5 search hits
search hits 1 to 5
- A genome-wide scan for common alleles affecting risk for autism (2010)
- Richard Anney Lambertus Klei Dalila Pinto Regina Regan Judith Conroy Tiago R. Magalhaes Catarina Correia Brett S. Abrahams Nuala Sykes Alistair T. Pagnamenta Joana Almeida Elena Bacchelli Anthony J. Bailey Gillian Baird Agatino Battaglia Tom Berney Nadia Bolshakova Sven Bölte Patrick F. Bolton Thomas Bourgeron Sean Brennan Jessica Brian Andrew R. Carson Guillermo Casallo Jillian Casey Su H. Chu Lynne Cochrane Christina Corsello Emily L. Crawford Andrew Crossett Geraldine Dawson Maretha de Jonge Richard Delorme Irene Drmic Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A. Fernandez Susan E. Folstein Eric Fombonne Christine M. Freitag John Gilbert Christopher Gillberg Joseph T. Glessner Jeremy Goldberg Jonathan Green Stephen J. Guter Hakon Hakonarson Elizabeth A. Heron Matthew Hill Richard Holt Jennifer L. Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M. Klauck Alexander Kolevzon Olena Korvatska Vlad Kustanovich Clara M. Lajonchere Janine A. Lamb Magdalena Laskawiec Marion Leboyer Ann Le Couteur Bennett L. Leventhal Anath C. Lionel Xiao-Qing Liu Catherine Lord Linda Lotspeich Sabata C. Lund Elena Maestrini William Mahoney Carine Mantoulan Christian R. Marshall Helen McConachie Christopher J. McDougle Jane McGrath William M. McMahon Nadine M. Melhem Alison Merikangas Ohsuke Migita Nancy J. Minshew Ghazala K. Mirza Jeff Munson Stanley F. Nelson Carolyn Noakes Abdul Noor Gudrun Nygren Guiomar Oliveira Katerina Papanikolaou Jeremy R. Parr Barbara Parrini Tara Paton Andrew Pickles Joseph Piven David J. Posey Annemarie Poustka Fritz Poustka Aparna Prasad Jiannis Ragoussis Katy Renshaw Jessica Rickaby Wendy Roberts Kathryn Roeder Bernadette Roge Michael L. Rutter Laura J. Bierut John P. Rice Jeff Salt Katherine Sansom Daisuke Sato Ricardo Segurado Lili Senman Naisha Shah Val C. Sheffield Latha Soorya Ines Sousa Vera Stoppioni Christina Strawbridge Raffaella Tancredi Katherine Tansey Bhooma Thiruvahindrapduram Ann P. Thompson Susanne Thomson Ana Tryfon John Tsiantis Herman Van Engeland John B. Vincent Fred Volkmar Simon Wallace Kai Wang Zhouzhi Wang Thomas H. Wassink Kirsty Wing Kerstin Wittemeyer Shawn Wood Brian L. Yaspan Danielle Zurawieck Lonnie Zwaigenbaum Catalina Betancur Joseph D. Buxbaum Rita M. Cantor Edwin H. Cook Hilary Coon Michael L. Cuccaro Louise Gallagher Daniel H. Geschwind Michael Gill Jonathan L. Haines Judith Miller Anthony P. Monaco John I. Jr. Nurnberger Andrew D. Paterson Margaret A. Pericak-Vance 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
- 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 3 10 exp -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 3 10 exp -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.
- Individual common variants exert weak effects on the risk for autism spectrum disorders (2012)
- Richard Anney Lambertus Klei Dalila Pinto Joana Almeida Elena Bacchelli Gillian Baird Nadia Bolshakova Sven Bölte Patrick F. Bolton Thomas Bourgeron Sean Brennan Jessica Brian Jillian Casey Judith Conroy Catarina Correia Christina Corsello Emily L. Crawford Maretha de Jonge Richard Delorme Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A. Fernandez Susan E. Folstein Eric Fombonne John Gilbert Christopher Gillberg Joseph T. Glessner Andrew Green Jonathan Green Stephen J. Guter Elizabeth A. Heron Richard Holt Jennifer L. Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Suma Jacob Graham P. Kenny Cecilia Kim Alexander Kolevzon Vlad Kustanovich Clara M. Lajonchere Janine A. Lamb Miriam Law-Smith Marion Leboyer Ann Le Couteur Bennett L. Leventhal Xiao-Qing Liu Frances Lombard Catherine Lord Linda Lotspeich Linda Lotspeich Sabata C. Lund Tiago R. Magalhaes Carine Mantoulan Christopher J. McDougle Nadine M. Melhem Alison Merikangas Nancy J. Minshew Ghazala K. Mirza Jeff Munson Carolyn Noakes Gudrun Nygren Katerina Papanikolaou Alistair T. Pagnamenta Barbara Parrini Tara Paton Tara Paton Andrew Pickles David J. Posey Fritz Poustka Jiannis Ragoussis Regina Regan Wendy Roberts Kathryn Roeder Bernadette Roge Michael L. Rutter Sabine Schlitt Naisha Shah Val C. Sheffield Latha Soorya Inês Sousa Vera Stoppioni Nuala Sykes Raffaella Tancredi Ann P. Thompson Susanne Thomson Ana Tryfon John Tsiantis Herman Van Engeland John B. Vincent Fred Volkmar JAS Vorstman Simon Wallace Kirsty Wing Kerstin Wittemeyer Shawn Wood Danielle Zurawiecki Lonnie Zwaigenbaum Anthony J. Bailey Agatino Battaglia Rita M. Cantor Hilary Coon Michael L. Cuccaro Geraldine Dawson Sean Ennis Christine M. Freitag Daniel H. Geschwind Jonathan L. Haines Sabine M. Klauck William M. McMahon Elena Maestrini Judith Miller Anthony P. Monaco Stanley F. Nelson John I. Nurnberger Guiomar Oliveira Jeremy R. Parr Margaret A. Pericak-Vance Joseph Piven Gerard D. Schellenberg Stephen W. Scherer Astrid M. Vicente Thomas H. Wassink Ellen M. Wijsman Catalina Betancur Joseph D. Buxbaum Edwin H. Cook Louise Gallagher Michael Gill Joachim Hallmayer Andrew D. Paterson James S. Sutcliffe Peter Szatmari Veronica J. Vieland Hakon Hakonarson Bernie Devlin
- 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.
- A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder (2011)
- Jillian P. Casey Tiago Magalhaes Judith M. Conroy Regina Regan Naisha Shah Richard Anney Denis C. Shields Brett S. Abrahams Joana Almeida Elena Bacchelli Anthony J. Bailey Gillian Baird Agatino Battaglia Tom Berney Nadia Bolshakova Patrick F. Bolton Thomas Bourgeron Sean Brennan Phil Cali Catarina Correia Christina Corsello Marc Coutanche Geraldine Dawson Maretha de Jonge Richard Delorme Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A. Fernandez Susan E. Folstein Suzanne Foley Eric Fombonne Christine M. Freitag John Gilbert Christopher Gillberg Joseph T. Glessner Jonathan Green Stephen J. Guter Hakon Hakonarson Richard Holt Gillian Hughes Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M. Klauck Alexander Kolevzon Janine A. Lamb Marion Leboyer Ann Le Couteur Bennett L. Leventhal Catherine Lord Sabata C. Lund Elena Maestrini Carine Mantoulan Christian R. Marshall Helen McConachie Christopher J. McDougle Jane McGrath William M. McMahon Alison Merikangas Judith Miller Fiorella Minopoli Ghazala K. Mirza Jeff Munson Stanley F. Nelson Gudrun Nygren Guiomar Oliveira Alistair T. Pagnamenta Katerina Papanikolaou Jeremy R. Parr Barbara Parrini Andrew Pickles Dalila Pinto Joseph Piven David J. Posey Annemarie Poustka Fritz Poustka Jiannis Ragoussis Bernadette Roge Michael L. Rutter Ana F. Sequeira Latha Soorya Inês Sousa Nuala Sykes Vera Stoppioni Raffaella Tancredi Maïté Tauber Ann P. Thompson Susanne Thomson John Tsiantis Herman Van Engeland John B. Vincent Fred Volkmar Jacob A. S. Vorstman Simon Wallace Kai Wang Thomas H. Wassink Kathy White Kirsty Wing Kerstin Wittemeyer Brian L. Yaspan Lonnie Zwaigenbaum Catalina Betancur Joseph D. Buxbaum Rita M. Cantor Edwin H. Cook Hilary Coon Michael L. Cuccaro Daniel H. Geschwind Jonathan L. Haines Joachim Hallmayer Anthony P. Monaco John I. Nurnberger Jr. Margaret A. Pericak-Vance Gerard D. Schellenberg Stephen W. Scherer James S. Sutcliffe Peter Szatmari Veronica J. Vieland Ellen M. Wijsman Andrew Green Michael Gill Louise Gallagher Astrid Vicente Sean Ennis
- 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.
- Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease (2014)
- Valentina Escott-Price Céline Bellenguez Li-San Wang Seung-Hoan Choi Denise Harold Lesley Jones Peter Holmans Amy Gerrish Alexey Vedernikov Alexander Richards Anita L. DeStefano Jean-Charles Lambert Carla A. Ibrahim-Verbaas Adam C. Naj Rebecca Sims Gyungah Jun Joshua C. Bis Gary W. Beecham Benjamin Grenier-Boley Giancarlo Russo Tricia A. Thornton-Wells Nicola Denning Albert V. Smith Vincent Chouraki Charlene Thomas M. Arfan Ikram Diana Zelenika Badri N. Vardarajan Yoichiro Kamatani Chiao-Feng Lin Helena Schmidt Brian Kunkle Melanie L. Dunstan Maria Vronskaya Andrew D. Johnson Agustin Ruiz Marie-Thérèse Bihoreau Christiane Reitz Florence Pasquier Paul Hollingworth Olivier Hanon Annette L. Fitzpatrick Joseph D. Buxbaum Dominique Campion Paul K. Crane Clinton Baldwin Tim Becker Vilmundur Gudnason Carlos Cruchaga David Craig Najaf Amin Claudine Berr Oscar L. Lopez Philip L. De Jager Vincent Deramecourt Janet A. Johnston Denis Evans Simon Lovestone Luc Letenneur Isabel Hernández David C. Rubinsztein Gudny Eiriksdottir Kristel Sleegers Alison M. Goate Nathalie Fiévet Matthew J. Huentelman Michael Gill Kristelle Brown M. Ilyas Kamboh Lina Keller Pascale Barberger-Gateau Bernadette McGuinness Eric B. Larson Amanda J. Myers Carole Dufouil Stephen Todd David Wallon Seth Love Ekaterina Rogaeva John Gallacher Peter St George-Hyslop Jordi Clarimon Alberto Lleo Anthony Bayer Debby W. Tsuang Lei Yu Magda Tsolaki Paola Bossù Gianfranco Spalletta Petra Proitsi John Collinge Sandro Sorbi Florentino Sanchez Garcia Nick C. Fox John Hardy Maria Candida Deniz Naranjo Paolo Bosco Robert Clarke Carol Brayne Daniela Galimberti Elio Scarpini Ubaldo Bonuccelli Michelangelo Mancuso Gabriele Siciliano Susanne Moebus Patrizia Mecocci Maria Del Zompo Wolfgang Maier Harald Hampel Alberto Pilotto Ana Frank-García Francesco Panza Vincenzo Solfrizzi Paolo Caffarra Benedetta Nacmias William Perry Manuel Mayhaus Lars Lannfelt Hakon Hakonarson Sabrina Pichler Minerva M. Carrasquillo Martin Ingelsson Duane Beekly Victoria Alvarez Fanggeng Zou Otto Valladares Steven G. Younkin Eliecer Coto Kara L. Hamilton-Nelson Wei Gu Cristina Razquin Pau Pastor Ignacio Mateo Michael J. Owen Kelley M. Faber Palmi V. Jonsson Onofre Combarros Michael C. O'Donovan Laura B. Cantwell Hilkka Soininen Deborah Blacker Simon Mead Thomas H. Mosley David A. Bennett Tamara B. Harris Laura Fratiglioni Clive Holmes Renee F. A. G. de Bruijn Peter Passmore Thomas J. Montine Karolien Bettens Jerome I. Rotter Alexis Brice Kevin Morgan Tatiana M. Foroud Walter A. Kukull Didier Hannequin John F. Powell Michael A. Nalls Karen Ritchie Kathryn L. Lunetta John S. K. Kauwe Eric Boerwinkle Matthias Riemenschneider Mercè Boada Mikko Hiltunen Eden R. Martin Reinhold Schmidt Dan Rujescu Jean-François Dartigues Richard Mayeux Christophe Tzourio Albert Hofman Markus M. Nöthen Caroline Graff Bruce M. Psaty Jonathan L. Haines Mark Lathrop Margaret A. Pericak-Vance Lenore J. Launer Christine Van Broeckhoven Lindsay A. Farrer Cornelia M. van Duijn Alfredo Ramirez Sudha Seshadri Gerard D. Schellenberg Philippe Amouyel Julie Williams
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
- Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014)
- Dalila Pinto Elsa Delaby Daniele Merico Mafalda Barbosa Alison Merikangas Lambertus Klei Bhooma Thiruvahindrapuram Xiao Xu Robert Ziman Zhuozhi Wang Jacob A. S. Vorstman Ann Thompson Regina Regan Marion Pilorge Giovanna Pellecchia Alistair T. Pagnamenta Bárbara Oliveira Christian R. Marshall Tiago R. Magalhaes Jennifer K. Lowe Jennifer L. Howe Anthony J. Griswold John Gilbert Eftichia Duketis Beth A. Dombroski Maretha V. De Jonge Michael Cuccaro Emily L. Crawford Catarina T. Correia Judith Conroy Inȇs C. Conceição Andreas G. Chiocchetti Jillian P. Casey Guiqing Cai Christelle Cabrol Nadia Bolshakova Elena Bacchelli Richard Anney Steven Gallinger Michelle Cotterchio Graham Casey Lonnie Zwaigenbaum Kerstin Wittemeyer Kirsty Wing Simon Wallace Herman van Engeland Ana Tryfon Susanne Thomson Latha Soorya Bernadette Roge Wendy Roberts Fritz Poustka Susana Mouga Nancy Minshew L. Alison McInnes Susan G. McGrew Catherine Lord Marion Leboyer Ann S. Le Couteur Alexander Kolevzon Patricia Jiménez González Suma Jacob Richard Holt Stephen Guter Jonathan Green Andrew Green Christopher Gillberg Bridget A. Fernandez Frederico Duque Richard Delorme Geraldine Dawson Pauline Chaste Cátia Café Sean Brennan Thomas Bourgeron Patrick F. Bolton Sven Bölte Raphael Bernier Gillian Baird Anthony J. Bailey Evdokia Anagnostou Joana Almeida Ellen M. Wijsman Veronica J. Vieland Astrid M. Vicente Gerard D. Schellenberg Margaret Pericak-Vance Andrew D. Paterson Jeremy R. Parr Guiomar Oliveira John I. Nurnberger Anthony P. Monaco Elena Maestrini Sabine M. Klauck Hakon Hakonarson Jonathan L. Haines Daniel H. Geschwind Christine M. Freitag Susan E. Folstein Sean Ennis Hilary Coon Agatino Battaglia Peter Szatmari James S. Sutcliffe Joachim Hallmayer Michael Gill Edwin H. Cook Joseph D. Buxbaum Bernie Devlin Louise Gallagher Catalina Betancur Stephen W. Scherer
- Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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