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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
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Advisor(s)
Abstract(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) <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.
Description
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium - Collaborators (162): 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.
Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA.
PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/
Astrid M. Vicente .- Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do INSA.
PMS free full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441062/
Keywords
Autism Spectrum Disorder Gene-set Analysis Genetic Correlation Genome-wide Association Study Heritability Meta-analysis Neurodevelopment Schizophrenia Perturbações do Desenvolvimento Infantil e Saúde Mental Autismo
Pedagogical Context
Citation
Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
Publisher
BioMed Central