, ON M5S 3G3, Canada;
                [74] vvvProgram in Genetics and Genome Biology and the Centre for Applied Genomics, Hospital for Sick Children , Toronto, ON M5G 1X8, Canada;
                [75] wwwInstitute for Health and Neurodevelopment, Aston University , Birmingham B4 7ET, United Kingdom;
                [76] xxxT. H. Chan School of Public Health, Harvard , Boston, MA 02115;
                [77] yyyDepartment of Otolaryngology, Head and Neck Surgery, Erasmus University Medical Center , 3015 GD Rotterdam, the Netherlands;
                [78] zzzGeneration R Study Group, Erasmus University Medical Center , 3015 GD Rotterdam, the Netherlands;
                [79] aaaaQueensland Brain Institute, University of Queensland , Brisbane, QLD 4072, Australia;
                [80] bbbbNetherlands Twin Register , 1081 BT Amsterdam, the Netherlands;
                [81] ccccAmsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center , 1105 AZ Amsterdam, the Netherlands;
                [82] ddddBasque Center on Cognition, Brain and Language, Donostia-San Sebastian , 20009 Gipuzkoa, Spain;
                [83] eeeeIkerbasque, Basque Foundation for Science , 48009 Bilbao, Vizcaya, Spain;
                [84] ffffLengua Vasca y Comunicación, University of the Basque Country , 48940 Bilbao, Vizcaya, Spain;
                [85] ggggDepartment of Health Science, University of Liverpool , Liverpool L69 7ZX, United Kingdom;
                [86] hhhhDepartment of Psychiatry and Neuroscience and Centre Hospitalier Universitaire Sainte Justine, University of Montreal , Montreal, QC H3T 1J4, Canada;
                [87] iiiiMenzies Health Institute Queensland, Griffith University , Gold Coast, QLD 4222, Australia;
                [88] jjjjCommunication Sciences and Disorders, University of Iowa , Iowa City, IA 52242;
                [89] kkkkResearch Institute LEARN!, Vrije Universiteit Amsterdam , 1081 BT Amsterdam, the Netherlands;
                [90] llllTelethon Kids Institute, The University of Western Australia , Perth, WA 6009, Australia;
                [91] mmmmDonders Institute for Brain, Cognition and Behaviour, Radboud University , 6525 EN Nijmegen, the Netherlands;
                [92] nnnnDepartment of Human Genetics, Radboud University Medical Center , 6525 GA Nijmegen, the Netherlands
                Author notes
                2To whom correspondence may be addressed. Email: simon.fisher@ 123456mpi.nl .

                Edited by Uta Frith, University College London, London, United Kingdom; received February 18, 2022; accepted May 31, 2022

                Author contributions: E.E., B.S.P., C.F., and S.E.F. designed research; E.E., E.L.d.Z., T.F.M.A., T.C.B., M.Be., K.B., M.Bo, A.D.B., T.B., D.B., F.C., V.C., P.S.D., J.C.D., J-F.D., D.D., Y.F., S.L.G., M.E.H.-T., J.-J.H., C.H., J.K., E.N.K., K.L., G.T.L., M.W.L., H.L., N.G.M., A.M., U.M., J.J.M., K.M., A.P.M., A.T.M., M.M.N., Z.P., C.E.P., F.R., L.R., H.T., M.P.v.d.S., K.E.W., M.W., M.J.W., C.L.B., D.I.B., M.C., M.-C.J.F., J.R.G., R.K.O., S.P., T.P., R.P., S.R., G.S.-K., J.B.To., E.v.B., A.J.O.W., and E.G.W. performed research; E.E., N.M.-S., E.L.d.Z., C.A.W., D.T.T., A.G.A., C.Y.S., G.Z., K.G.W., M.L.G., B.M., G.A., A.G., F.A., K.R., M.v.D., Z.L., P.R.J., T.F.M.A., T.C.B., M.Be., D.B., P.F.d.J., Y.F., S.D.G., J.A.H.-C., J.-J.H., T.K., K.L., U.M., A.P.M., A.T.M., B.F.P., K.M.P., V.M.R., F.R., N.H.S., S.D.S., M.J.S., J.S., L.J.S., J.B.Ta., E.V., M.L., B.M.-M., D.F.N., S.P., S.R., G.S.-K., E.v.B., and B.S.P. analyzed data; M.Bo., A.D.B., T.B., D.B., V.C., P.F.d.J., J-F.D., D.D., M.E.H.-T., C.H., J.K., K.L., N.G.M., J.J.M., M.M.N., Z.P., L.R., J.S., J.B.T., M.P.v.d.S., M.J.W., C.L.B., D.I.B., M.C., J.R.G., S.P., T.P., R.P., S.R., G.S.-K., E.v.B., A.J.O.W., and E.G.W. were cohort principal investigators; and E.E., B.S.P., C.F., and S.E.F. wrote the paper.

                1B.S.P. and C.F. contributed equally to this work.

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                https://orcid.org/0000-0002-5797-1241
                https://orcid.org/0000-0002-9300-761X
                https://orcid.org/0000-0003-0530-2780
                https://orcid.org/0000-0002-7388-4463
                https://orcid.org/0000-0001-5139-065X
                https://orcid.org/0000-0003-2351-0022
                https://orcid.org/0000-0002-2917-5889
                https://orcid.org/0000-0002-1153-9007
                https://orcid.org/0000-0002-0080-8320
                https://orcid.org/0000-0002-7474-6361
                https://orcid.org/0000-0002-7697-8510
                https://orcid.org/0000-0002-8806-0563
                https://orcid.org/0000-0001-9124-2766
                https://orcid.org/0000-0003-1163-2671
                https://orcid.org/0000-0001-9499-5958
                https://orcid.org/0000-0002-9589-6502
                https://orcid.org/0000-0001-7480-3197
                https://orcid.org/0000-0003-1147-7405
                https://orcid.org/0000-0002-8770-2464
                https://orcid.org/0000-0001-9541-8204
                https://orcid.org/0000-0002-5236-168X
                https://orcid.org/0000-0002-6590-3046
                https://orcid.org/0000-0003-0836-3861
                https://orcid.org/0000-0001-5843-8986
                https://orcid.org/0000-0003-0503-9740
                https://orcid.org/0000-0002-1360-8782
                https://orcid.org/0000-0002-8315-1095
                https://orcid.org/0000-0002-2621-482X
                https://orcid.org/0000-0001-5735-4051
                https://orcid.org/0000-0003-0361-0106
                https://orcid.org/0000-0002-7099-7972
                https://orcid.org/0000-0001-6726-7613
                https://orcid.org/0000-0001-7640-2071
                https://orcid.org/0000-0002-7306-3008
                https://orcid.org/0000-0002-0719-101X
                https://orcid.org/0000-0001-6506-4767
                https://orcid.org/0000-0002-9098-890X
                https://orcid.org/0000-0002-3132-1996
                Article
                202202764
                10.1073/pnas.2202764119
                9436320
                35998220
                344988ec-fe4c-48be-af74-176f404271ca
                Copyright © 2022 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

                History
                : 31 May 2022
                Page count
                Pages: 12
                Funding
                Funded by: Department of Health | National Health and Medical Research Council (NHMRC) 501100000925
                Award ID: 1105008
                Award Recipient : Alessandro Gialluisi Award Recipient : Andrew J.O. Whitehouse
                Funded by: Department of Health | National Health and Medical Research Council (NHMRC) 501100000925
                Award ID: 1195955
                Award Recipient : Alessandro Gialluisi Award Recipient : Andrew J.O. Whitehouse
                Funded by: Department of Health | National Health and Medical Research Council (NHMRC) 501100000925
                Award ID: 1173896
                Award Recipient : Alessandro Gialluisi Award Recipient : Andrew J.O. Whitehouse
                Funded by: Simons Foundation Autism Research Initiative (SFARI) 100014370
                Award ID: 514787
                Award Recipient : Marjolein Van Donkelaar Award Recipient : Beate St Pourcain
                Funded by: Koninklijke Nederlandse Akademie van Wetenschappen (KNAW) 501100001722
                Award ID: PAH/6635
                Award Recipient : Dorret I Boomsma
                Funded by: HHS | National Institutes of Health (NIH) 100000002
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                Award Recipient : Else Eising Award Recipient : Tanner Koomar Award Recipient : Jacob Michaelson Award Recipient : Bruce Tomblin
                Funded by: HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 100009633
                Award ID: P50 HD 27802
                Award Recipient : John C. DeFries Award Recipient : Erik G Willcutt
                Funded by: Agence Nationale de la Recherche (ANR) 501100001665
                Award ID: ANR-06-NEURO-019-01
                Award ID: ANR-17-EURE-0017 IEC
                Award ID: ANR-10-IDEX-0001-02 PSL
                Award ID: ANR-11-BSV4-014-01
                Award Recipient : Franck Ramus
                Funded by: European Commission (EC) 501100000780
                Award ID: LSHM-CT-2005-018696
                Award Recipient : Franck Ramus
                Funded by: HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 100009633
                Award ID: P50 HD 27802
                Award Recipient : John C. DeFries Award Recipient : Erik G Willcutt
                Funded by: ZonMw (Netherlands Organisation for Health Research and Development) 501100001826
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                Funded by: Wellcome Trust (WT) 100010269
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                Award Recipient : Kaili Rimfeld
                Funded by: Royal Society (The Royal Society) 501100000288
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                Categories
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                Social Sciences
                Psychological and Cognitive Sciences
                Biological Sciences
                Genetics

                reading,language,genome-wide association study,meta-analysis

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