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Claire S Leblond,
Jutta Heinrich,
Richard Delorme,
Christian Proepper,
Catalina Betancur,
Guillaume Huguet,
Marina Konyukh,
Pauline Chaste,
Elodie Ey,
Maria Rastam, [......],
Mark Lathrop,
Dominique Bonneau,
Vincent Guinchat,
Françoise Devillard,
Brigitte Assouline,
Marie-Christine Mouren,
Marion Leboyer,
Christopher Gillberg,
Tobias M Boeckers,
Thomas Bourgeron
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Richard Anney,
Lambertus Klei, Dalila Pinto,
Joana Almeida,
Elena Bacchelli,
Gillian Baird,
Nadia Bolshakova,
Sven Bölte,
Patrick F Bolton,
Thomas Bourgeron, [......],
Edwin H Cook,
Louise Gallagher,
Michael Gill,
Joachim Hallmayer,
Andrew D Paterson,
James S Sutcliffe,
Peter Szatmari,
Veronica J Vieland,
Hakon Hakonarson,
Bernie Devlin
[show abstract]
[hide abstract]
ABSTRACT: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Human Molecular Genetics 07/2012; 21(21):4781-92. · 7.64 Impact Factor
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Daisuke Sato,
Anath C Lionel,
Claire S Leblond,
Aparna Prasad, Dalila Pinto,
Susan Walker,
Irene O'Connor,
Carolyn Russell,
Irene E Drmic,
Fadi F Hamdan, [......],
Rosanna Weksberg,
Eric Fombonne,
Lonnie Zwaigenbaum,
Bridget A Fernandez,
Wendy Roberts,
Gudrun A Rappold,
Christian R Marshall,
Thomas Bourgeron,
Peter Szatmari,
Stephen W Scherer
[show abstract]
[hide abstract]
ABSTRACT: Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.
The American Journal of Human Genetics 04/2012; 90(5):879-87. · 10.60 Impact Factor
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Claire S Leblond,
Jutta Heinrich,
Richard Delorme,
Christian Proepper,
Catalina Betancur,
Guillaume Huguet,
Marina Konyukh,
Pauline Chaste,
Elodie Ey,
Maria Rastam, [......],
Mark Lathrop,
Dominique Bonneau,
Vincent Guinchat,
Françoise Devillard,
Brigitte Assouline,
Marie-Christine Mouren,
Marion Leboyer,
Christopher Gillberg,
Tobias M Boeckers,
Thomas Bourgeron
[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
PLoS Genetics 02/2012; 8(2):e1002521. · 8.69 Impact Factor
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Andrea K Vaags,
Anath C Lionel,
Daisuke Sato,
McKinsey Goodenberger,
Quinn P Stein,
Sarah Curran,
Caroline Ogilvie,
Joo Wook Ahn,
Irene Drmic,
Lili Senman, [......],
Dimitri J Stavropoulos,
Lonnie Zwaigenbaum,
Bridget A Fernandez,
Eric Fombonne,
Patrick F Bolton,
David A Collier,
Jennelle C Hodge,
Wendy Roberts,
Peter Szatmari,
Stephen W Scherer
[show abstract]
[hide abstract]
ABSTRACT: The three members of the human neurexin gene family, neurexin 1 (NRXN1), neurexin 2 (NRXN2), and neurexin 3 (NRXN3), encode neuronal adhesion proteins that have important roles in synapse development and function. In autism spectrum disorder (ASD), as well as in other neurodevelopmental conditions, rare exonic copy-number variants and/or point mutations have been identified in the NRXN1 and NRXN2 loci. We present clinical characterization of four index cases who have been diagnosed with ASD and who possess rare inherited or de novo microdeletions at 14q24.3-31.1, a region that overlaps exons of the alpha and/or beta isoforms of NRXN3. NRXN3 deletions were found in one father with subclinical autism and in a carrier mother and father without formal ASD diagnoses, indicating issues of penetrance and expressivity at this locus. Notwithstanding these clinical complexities, this report on ASD-affected individuals who harbor NRXN3 exonic deletions advances the understanding of the genetic etiology of autism, further enabling molecular diagnoses.
The American Journal of Human Genetics 12/2011; 90(1):133-41. · 10.60 Impact Factor
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Jillian P Casey,
Tiago Magalhaes,
Judith M Conroy,
Regina Regan,
Naisha Shah,
Richard Anney,
Denis C Shields,
Brett S Abrahams,
Joana Almeida,
Elena Bacchelli, [......],
Stephen W Scherer,
James S Sutcliffe,
Peter Szatmari,
Veronica J Vieland,
Ellen M Wijsman,
Andrew Green,
Michael Gill,
Louise Gallagher,
Astrid Vicente,
Sean Ennis
[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Human Genetics 10/2011; 131(4):565-79. · 5.07 Impact Factor
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Dalila Pinto,
Alistair Pagnamenta,
Lambertus Klei,
Richard Anney,
Daniele Merico,
Regina Regan,
Judith Conroy,
Tiago Magalhaes,
Catarina Correia,
Brett Abrahams, [......],
Andrew Paterson,
Margaret Pericak-Vance,
Gerard Schellenberg,
Peter Szatmari,
Astrid Vicente,
Veronica Vieland,
Ellen Wijsman,
Stephen Scherer,
James Sutcliffe,
Catalina Betancur
[show abstract]
[hide abstract]
ABSTRACT: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Nature 07/2011; 466:368-372. · 36.28 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorder is a genetically complex and clinically heterogeneous neurodevelopmental disorder. A recent study by the Autism Genome Project (AGP) used 1M single-nucleotide polymorphism arrays to show that rare genic copy number variants (CNVs), possibly acting in tandem, play a significant role in the genetic aetiology of this condition. In this study, we describe the phenotypic and genomic characterisation of a multiplex autism family from the AGP study that was found to harbour a duplication of exons 31-44 of the Duchenne/Becker muscular dystrophy gene DMD and also a rare deletion involving exons 1-9 of TRPM3. Further characterisation of these extremely rare CNVs was carried out using quantitative PCR, fluorescent in situ hybridisation, long-range PCR amplification and sequencing of junction fragments. The maternal chrX:32,097,213-32,321,945 tandem duplication and paternal chr9:72,480,413-73,064,196 deletion (NCBI build 36 coordinates) were transmitted to both affected boys, potentially signifying a multi-hit mechanism. The DMD reading frame rule predicts a Becker phenotype, characterised by later onset and milder symptoms. When last evaluated, neither child had developed signs of muscular dystrophy. These data are consistent with a degree of comorbidity between autism and muscular dystrophy and suggest that genomic background as well as the position of the mutation within the DMD gene may impact on the neurological correlates of Duchenne/Becker muscular dystrophy. Finally, communicating unexpected findings such as these back to families raises a number of ethical questions, which are discussed.
Journal of Neurodevelopmental Disorders 06/2011; 3(2):124-31. · 3.06 Impact Factor
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Veronica J Vieland,
Joachim Hallmayer,
Yungui Huang,
Alistair T Pagnamenta, Dalila Pinto,
Hameed Khan,
Anthony P Monaco,
Andrew D Paterson,
Stephen W Scherer,
James S Sutcliffe,
Peter Szatmari
[show abstract]
[hide abstract]
ABSTRACT: The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well.
Journal of Neurodevelopmental Disorders 06/2011; 3(2):113-23. · 3.06 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Accumulating data indicate that there is significant genetic heterogeneity underlying the etiology in individuals diagnosed with autism spectrum disorder (ASD). Some rare and highly-penetrant gene variants and copy number variation (CNV) regions including NLGN3, NLGN4, NRXN1, SHANK2, SHANK3, PTCHD1, 1q21.1, maternally-inherited duplication of 15q11-q13, 16p11.2, amongst others, have been identified to be involved in ASD. Genome-wide association studies have identified other apparently low risk loci and in some other cases, ASD arises as a co-morbid phenotype with other medical genetic conditions (e.g. fragile X). The progress studying the genetics of ASD has largely been accomplished using genomic analyses of germline-derived DNA. Here, we used gene and miRNA expression profiling using cell-line derived total RNA to evaluate possible transcripts and networks of molecules involved in ASD. Our analysis identified several novel dysregulated genes and miRNAs in ASD compared with controls, including HEY1, SOX9, miR-486 and miR-181b. All of these are involved in nervous system development and function and some others, for example, are involved in NOTCH signaling networks (e.g. HEY1). Further, we found significant enrichment in molecules associated with neurological disorders such as Rett syndrome and those associated with nervous system development and function including long-term potentiation. Our data will provide a valuable resource for discovery purposes and for comparison to other gene expression-based, genome-wide DNA studies and other functional data.
Brain research 03/2011; 1380:85-97. · 2.46 Impact Factor
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Sanaa Choufani,
Jonathan S Shapiro,
Martha Susiarjo,
Darci T Butcher,
Daria Grafodatskaya,
Youliang Lou,
Jose C Ferreira, Dalila Pinto,
Stephen W Scherer,
Lisa G Shaffer,
Philippe Coullin,
Isabella Caniggia,
Joseph Beyene,
Rima Slim,
Marisa S Bartolomei,
Rosanna Weksberg
[show abstract]
[hide abstract]
ABSTRACT: Imprinted genes are critical for normal human growth and neurodevelopment. They are characterized by differentially methylated regions (DMRs) of DNA that confer parent of origin-specific transcription. We developed a new strategy to identify imprinted gene-associated DMRs. Using genome-wide methylation profiling of sodium bisulfite modified DNA from normal human tissues of biparental origin, candidate DMRs were identified by selecting CpGs with methylation levels consistent with putative allelic differential methylation. In parallel, the methylation profiles of tissues of uniparental origin, i.e., paternally-derived androgenetic complete hydatidiform moles (AnCHMs), and maternally-derived mature cystic ovarian teratoma (MCT), were examined and then used to identify CpGs with parent of origin-specific DNA methylation. With this approach, we found known DMRs associated with imprinted genomic regions as well as new DMRs for known imprinted genes, NAP1L5 and ZNF597, and novel candidate imprinted genes. The paternally methylated DMR for one candidate, AXL, a receptor tyrosine kinase, was also validated in experiments with mouse embryos that demonstrated Axl was expressed preferentially from the maternal allele in a DNA methylation-dependent manner.
Genome Research 02/2011; 21(3):465-76. · 13.61 Impact Factor
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Dalila Pinto,
Katayoon Darvishi,
Xinghua Shi,
Diana Rajan,
Diane Rigler,
Tom Fitzgerald,
Anath C Lionel,
Bhooma Thiruvahindrapuram,
Jeffrey R Macdonald,
Ryan Mills, [......],
Susan Gribble,
Elena Prigmore,
Patricia K Donahoe,
Richard S Smith,
Ji Hyeon Park,
Matthew E Hurles,
Nigel P Carter,
Charles Lee,
Stephen W Scherer,
Lars Feuk
[show abstract]
[hide abstract]
ABSTRACT: We have systematically compared copy number variant (CNV) detection on eleven microarrays to evaluate data quality and CNV calling, reproducibility, concordance across array platforms and laboratory sites, breakpoint accuracy and analysis tool variability. Different analytic tools applied to the same raw data typically yield CNV calls with <50% concordance. Moreover, reproducibility in replicate experiments is <70% for most platforms. Nevertheless, these findings should not preclude detection of large CNVs for clinical diagnostic purposes because large CNVs with poor reproducibility are found primarily in complex genomic regions and would typically be removed by standard clinical data curation. The striking differences between CNV calls from different platforms and analytic tools highlight the importance of careful assessment of experimental design in discovery and association studies and of strict data curation and filtering in diagnostics. The CNV resource presented here allows independent data evaluation and provides a means to benchmark new algorithms.
Nature Biotechnology 01/2011; 29(6):512-20. · 29.50 Impact Factor
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Richard F Wintle,
Anath C Lionel,
Pingzhao Hu,
Stephen D Ginsberg, Dalila Pinto,
Bhooma Thiruvahindrapduram,
John Wei,
Christian R Marshall,
Jane Pickett,
Edwin H Cook,
Stephen W Scherer
[show abstract]
[hide abstract]
ABSTRACT: The Autism Tissue Program (ATP), a science program of Autism Speaks, provides researchers with access to well-characterized postmortem brain tissues. Researchers access these tissues through a peer-reviewed, project-based approval process, and obtain related clinical information from a secure, online informatics portal. However, few of these samples have DNA banked from other sources (such as a blood sample from the same individual), hindering genotype-phenotype correlation and interpretation of gene expression data derived from the banked brain tissue. Here, we describe an initiative to extract DNA from Brodmann Area 19, and genotype these samples using both the Affymetrix Genome-Wide Human SNP Array 6.0 and the Illumina Human1M-Duo DNA Analysis BeadChip genome-wide microarray technologies. We additionally verify reported gender, and infer ethnic background from the single nucleotide polymorphism data. We have also used a rigorous, multiple algorithm approach to identify genomic copy number variation (CNV) from these array data. Following an initial proof of principle study using two samples, 52 experimental samples, consisting of 27 subjects with confirmed or suspected autism and related disorders, 5 subjects with cytogenetically visible duplications of 15q, 2 with epilepsy and 18 age-matched normal controls were processed, yielding high-quality genotype data in all cases. The genotype and CNV data are provided via the ATP informatics portal as a resource for the autism research community.
Autism Research 01/2011; 4(2):89-97. · 3.69 Impact Factor
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Richard Anney,
Lambertus Klei, Dalila Pinto,
Regina Regan,
Judith Conroy,
Tiago R Magalhaes,
Catarina Correia,
Brett S Abrahams,
Nuala Sykes,
Alistair T Pagnamenta, [......],
Gerard D Schellenberg,
Stephen W Scherer,
James S Sutcliffe,
Peter Szatmari,
Astrid M Vicente,
Veronica J Vieland,
Ellen M Wijsman,
Bernie Devlin,
Sean Ennis,
Joachim Hallmayer
[show abstract]
[hide abstract]
ABSTRACT: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Human Molecular Genetics 10/2010; 19(20):4072-82. · 7.64 Impact Factor
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Richard Anney,
Lambertus Klei, Dalila Pinto,
Regina Regan,
Judith Conroy,
Tiago Magalhaes,
Catarina Correia,
Brett Abrahams,
Nuala Sykes,
Alistair Pagnamenta, [......],
Gerard Schellenberg,
Stephen Scherer,
James Sutcliffe,
Peter Szatmari,
Astrid Vicente,
Veronica Vieland,
Ellen Wijsman,
Bernie Devlin,
Sean Ennis,
Joachim Hallmayer
[show abstract]
[hide abstract]
ABSTRACT: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 x 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 x 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Human Molecular Genetics 10/2010; 19(20):4072-4082. · 7.64 Impact Factor
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Alistair T Pagnamenta,
Hameed Khan,
Susan Walker,
Dianne Gerrelli,
Kirsty Wing,
Maria Clara Bonaglia,
Roberto Giorda,
Tom Berney,
Elisa Mani,
Massimo Molteni, Dalila Pinto,
Ann Le Couteur,
Joachim Hallmayer,
James S Sutcliffe,
Peter Szatmari,
Andrew D Paterson,
Stephen W Scherer,
Veronica J Vieland,
Anthony P Monaco
[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD.
In this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos.
The deletion of chr16: 60 025 584-61 667 839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58 724 527-60 547 472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex.
Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD.
Journal of Medical Genetics 10/2010; 48(1):48-54. · 6.36 Impact Factor
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Abdul Noor,
Annabel Whibley,
Christian R Marshall,
Peter J Gianakopoulos,
Amelie Piton,
Andrew R Carson,
Marija Orlic-Milacic,
Anath C Lionel,
Daisuke Sato, Dalila Pinto, [......],
Jozef Gecz,
Angela F Brady,
Charles E Schwartz,
Russell J Schachar,
Anthony P Monaco,
Guy A Rouleau,
Chi-Chung Hui,
F Lucy Raymond,
Stephen W Scherer,
John B Vincent
[show abstract]
[hide abstract]
ABSTRACT: Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.
Science translational medicine 09/2010; 2(49):49ra68. · 7.80 Impact Factor
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Dalila Pinto,
Alistair T Pagnamenta,
Lambertus Klei,
Richard Anney,
Daniele Merico,
Regina Regan,
Judith Conroy,
Tiago R Magalhaes,
Catarina Correia,
Brett S Abrahams, [......],
Andrew D Paterson,
Margaret A Pericak-Vance,
Gerard D Schellenberg,
Peter Szatmari,
Astrid M Vicente,
Veronica J Vieland,
Ellen M Wijsman,
Stephen W Scherer,
James S Sutcliffe,
Catalina Betancur
[show abstract]
[hide abstract]
ABSTRACT: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Nature 07/2010; 466(7304):368-72. · 36.28 Impact Factor
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Simone Berkel,
Christian R Marshall,
Birgit Weiss,
Jennifer Howe,
Ralph Roeth,
Ute Moog,
Volker Endris,
Wendy Roberts,
Peter Szatmari, Dalila Pinto,
Michael Bonin,
Angelika Riess,
Hartmut Engels,
Rolf Sprengel,
Stephen W Scherer,
Gudrun A Rappold
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ABSTRACT: Using microarrays, we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation. DNA sequencing of SHANK2 in 396 individuals with ASD, 184 individuals with mental retardation and 659 unaffected individuals (controls) revealed additional variants that were specific to ASD and mental retardation cases, including a de novo nonsense mutation and seven rare inherited changes. Our findings further link common genes between ASD and intellectual disability.
Nature Genetics 05/2010; 42(6):489-491. · 35.53 Impact Factor
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Nick Craddock,
Matthew E. Hurles,
Niall Cardin,
Richard D. Pearson,
Vincent Plagnol,
Samuel Robson,
Damjan Vukcevic,
Chris Barnes,
Donald F. Conrad,
Eleni Giannoulatou, [......],
Panos Deloukas,
Audrey Duncanson,
Dominic P. Kwiatkowski,
Mark I. McCarthy,
Willem H. Ouwehand,
Miles Parkes,
Nazneen Rahman,
John A. Todd,
Nilesh J. Samani,
Peter Donnelly
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ABSTRACT: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed ~19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated ~50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease—IRGM for Crohn’s disease, HLA for Crohn’s disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes—although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
Nature 03/2010; 464(7289):713-720. · 36.28 Impact Factor
