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

Richard J.L. Anney; Stephan Ripke; Verneri Anttila; Jakob Grove; Peter Holmans; Hailiang Huang; Lambertus Klei; Phil H. Lee; Sarah E. Medland; Benjamin Neale; Elise Robinson; Lauren A. Weiss; Lonnie Zwaigenbaum; Timothy W. Yu; Kerstin Wittemeyer; A. Jeremy Willsey; Ellen M. Wijsman; Thomas Werge; Thomas H. Wassink; Regina Waltes; Christopher A. Walsh; Simon Wallace; Jacob A.S. Vorstman; Veronica J. Vieland; Astrid M. Vicente; Herman Vanengeland; Kathryn Tsang; Ann P. Thompson; Peter Szatmari; Oscar Svantesson; Stacy Steinberg; Kari Stefansson; Hreinn Stefansson; Matthew W. State; Latha Soorya; Teimuraz Silagadze; Stephen W. Scherer; Gerard D. Schellenberg; Sven Sandin; Stephan J. Sanders; Evald Saemundsen; Guy A. Rouleau; Bernadette Rogé; Kathryn Roeder; Wendy Roberts; Jennifer Reichert; Abraham Reichenberg; Karola Rehnström; Regina Regan; Fritz Poustka; Christopher S. Poultney; Joseph Piven; Dalila Pinto; Margaret A. Pericak-Vance; Milica Pejovic-Milovancevic; Marianne Giørtz Pedersen; Carsten Bøcker Pedersen; Andrew D. Paterson; Jeremy R. Parr; Alistair T. Pagnamenta; Guiomar Oliveira; John I. Nurnberger; Merete Nordentoft; Michael T. Murtha; Susana Mouga; Preben Bo Mortensen; Ole Mors; Eric M. Morrow; Daniel Moreno-De-Luca; Anthony P. Monaco; Nancy Minshew; Alison Merikangas; William M. McMahon; Susan G. McGrew; Manuel Mattheisen; Igor Martsenkovsky; Donna M. Martin; Shrikant M. Mane; Pall Magnusson; Tiago Magalhaes; Elena Maestrini; Jennifer K. Lowe; Catherine Lord; Pat Levitt; Christa Lese Martin; David H. Ledbetter; Marion Leboyer; Ann S. Lecouteur; Christine Ladd-Acosta; Alexander Kolevzon; Sabine M. Klauck; Suma Jacob; Bozenna Iliadou; Christina M. Hultman; David M. Hougaard; Irva Hertz-Picciotto; Robert Hendren; Christine Søholm Hansen; Jonathan L. Haines; Stephen J. Guter; Dorothy E. Grice; Jonathan M. Green; Andrew Green; Arthur P. Goldberg; Christopher Gillberg; John Gilbert; Louise Gallagher; Christine M. Freitag; Eric Fombonne; Susan E. Folstein; Bridget Fernandez; M. Daniele Fallin; A. Gulhan Ercan-Sencicek; Sean Ennis; Frederico Duque; Eftichia Duketis; Richard Delorme; Silvia Derubeis; Maretha V. Dejonge; Geraldine Dawson; Michael L. Cuccaro; Catarina T. Correia; Judith Conroy; Ines C. Conceição; Andreas G. Chiocchetti; Patrícia B.S. Celestino-Soper; Jillian Casey; Rita M. Cantor; Cátia Café; Jonas Bybjerg-Grauholm; Sean Brennan; Thomas Bourgeron; Patrick F. Bolton; Sven Bölte; Nadia Bolshakova; Catalina Betancur; Raphael Bernier; Arthur L. Beaudet; Agatino Battaglia; Vanessa H. Bal; Gillian Baird; Anthony J. Bailey; Marie Bækvad-Hansen; Joel S. Bader; Elena Bacchelli; Evdokia Anagnostou; David Amaral; Joana Almeida; Anders D. Børglum; Joseph D. Buxbaum; Aravinda Chakravarti; Edwin H. Cook; Hilary Coon; Daniel H. Geschwind; Michael Gill; Joachim Hallmayer; Aarno Palotie; Susan Santangelo; James S. Sutcliffe; Dan E. Arking; Bernie Devlin; Mark J. Daly; Hakon Hakonarson

doi:10.1186/s13229-017-0137-9

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

Richard J.L. Anney, Stephan Ripke, Verneri Anttila, Jakob Grove, Peter Holmans, Hailiang Huang, Lambertus Klei, Phil H. Lee, Sarah E. Medland, Benjamin Neale, Elise Robinson, Lauren A. Weiss, Lonnie Zwaigenbaum, Timothy W. Yu, Kerstin Wittemeyer, A. Jeremy Willsey, Ellen M. Wijsman, Thomas Werge, Thomas H. Wassink, Regina WaltesChristopher A. Walsh, Simon Wallace, Jacob A.S. Vorstman, Veronica J. Vieland, Astrid M. Vicente, Herman Vanengeland, Kathryn Tsang, Ann P. Thompson, Peter Szatmari, Oscar Svantesson, Stacy Steinberg, Kari Stefansson, Hreinn Stefansson, Matthew W. State, Latha Soorya, Teimuraz Silagadze, Stephen W. Scherer, Gerard D. Schellenberg, Sven Sandin, Stephan J. Sanders, Evald Saemundsen, Guy A. Rouleau, Bernadette Rogé, Kathryn Roeder, Wendy Roberts, Jennifer Reichert, Abraham Reichenberg, Karola Rehnström, Regina Regan, Fritz Poustka, Christopher S. Poultney, Joseph Piven, Dalila Pinto, Margaret A. Pericak-Vance, Milica Pejovic-Milovancevic, Marianne Giørtz Pedersen, Carsten Bøcker Pedersen, Andrew D. Paterson, Jeremy R. Parr, Alistair T. Pagnamenta, Guiomar Oliveira, John I. Nurnberger, Merete Nordentoft, Michael T. Murtha, Susana Mouga, Preben Bo Mortensen, Ole Mors, Eric M. Morrow, Daniel Moreno-De-Luca, Anthony P. Monaco, Nancy Minshew, Alison Merikangas, William M. McMahon, Susan G. McGrew, Manuel Mattheisen, Igor Martsenkovsky, Donna M. Martin, Shrikant M. Mane, Pall Magnusson, Tiago Magalhaes, Elena Maestrini, Jennifer K. Lowe, Catherine Lord, Pat Levitt, Christa Lese Martin, David H. Ledbetter, Marion Leboyer, Ann S. Lecouteur, Christine Ladd-Acosta, Alexander Kolevzon, Sabine M. Klauck, Suma Jacob, Bozenna Iliadou, Christina M. Hultman, David M. Hougaard, Irva Hertz-Picciotto, Robert Hendren, Christine Søholm Hansen, Jonathan L. Haines, Stephen J. Guter, Dorothy E. Grice, Jonathan M. Green, Andrew Green, Arthur P. Goldberg, Christopher Gillberg, John Gilbert, Louise Gallagher, Christine M. Freitag, Eric Fombonne, Susan E. Folstein, Bridget Fernandez, M. Daniele Fallin, A. Gulhan Ercan-Sencicek, Sean Ennis, Frederico Duque, Eftichia Duketis, Richard Delorme, Silvia Derubeis, Maretha V. Dejonge, Geraldine Dawson, Michael L. Cuccaro, Catarina T. Correia, Judith Conroy, Ines C. Conceição, Andreas G. Chiocchetti, Patrícia B.S. Celestino-Soper, Jillian Casey, Rita M. Cantor, Cátia Café, Jonas Bybjerg-Grauholm, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Bölte, Nadia Bolshakova, Catalina Betancur, Raphael Bernier, Arthur L. Beaudet, Agatino Battaglia, Vanessa H. Bal, Gillian Baird, Anthony J. Bailey, Marie Bækvad-Hansen, Joel S. Bader, Elena Bacchelli, Evdokia Anagnostou, David Amaral, Joana Almeida, Anders D. Børglum, Joseph D. Buxbaum, Aravinda Chakravarti, Edwin H. Cook, Hilary Coon, Daniel H. Geschwind, Michael Gill, Joachim Hallmayer, Aarno Palotie, Susan Santangelo, James S. Sutcliffe, Dan E. Arking, Bernie Devlin, Mark J. Daly, Hakon Hakonarson

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

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) <1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10^-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.

Original language	English (US)
Article number	21
Journal	Molecular Autism
Volume	8
Issue number	1
DOIs	https://doi.org/10.1186/s13229-017-0137-9
State	Published - May 22 2017

Keywords

Autism spectrum disorder
Gene-set analysis
Genetic correlation
Genome-wide association study
Heritability
Meta-analysis
Neurodevelopment
Schizophrenia

ASJC Scopus subject areas

Molecular Biology
Developmental Neuroscience
Developmental Biology
Psychiatry and Mental health

Access to Document

10.1186/s13229-017-0137-9

Cite this

Anney, R. J. L., Ripke, S., Anttila, V., Grove, J., Holmans, P., Huang, H., Klei, L., Lee, P. H., Medland, S. E., Neale, B., Robinson, E., Weiss, L. A., Zwaigenbaum, L., Yu, T. W., Wittemeyer, K., Willsey, A. J., Wijsman, E. M., Werge, T., Wassink, T. H., ... Hakonarson, H. (2017). 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. Molecular Autism, 8(1), [21]. https://doi.org/10.1186/s13229-017-0137-9

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, Parr, JR, Pagnamenta, AT, Oliveira, G, Nurnberger, JI, Nordentoft, M, Murtha, MT, Mouga, S, Mortensen, PB, Mors, O, Morrow, EM, Moreno-De-Luca, D, Monaco, AP, Minshew, N, Merikangas, A, McMahon, WM, McGrew, SG, Mattheisen, M, Martsenkovsky, I, Martin, DM, Mane, SM, Magnusson, P, Magalhaes, T, Maestrini, E, Lowe, JK, Lord, C, Levitt, P, Martin, CL, Ledbetter, DH, Leboyer, M, Lecouteur, AS, Ladd-Acosta, C, Kolevzon, A, Klauck, SM, Jacob, S, Iliadou, B, Hultman, CM, Hougaard, DM, Hertz-Picciotto, I, Hendren, R, Hansen, CS, Haines, JL, Guter, SJ, Grice, DE, Green, JM, Green, A, Goldberg, AP, Gillberg, C, Gilbert, J, Gallagher, L, Freitag, CM, Fombonne, E, Folstein, SE, Fernandez, B, Fallin, MD, Ercan-Sencicek, AG, Ennis, S, Duque, F, Duketis, E, Delorme, R, Derubeis, S, Dejonge, MV, Dawson, G, Cuccaro, ML, Correia, CT, Conroy, J, Conceição, IC, Chiocchetti, AG, Celestino-Soper, PBS, Casey, J, Cantor, RM, Café, C, Bybjerg-Grauholm, J, Brennan, S, Bourgeron, T, Bolton, PF, Bölte, S, Bolshakova, N, Betancur, C, Bernier, R, Beaudet, AL, Battaglia, A, Bal, VH, Baird, G, Bailey, AJ, Bækvad-Hansen, M, Bader, JS, Bacchelli, E, Anagnostou, E, Amaral, D, Almeida, J, Børglum, AD, Buxbaum, JD, Chakravarti, A, Cook, EH, Coon, H, Geschwind, DH, Gill, M, Hallmayer, J, Palotie, A, Santangelo, S, Sutcliffe, JS, Arking, DE, Devlin, B, Daly, MJ & Hakonarson, H 2017, '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', Molecular Autism, vol. 8, no. 1, 21. https://doi.org/10.1186/s13229-017-0137-9

@article{5d10b5422e3940b5bcc02c6e8ef080cc,

title = "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",

abstract = "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) <1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.",

keywords = "Autism spectrum disorder, Gene-set analysis, Genetic correlation, Genome-wide association study, Heritability, Meta-analysis, Neurodevelopment, Schizophrenia",

author = "Anney, {Richard J.L.} and Stephan Ripke and Verneri Anttila and Jakob Grove and Peter Holmans and Hailiang Huang and Lambertus Klei and Lee, {Phil H.} and Medland, {Sarah E.} and Benjamin Neale and Elise Robinson and Weiss, {Lauren A.} and Lonnie Zwaigenbaum and Yu, {Timothy W.} and Kerstin Wittemeyer and Willsey, {A. Jeremy} and Wijsman, {Ellen M.} and Thomas Werge and Wassink, {Thomas H.} and Regina Waltes and Walsh, {Christopher A.} and Simon Wallace and Vorstman, {Jacob A.S.} and Vieland, {Veronica J.} and Vicente, {Astrid M.} and Herman Vanengeland and Kathryn Tsang and Thompson, {Ann P.} and Peter Szatmari and Oscar Svantesson and Stacy Steinberg and Kari Stefansson and Hreinn Stefansson and State, {Matthew W.} and Latha Soorya and Teimuraz Silagadze and Scherer, {Stephen W.} and Schellenberg, {Gerard D.} and Sven Sandin and Sanders, {Stephan J.} and Evald Saemundsen and Rouleau, {Guy A.} and Bernadette Rog{\'e} and Kathryn Roeder and Wendy Roberts and Jennifer Reichert and Abraham Reichenberg and Karola Rehnstr{\"o}m and Regina Regan and Fritz Poustka and Poultney, {Christopher S.} and Joseph Piven and Dalila Pinto and Pericak-Vance, {Margaret A.} and Milica Pejovic-Milovancevic and Pedersen, {Marianne Gi{\o}rtz} and Pedersen, {Carsten B{\o}cker} and Paterson, {Andrew D.} and Parr, {Jeremy R.} and Pagnamenta, {Alistair T.} and Guiomar Oliveira and Nurnberger, {John I.} and Merete Nordentoft and Murtha, {Michael T.} and Susana Mouga and Mortensen, {Preben Bo} and Ole Mors and Morrow, {Eric M.} and Daniel Moreno-De-Luca and Monaco, {Anthony P.} and Nancy Minshew and Alison Merikangas and McMahon, {William M.} and McGrew, {Susan G.} and Manuel Mattheisen and Igor Martsenkovsky and Martin, {Donna M.} and Mane, {Shrikant M.} and Pall Magnusson and Tiago Magalhaes and Elena Maestrini and Lowe, {Jennifer K.} and Catherine Lord and Pat Levitt and Martin, {Christa Lese} and Ledbetter, {David H.} and Marion Leboyer and Lecouteur, {Ann S.} and Christine Ladd-Acosta and Alexander Kolevzon and Klauck, {Sabine M.} and Suma Jacob and Bozenna Iliadou and Hultman, {Christina M.} and Hougaard, {David M.} and Irva Hertz-Picciotto and Robert Hendren and Hansen, {Christine S{\o}holm} and Haines, {Jonathan L.} and Guter, {Stephen J.} and Grice, {Dorothy E.} and Green, {Jonathan M.} and Andrew Green and Goldberg, {Arthur P.} and Christopher Gillberg and John Gilbert and Louise Gallagher and Freitag, {Christine M.} and Eric Fombonne and Folstein, {Susan E.} and Bridget Fernandez and Fallin, {M. Daniele} and Ercan-Sencicek, {A. Gulhan} and Sean Ennis and Frederico Duque and Eftichia Duketis and Richard Delorme and Silvia Derubeis and Dejonge, {Maretha V.} and Geraldine Dawson and Cuccaro, {Michael L.} and Correia, {Catarina T.} and Judith Conroy and Concei{\c c}{\~a}o, {Ines C.} and Chiocchetti, {Andreas G.} and Celestino-Soper, {Patr{\'i}cia B.S.} and Jillian Casey and Cantor, {Rita M.} and C{\'a}tia Caf{\'e} and Jonas Bybjerg-Grauholm and Sean Brennan and Thomas Bourgeron and Bolton, {Patrick F.} and Sven B{\"o}lte and Nadia Bolshakova and Catalina Betancur and Raphael Bernier and Beaudet, {Arthur L.} and Agatino Battaglia and Bal, {Vanessa H.} and Gillian Baird and Bailey, {Anthony J.} and Marie B{\ae}kvad-Hansen and Bader, {Joel S.} and Elena Bacchelli and Evdokia Anagnostou and David Amaral and Joana Almeida and B{\o}rglum, {Anders D.} and Buxbaum, {Joseph D.} and Aravinda Chakravarti and Cook, {Edwin H.} and Hilary Coon and Geschwind, {Daniel H.} and Michael Gill and Joachim Hallmayer and Aarno Palotie and Susan Santangelo and Sutcliffe, {James S.} and Arking, {Dan E.} and Bernie Devlin and Daly, {Mark J.} and Hakon Hakonarson",

note = "Funding Information: The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland; AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA; the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium); approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https:// base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980; National Health Medical Research Council grant 0034328; and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford); and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http:// www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = may,

day = "22",

doi = "10.1186/s13229-017-0137-9",

language = "English (US)",

volume = "8",

journal = "Molecular Autism",

issn = "2040-2392",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - 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

AU - Anney, Richard J.L.

AU - Ripke, Stephan

AU - Anttila, Verneri

AU - Grove, Jakob

AU - Holmans, Peter

AU - Huang, Hailiang

AU - Klei, Lambertus

AU - Lee, Phil H.

AU - Medland, Sarah E.

AU - Neale, Benjamin

AU - Robinson, Elise

AU - Weiss, Lauren A.

AU - Zwaigenbaum, Lonnie

AU - Yu, Timothy W.

AU - Wittemeyer, Kerstin

AU - Willsey, A. Jeremy

AU - Wijsman, Ellen M.

AU - Werge, Thomas

AU - Wassink, Thomas H.

AU - Waltes, Regina

AU - Walsh, Christopher A.

AU - Wallace, Simon

AU - Vorstman, Jacob A.S.

AU - Vieland, Veronica J.

AU - Vicente, Astrid M.

AU - Vanengeland, Herman

AU - Tsang, Kathryn

AU - Thompson, Ann P.

AU - Szatmari, Peter

AU - Svantesson, Oscar

AU - Steinberg, Stacy

AU - Stefansson, Kari

AU - Stefansson, Hreinn

AU - State, Matthew W.

AU - Soorya, Latha

AU - Silagadze, Teimuraz

AU - Scherer, Stephen W.

AU - Schellenberg, Gerard D.

AU - Sandin, Sven

AU - Sanders, Stephan J.

AU - Saemundsen, Evald

AU - Rouleau, Guy A.

AU - Rogé, Bernadette

AU - Roeder, Kathryn

AU - Roberts, Wendy

AU - Reichert, Jennifer

AU - Reichenberg, Abraham

AU - Rehnström, Karola

AU - Regan, Regina

AU - Poustka, Fritz

AU - Poultney, Christopher S.

AU - Piven, Joseph

AU - Pinto, Dalila

AU - Pericak-Vance, Margaret A.

AU - Pejovic-Milovancevic, Milica

AU - Pedersen, Marianne Giørtz

AU - Pedersen, Carsten Bøcker

AU - Paterson, Andrew D.

AU - Parr, Jeremy R.

AU - Pagnamenta, Alistair T.

AU - Oliveira, Guiomar

AU - Nurnberger, John I.

AU - Nordentoft, Merete

AU - Murtha, Michael T.

AU - Mouga, Susana

AU - Mortensen, Preben Bo

AU - Mors, Ole

AU - Morrow, Eric M.

AU - Moreno-De-Luca, Daniel

AU - Monaco, Anthony P.

AU - Minshew, Nancy

AU - Merikangas, Alison

AU - McMahon, William M.

AU - McGrew, Susan G.

AU - Mattheisen, Manuel

AU - Martsenkovsky, Igor

AU - Martin, Donna M.

AU - Mane, Shrikant M.

AU - Magnusson, Pall

AU - Magalhaes, Tiago

AU - Maestrini, Elena

AU - Lowe, Jennifer K.

AU - Lord, Catherine

AU - Levitt, Pat

AU - Martin, Christa Lese

AU - Ledbetter, David H.

AU - Leboyer, Marion

AU - Lecouteur, Ann S.

AU - Ladd-Acosta, Christine

AU - Kolevzon, Alexander

AU - Klauck, Sabine M.

AU - Jacob, Suma

AU - Iliadou, Bozenna

AU - Hultman, Christina M.

AU - Hougaard, David M.

AU - Hertz-Picciotto, Irva

AU - Hendren, Robert

AU - Hansen, Christine Søholm

AU - Haines, Jonathan L.

AU - Guter, Stephen J.

AU - Grice, Dorothy E.

AU - Green, Jonathan M.

AU - Green, Andrew

AU - Goldberg, Arthur P.

AU - Gillberg, Christopher

AU - Gilbert, John

AU - Gallagher, Louise

AU - Freitag, Christine M.

AU - Fombonne, Eric

AU - Folstein, Susan E.

AU - Fernandez, Bridget

AU - Fallin, M. Daniele

AU - Ercan-Sencicek, A. Gulhan

AU - Ennis, Sean

AU - Duque, Frederico

AU - Duketis, Eftichia

AU - Delorme, Richard

AU - Derubeis, Silvia

AU - Dejonge, Maretha V.

AU - Dawson, Geraldine

AU - Cuccaro, Michael L.

AU - Correia, Catarina T.

AU - Conroy, Judith

AU - Conceição, Ines C.

AU - Chiocchetti, Andreas G.

AU - Celestino-Soper, Patrícia B.S.

AU - Casey, Jillian

AU - Cantor, Rita M.

AU - Café, Cátia

AU - Bybjerg-Grauholm, Jonas

AU - Brennan, Sean

AU - Bourgeron, Thomas

AU - Bolton, Patrick F.

AU - Bölte, Sven

AU - Bolshakova, Nadia

AU - Betancur, Catalina

AU - Bernier, Raphael

AU - Beaudet, Arthur L.

AU - Battaglia, Agatino

AU - Bal, Vanessa H.

AU - Baird, Gillian

AU - Bailey, Anthony J.

AU - Bækvad-Hansen, Marie

AU - Bader, Joel S.

AU - Bacchelli, Elena

AU - Anagnostou, Evdokia

AU - Amaral, David

AU - Almeida, Joana

AU - Børglum, Anders D.

AU - Buxbaum, Joseph D.

AU - Chakravarti, Aravinda

AU - Cook, Edwin H.

AU - Coon, Hilary

AU - Geschwind, Daniel H.

AU - Gill, Michael

AU - Hallmayer, Joachim

AU - Palotie, Aarno

AU - Santangelo, Susan

AU - Sutcliffe, James S.

AU - Arking, Dan E.

AU - Devlin, Bernie

AU - Daly, Mark J.

AU - Hakonarson, Hakon

N1 - Funding Information: The Autism Working Group of the Psychiatric Genomics Consortium was supported by National Institutes of Mental Health (NIMH, USA) grant MH109539, MH094432 and MH094421 to M.J.D. The ACE Network was supported by MH081754 and MH100027 to D.H.G. The Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) and was supported by grant MH081810. The Autism Genome Project (AGP) was supported by grants from Autism Speaks, the Canadian Institutes of Health Research (CIHR), Genome Canada, the Health Research Board (Ireland; AUT/ 2006/1, AUT/2006/2, PD/2006/48), the Hilibrand Foundation (USA), the Medical Research Council (UK), the National Institutes of Health (USA; the National Institute of Child Health and Human Development and the National Institute of Mental Health), the Ontario Genomics Institute, and the University of Toronto McLaughlin Centre. The Simons Simplex Collection (SSC) was supported by a grant from the Simons Foundation (SFARI 124827 to the investigators of the Simons Simplex Collection Genetic Consortium); approved researchers can obtain the SSC population dataset described in this study (http://sfari.org/resources/sfari-base) by applying at https:// base.sfari.org. The Gene Discovery Project of Johns Hopkins was funded by MH060007, MH081754, and the Simons Foundation. The MonBos Collection study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample (part of the MonBos collection) was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. The PAGES collection was funded by NIMH grant MH097849. The collection of data and biomaterials that participated in the NIMH Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219, and MH00980; National Health Medical Research Council grant 0034328; and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the endowment fund of the Nancy Pritzker Laboratory (Stanford); and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The iPSYCH project is funded by The Lundbeck Foundation and the universities and university hospitals of Aarhus and Copenhagen. In addition, the genotyping of iPSYCH samples was supported by grants from the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432-02 to MJD). The Study to Explore Early Development (SEED) was funded by the Centers for Disease Control and Prevention (CDC) grants U10DD000180, U10DD000181, U10DD000182, U10DD000183, U10DD000184, and U10DD000498. Statistical analyses were carried out on the Genetic Cluster Computer (http:// www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. Additional statistical analyses were performed and supported by the Trinity Centre for High Performance Computing (http://www.tchpc.tcd.ie/) funded through Science Foundation Ireland. Computational support for the PAGES collection was provided in part through the computational resources and staff expertise of the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (https://hpc.mssm.edu). Data QC and statistical analyses of the iPSYCH samples were performed at the high-performance computing cluster GenomeDK (http://genome.au.dk) at the Center for Integrative Sequencing, iSEQ, Aarhus University. iSEQ provided computed time, data storage, and technical support for the study. Publisher Copyright: © 2017 The Author(s).

PY - 2017/5/22

Y1 - 2017/5/22

N2 - 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) <1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.

AB - 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) <1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.

KW - Autism spectrum disorder

KW - Gene-set analysis

KW - Genetic correlation

KW - Genome-wide association study

KW - Heritability

KW - Meta-analysis

KW - Neurodevelopment

KW - Schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=85019753129&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019753129&partnerID=8YFLogxK

U2 - 10.1186/s13229-017-0137-9

DO - 10.1186/s13229-017-0137-9

M3 - Article

C2 - 28540026

AN - SCOPUS:85019753129

SN - 2040-2392

VL - 8

JO - Molecular Autism

JF - Molecular Autism

IS - 1

M1 - 21

ER -

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

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