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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 21 |
| Tidsskrift | Molecular Autism |
| Vol/bind | 8 |
| Antal sider | 17 |
| ISSN | 2040-2392 |
| DOI | |
| Status | Udgivet - 22 maj 2017 |
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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. / Anney, Richard J.L.; Ripke, Stephan; Anttila, Verneri; Grove, Jakob; Holmans, Peter; Huang, Hailiang; Klei, Lambertus; Lee, Phil H.; Medland, Sarah E.; Neale, Benjamin; Robinson, Elise; Weiss, Lauren A.; Zwaigenbaum, Lonnie; Yu, Timothy W.; Wittemeyer, Kerstin; Willsey, A. Jeremy; Wijsman, Ellen M.; Werge, Thomas; Wassink, Thomas H.; Waltes, Regina; Walsh, Christopher A.; Wallace, Simon; Vorstman, Jacob A.S.; Vieland, Veronica J.; Vicente, Astrid M.; Vanengeland, Herman; Tsang, Kathryn; Thompson, Ann P.; Szatmari, Peter; Svantesson, Oscar; Steinberg, Stacy; Stefansson, Kari; Stefansson, Hreinn; State, Matthew W.; Soorya, Latha; Silagadze, Teimuraz; Scherer, Stephen W.; Schellenberg, Gerard D.; Sandin, Sven; Sanders, Stephan J.; Saemundsen, Evald; Rouleau, Guy A.; Rogé, Bernadette; Roeder, Kathryn; Roberts, Wendy; Reichert, Jennifer; Reichenberg, Abraham; Rehnström, Karola; Regan, Regina; Poustka, Fritz; Poultney, Christopher S.; Piven, Joseph; Pinto, Dalila; Pericak-Vance, Margaret A.; Pejovic-Milovancevic, Milica; Pedersen, Marianne Giørtz; Pedersen, Carsten Bøcker; Paterson, Andrew D.; Parr, Jeremy R.; Pagnamenta, Alistair T.; Oliveira, Guiomar; Nurnberger, John I.; Nordentoft, Merete; Murtha, Michael T.; Mouga, Susana; Mortensen, Preben Bo; Mors, Ole; Morrow, Eric M.; Moreno-De-Luca, Daniel; Monaco, Anthony P.; Minshew, Nancy; Merikangas, Alison; McMahon, William M.; McGrew, Susan G.; Mattheisen, Manuel; Martsenkovsky, Igor; Martin, Donna M.; Mane, Shrikant M.; Magnusson, Pall; Magalhaes, Tiago; Maestrini, Elena; Lowe, Jennifer K.; Lord, Catherine; Levitt, Pat; Martin, Christa Lese; Ledbetter, David H.; Leboyer, Marion; Lecouteur, Ann S.; Ladd-Acosta, Christine; Kolevzon, Alexander; Klauck, Sabine M.; Jacob, Suma; Iliadou, Bozenna; Hultman, Christina M.; Hougaard, David M.; Hertz-Picciotto, Irva; Hendren, Robert; Hansen, Christine Søholm; Haines, Jonathan L.; Guter, Stephen J.; Grice, Dorothy E.; Green, Jonathan M.; Green, Andrew; Goldberg, Arthur P.; Gillberg, Christopher; Gilbert, John; Gallagher, Louise; Freitag, Christine M.; Fombonne, Eric; Folstein, Susan E.; Fernandez, Bridget; Fallin, M. Daniele; Ercan-Sencicek, A. Gulhan; Ennis, Sean; Duque, Frederico; Duketis, Eftichia; Delorme, Richard; Derubeis, Silvia; Dejonge, Maretha V.; Dawson, Geraldine; Cuccaro, Michael L.; Correia, Catarina T.; Conroy, Judith; Conceição, Ines C.; Chiocchetti, Andreas G.; Celestino-Soper, Patrícia B.S.; Casey, Jillian; Cantor, Rita M.; Café, Cátia; Bybjerg-Grauholm, Jonas; Brennan, Sean; Bourgeron, Thomas; Bolton, Patrick F.; Bölte, Sven; Bolshakova, Nadia; Betancur, Catalina; Bernier, Raphael; Beaudet, Arthur L.; Battaglia, Agatino; Bal, Vanessa H.; Baird, Gillian; Bailey, Anthony J.; Bækvad-Hansen, Marie; Bader, Joel S.; Bacchelli, Elena; Anagnostou, Evdokia; Amaral, David; Almeida, Joana; Børglum, Anders D.; Buxbaum, Joseph D.; Chakravarti, Aravinda; Cook, Edwin H.; Coon, Hilary; Geschwind, Daniel H.; Gill, Michael; Hakonarson, Hakon; Hallmayer, Joachim; Palotie, Aarno; Santangelo, Susan; Sutcliffe, James S.; Arking, Dan E.; Devlin, Bernie; Daly, Mark J.
I: Molecular Autism, Bind 8, 21, 22.05.2017.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
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 - Hakonarson, Hakon
AU - Hallmayer, Joachim
AU - Palotie, Aarno
AU - Santangelo, Susan
AU - Sutcliffe, James S.
AU - Arking, Dan E.
AU - Devlin, Bernie
AU - Daly, Mark J.
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
U2 - 10.1186/s13229-017-0137-9
DO - 10.1186/s13229-017-0137-9
M3 - Journal article
C2 - 28540026
AN - SCOPUS:85019753129
VL - 8
JO - Molecular Autism
JF - Molecular Autism
SN - 2040-2392
M1 - 21
ER -