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1.  Patterns and rates of exonic de novo mutations in autism spectrum disorders 
Nature  2012;485(7397):242-245.
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors.
doi:10.1038/nature11011
PMCID: PMC3613847  PMID: 22495311
2.  Individual common variants exert weak effects on the risk for autism spectrum disorderspi 
Anney, Richard | Klei, Lambertus | Pinto, Dalila | Almeida, Joana | Bacchelli, Elena | Baird, Gillian | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Casey, Jillian | Conroy, Judith | Correia, Catarina | Corsello, Christina | Crawford, Emily L. | de Jonge, Maretha | Delorme, Richard | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Folstein, Susan E. | Fombonne, Eric | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Green, Andrew | Green, Jonathan | Guter, Stephen J. | Heron, Elizabeth A. | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Jacob, Suma | Kenny, Graham P. | Kim, Cecilia | Kolevzon, Alexander | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Law-Smith, Miriam | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Liu, Xiao-Qing | Lombard, Frances | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Magalhaes, Tiago R. | Mantoulan, Carine | McDougle, Christopher J. | Melhem, Nadine M. | Merikangas, Alison | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Noakes, Carolyn | Nygren, Gudrun | Papanikolaou, Katerina | Pagnamenta, Alistair T. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Posey, David J. | Poustka, Fritz | Ragoussis, Jiannis | Regan, Regina | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Schlitt, Sabine | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stoppioni, Vera | Sykes, Nuala | Tancredi, Raffaella | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Vorstman, JAS | Wallace, Simon | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Bailey, Anthony J. | Battaglia, Agatino | Cantor, Rita M. | Coon, Hilary | Cuccaro, Michael L. | Dawson, Geraldine | Ennis, Sean | Freitag, Christine M. | Geschwind, Daniel H. | Haines, Jonathan L. | Klauck, Sabine M. | McMahon, William M. | Maestrini, Elena | Miller, Judith | Monaco, Anthony P. | Nelson, Stanley F. | Nurnberger, John I. | Oliveira, Guiomar | Parr, Jeremy R. | Pericak-Vance, Margaret A. | Piven, Joseph | Schellenberg, Gerard D. | Scherer, Stephen W. | Vicente, Astrid M. | Wassink, Thomas H. | Wijsman, Ellen M. | Betancur, Catalina | Buxbaum, Joseph D. | Cook, Edwin H. | Gallagher, Louise | Gill, Michael | Hallmayer, Joachim | Paterson, Andrew D. | Sutcliffe, James S. | Szatmari, Peter | Vieland, Veronica J. | Hakonarson, Hakon | Devlin, Bernie
Human Molecular Genetics  2012;21(21):4781-4792.
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.
doi:10.1093/hmg/dds301
PMCID: PMC3471395  PMID: 22843504
3.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
doi:10.1038/nature07953
PMCID: PMC2925224  PMID: 19404257
4.  Multiple recurrent de novo copy number variations (CNVs), including duplications of the 7q11.23 Williams-Beuren syndrome region, are strongly associated with autism 
Neuron  2011;70(5):863-885.
Summary
Given prior evidence for the contribution of rare copy number variations (CNVs) to autism spectrum disorders (ASD), we studied these events in 4,457 individuals from 1,174 simplex families, composed of parents, a proband and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, featuring a highly social personality. We identify rare recurrent de novo CNVs at five additional regions including two novel ASD loci, 16p13.2 (including the genes USP7 and C16orf72) and Cadherin13, and implement a rigorous new approach to evaluating the statistical significance of these observations. Overall, we find large de novo CNVs carry substantial risk (OR=3.55; CI =2.16-7.46, p=6.9 × 10−6); estimate the presence of 130-234 distinct ASD-related CNV intervals across the genome; and, based on data from multiple studies, present compelling evidence for the association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin1.
doi:10.1016/j.neuron.2011.05.002
PMCID: PMC3939065  PMID: 21658581
5.  Functional Impact of Global Rare Copy Number Variation in Autism Spectrum Disorder 
Pinto, Dalila | Pagnamenta, Alistair T. | Klei, Lambertus | Anney, Richard | Merico, Daniele | Regan, Regina | Conroy, Judith | Magalhaes, Tiago R. | Correia, Catarina | Abrahams, Brett S. | Almeida, Joana | Bacchelli, Elena | Bader, Gary D. | Bailey, Anthony J. | Baird, Gillian | Battaglia, Agatino | Berney, Tom | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Bryson, Susan E. | Carson, Andrew R. | Casallo, Guillermo | Casey, Jillian | Cochrane, Lynne | Corsello, Christina | Crawford, Emily L. | Crossett, Andrew | Dawson, Geraldine | de Jonge, Maretha | Delorme, Richard | Drmic, Irene | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Filipa, Ana | Folstein, Susan E. | Fombonne, Eric | Freitag, Christine M. | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Goldberg, Jeremy | Green, Andrew | Green, Jonathan | Guter, Stephen J. | Hakonarson, Hakon | Heron, Elizabeth A. | Hill, Matthew | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Kim, Cecilia | Klauck, Sabine M. | Kolevzon, Alexander | Korvatska, Olena | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Laskawiec, Magdalena | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Lionel, Anath C. | Liu, Xiao-Qing | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Maestrini, Elena | Mahoney, William | Mantoulan, Carine | Marshall, Christian R. | McConachie, Helen | McDougle, Christopher J. | McGrath, Jane | McMahon, William M. | Merikangas, Alison | Migita, Ohsuke | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Nelson, Stanley F. | Noakes, Carolyn | Noor, Abdul | Nygren, Gudrun | Oliveira, Guiomar | Papanikolaou, Katerina | Parr, Jeremy R. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Pilorge, Marion | Piven, Joseph | Ponting, Chris P. | Posey, David J. | Poustka, Annemarie | Poustka, Fritz | Prasad, Aparna | Ragoussis, Jiannis | Renshaw, Katy | Rickaby, Jessica | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Bierut, Laura J. | Rice, John P. | Consortium, SAGE | Salt, Jeff | Sansom, Katherine | Sato, Daisuke | Segurado, Ricardo | Senman, Lili | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stein, Olaf | Stoppioni, Vera | Strawbridge, Christina | Tancredi, Raffaella | Tansey, Katherine | Thiruvahindrapduram, Bhooma | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Wallace, Simon | Wang, Kai | Wang, Zhouzhi | Wassink, Thomas H. | Webber, Caleb | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Wu, Jing | Yaspan, Brian L. | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Buxbaum, Joseph D. | Cantor, Rita M. | Cook, Edwin H. | Coon, Hilary | Cuccaro, Michael L. | Devlin, Bernie | Ennis, Sean | Gallagher, Louise | Geschwind, Daniel H. | Gill, Michael | Haines, Jonathan L. | Hallmayer, Joachim | Miller, Judith | Monaco, Anthony P. | Nurnberger, John I. | Paterson, Andrew D. | Pericak-Vance, Margaret A. | Schellenberg, Gerard D. | Szatmari, Peter | Vicente, Astrid M. | Vieland, Veronica J. | Wijsman, Ellen M. | Scherer, Stephen W. | Sutcliffe, James S. | Betancur, Catalina
Nature  2010;466(7304):368-372.
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 behaviors1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability (ID)2. While ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here, we analyzed the genome-wide characteristics of rare (<1% frequency) copy number variation (CNV) 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 CNVs (1.19 fold, P= 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P= 3.4×10−4). Among the CNVs, there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes like 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 signaling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
doi:10.1038/nature09146
PMCID: PMC3021798  PMID: 20531469
6.  A genome-wide scan for common alleles affecting risk for autism 
Anney, Richard | Klei, Lambertus | Pinto, Dalila | Regan, Regina | Conroy, Judith | Magalhaes, Tiago R. | Correia, Catarina | Abrahams, Brett S. | Sykes, Nuala | Pagnamenta, Alistair T. | Almeida, Joana | Bacchelli, Elena | Bailey, Anthony J. | Baird, Gillian | Battaglia, Agatino | Berney, Tom | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Carson, Andrew R. | Casallo, Guillermo | Casey, Jillian | Chu, Su H. | Cochrane, Lynne | Corsello, Christina | Crawford, Emily L. | Crossett, Andrew | Dawson, Geraldine | de Jonge, Maretha | Delorme, Richard | Drmic, Irene | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Folstein, Susan E. | Fombonne, Eric | Freitag, Christine M. | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Goldberg, Jeremy | Green, Jonathan | Guter, Stephen J. | Hakonarson, Hakon | Heron, Elizabeth A. | Hill, Matthew | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Kim, Cecilia | Klauck, Sabine M. | Kolevzon, Alexander | Korvatska, Olena | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Laskawiec, Magdalena | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Lionel, Anath C. | Liu, Xiao-Qing | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Maestrini, Elena | Mahoney, William | Mantoulan, Carine | Marshall, Christian R. | McConachie, Helen | McDougle, Christopher J. | McGrath, Jane | McMahon, William M. | Melhem, Nadine M. | Merikangas, Alison | Migita, Ohsuke | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Nelson, Stanley F. | Noakes, Carolyn | Noor, Abdul | Nygren, Gudrun | Oliveira, Guiomar | Papanikolaou, Katerina | Parr, Jeremy R. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Piven, Joseph | Posey, David J | Poustka, Annemarie | Poustka, Fritz | Prasad, Aparna | Ragoussis, Jiannis | Renshaw, Katy | Rickaby, Jessica | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Bierut, Laura J. | Rice, John P. | Salt, Jeff | Sansom, Katherine | Sato, Daisuke | Segurado, Ricardo | Senman, Lili | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stoppioni, Vera | Strawbridge, Christina | Tancredi, Raffaella | Tansey, Katherine | Thiruvahindrapduram, Bhooma | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Wallace, Simon | Wang, Kai | Wang, Zhouzhi | Wassink, Thomas H. | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Yaspan, Brian L. | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Betancur, Catalina | Buxbaum, Joseph D. | Cantor, Rita M. | Cook, Edwin H. | Coon, Hilary | Cuccaro, Michael L. | Gallagher, Louise | Geschwind, Daniel H. | Gill, Michael | Haines, Jonathan L. | Miller, Judith | Monaco, Anthony P. | Nurnberger, John I. | Paterson, Andrew D. | Pericak-Vance, Margaret A. | Schellenberg, Gerard D. | Scherer, Stephen W. | Sutcliffe, James S. | Szatmari, Peter | Vicente, Astrid M. | Vieland, Veronica J. | Wijsman, Ellen M. | Devlin, Bernie | Ennis, Sean | Hallmayer, Joachim
Human Molecular Genetics  2010;19(20):4072-4082.
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.
doi:10.1093/hmg/ddq307
PMCID: PMC2947401  PMID: 20663923

Results 1-6 (6)