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1.  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
2.  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
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.  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
5.  Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT 
BMC Medical Genomics  2008;1:50.
Background
It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications.
Methods
In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region.
Results
MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3, MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003).
Conclusion
MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.
doi:10.1186/1755-8794-1-50
PMCID: PMC2588447  PMID: 18925931

Results 1-5 (5)