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1. New interview and observation measures of the broader autism phenotype: impressions of interviewee measure

Author

Pickles, A., Parr, J.R., Rutter, M.L., De Jonge, M.V., Wallace, S., Le Couteur, A.S., van Engeland, H., Wittemeyer, K., McConachie, H., Roge, B., Mantoulan, C., Pedersen, L., Isager, T., Poustka, F., Bolte, S., Bolton, P., Weisblatt, E., Green, J., Papanikolaou, K., and Bailey, A.J.

Subjects
Pervasive developmental disorders -- Research -- Care and treatment, Interviewing -- Methods, Discriminant analysis -- Usage, Factor analysis -- Usage, Rating scales -- Analysis, Health
Abstract

A 20 item observational measure of social functioning, the Impression of Interviewee rating scale, is one of three measures devised to assess the broader autism phenotype. The sample studied included families containing at least two individuals with autism spectrum disorder; observations were undertaken by the researcher who interviewed the subject. An exploratory factor analysis suggested a single factor was most appropriate (Cronbach's [alpha] of 0.78). There was a modest but significant retest correlation of 0.42. Correlations between live ratings and blind consensus ratings of vignettes were high (0.93). Correlations with the interview measures were moderate but statistically significant. In conclusion, the observational scale provides a promising start but further work is required before general use can be recommended. Keywords Broader autism phenotype * Observer rating * Test-retest * Factor analysis * Social functioning, Introduction The broader autism phenotype (BAP) primarily comprises socio-communicative features that should be observable in the course of ordinary social interactions. The International Molecular Study of Autism Consortium (IMGSAC) developed [...]

Published
2013
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2. New interview and observation measures of the broader autism phenotype: Description of strategy and reliability findings for the interview measures

Author

Parr, J., De Jonge, M., Wallace, S., Pickles, A., Rutter, M., Le Couteur, A., van Engeland, H., Wittemeyer, K., Mcconachie, H., Roge, B., Mantoulan, C., Pedersen, L., Isager, T., Poustka, F., Bolte, Sven, Bolton, P., Weisblatt, E., Green, J., Papanikolaou, K., Baird, G., Bailey, A., Parr, J., De Jonge, M., Wallace, S., Pickles, A., Rutter, M., Le Couteur, A., van Engeland, H., Wittemeyer, K., Mcconachie, H., Roge, B., Mantoulan, C., Pedersen, L., Isager, T., Poustka, F., Bolte, Sven, Bolton, P., Weisblatt, E., Green, J., Papanikolaou, K., Baird, G., and Bailey, A.

Abstract

© 2015 International Society for Autism Research, Wiley Periodicals, Inc. Clinical genetic studies confirm the broader autism phenotype (BAP) in some relatives of individuals with autism, but there are few standardized assessment measures. We developed three BAP measures (informant interview, self-report interview, and impression of interviewee observational scale) and describe the development strategy and findings from the interviews. International Molecular Genetic Study of Autism Consortium data were collected from families containing at least two individuals with autism. Comparison of the informant and self-report interviews was restricted to samples in which the interviews were undertaken by different researchers from that site (251 UK informants, 119 from the Netherlands). Researchers produced vignettes that were rated blind by others. Retest reliability was assessed in 45 participants. Agreement between live scoring and vignette ratings was very high. Retest stability for the interviews was high. Factor analysis indicated a first factor comprising social-communication items and rigidity (but not other repetitive domain items), and a second factor comprised mainly of reading and spelling impairments. Whole scale Cronbach's alphas were high for both interviews. The correlation between interviews for factor 1 was moderate (adult items 0.50; childhood items 0.43); Kappa values for between-interview agreement on individual items were mainly low. The correlations between individual items and total score were moderate. The inclusion of several factor 2 items lowered the overall Cronbach's alpha for the total set. Both interview measures showed good reliability and substantial stability over time, but the findings were better for factor 1 than factor 2. We recommend factor 1 scores be used for characterising the BAP.

Published
2015

3. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Author

Casey, J.P. Magalhaes, T. Conroy, J.M. Regan, R. Shah, N. Anney, R. Shields, D.C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bolton, P.F. Bourgeron, T. Brennan, S. Cali, P. Correia, C. Corsello, C. Coutanche, M. Dawson, G. De Jonge, M. Delorme, R. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Foley, S. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Green, J. Guter, S.J. Hakonarson, H. Holt, R. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Lamb, J.A. Leboyer, M. Couteur, A.L. Leventhal, B.L. Lord, C. Lund, S.C. Maestrini, E. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Miller, J. Minopoli, F. Mirza, G.K. Munson, J. Nelson, S.F. Nygren, G. Oliveira, G. Pagnamenta, A.T. Papanikolaou, K. Parr, J.R. Parrini, B. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Ragoussis, J. Roge, B. Rutter, M.L. Sequeira, A.F. Soorya, L. Sousa, I. Sykes, N. Stoppioni, V. Tancredi, R. Tauber, M. Thompson, A.P. Thomson, S. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Vorstman, J.A.S. Wallace, S. Wang, K. Wassink, T.H. White, K. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Geschwind, D.H. Haines, J.L. Hallmayer, J. Monaco, A.P. Nurnberger Jr., J.I. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vieland, V.J. Wijsman, E.M. Green, A. Gill, M. Gallagher, L. Vicente, A. Ennis, S.

Subjects
mental disorders
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. © The Author(s) 2011.

Published
2012

4. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author

Anney, R.J., Kenny, E.M., O'Dushlaine, C., Parkhomenka, E., Buxbaum, J.D., Sutcliffe, J., Gill, M., Gallagher, L., Bailey, A.J., Fernandez, B.A., Szatmari, P., Nurnberger Jr, J.I., McDougle, C.J., Posey, D.J., Lord, C., Corsello, C., Hus, V., Kolevzon, A., Soorya, L., Parkhomenko, E., Scherer, S.W., Leventhal, B.L., Dawson, G., Vieland, V.J., Hakonarson, H., Glessner, J.T., Kim, C., Wang, K., Schellenberg, G.D., Devlin, B., Klei, L., Patterson, A., Minshew, N., Sutcliffe, J.S., Haines, J.L., Lund, S.C., Thomson, S., Yaspan, B.L., Coon, H., Miller, J., McMahon, W.M., Munson, J., Marshall, C.R., Estes, A., Wijsman, EM., The Autism Genome Project, Pinto, D., Vincent, J.B., Fombonne, E., Betancur, C., Delorme, R., Leboyer, M., Bourgeron, T., Mantoulan, C., Roge, B., Tauber, M., Freitag, C.M., Poustka, F., Duketis, E., Klauck, S.M., Poustka, A., Papanikolaou, K., Tsiantis, J., Anney, R., Bolshakova, N., Brennan, S., Hughes, G., McGrath, J., Merikangas, A., Ennis, S., Green, A., Casey, J.P., Conroy, J.M., Regan, R., Shah, N., Maestrini, E., Bacchelli, E., Minopoli, F., Stoppioni, V., Battaglia, A., Igliozzi, R., Parrini, B., Tancredi, R., Oliveira, G., Almeida, J., Duque, F., Vicente, A.M., Correia, C., Magalhaes, T.R., Gillberg, C., Nygren, G., Jonge, M.D., Van Engeland, H., Vorstman, J.A., Wittemeyer, K., Baird, G., Bolton, P.F, Rutter, M.L., Green, J., Lamb, J.A., Pickles, A., Parr, J.R., Couteur, A.L., Berney, T., McConachie, H., Wallace, S., Coutanche, M., Foley, S., White, K., Monaco, A.P., Holt, R., Farrar, P., Pagnamenta, A.T., Mirza, G.K., Ragoussis, J., Sousa, I., Sykes, N., Wing, K., Hallmayer, J., Cantor, R.M., Nelson, S.F., Geschwind, D.H., Abrahams, B.S., Volkmar, F., Pericak-Vance, M.A., Cuccaro, M.L., Gilbert, J., Cook, E.H., Guter, S.J., and Jacob, S.

Subjects
Pathway analysis, Autism, Perturbações do Desenvolvimento Infantil e Saúde Mental, Gene ontology, Genome-wide association analysis, Family-based association test
Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.

Published
2011

5. Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders

Author

Anney, R.J.L. Kenny, E.M. O'Dushlaine, C. Yaspan, B.L. Parkhomenka, E. Buxbaum, J.D. Sutcliffe, J. Gill, M. Gallagher, L. Bailey, A.J. Fernandez, B.A. Szatmari, P. Scherer, S.W. Patterson, A. Marshall, C.R. Pinto, D. Vincent, J.B. Fombonne, E. Betancur, C. Delorme, R. Leboyer, M. Bourgeron, T. Mantoulan, C. Roge, B. Tauber, M. Freitag, C.M. Poustka, F. Duketis, E. Klauck, S.M. Poustka, A. Papanikolaou, K. Tsiantis, J. Bolshakova, N. Brennan, S. Hughes, G. McGrath, J. Merikangas, A. Ennis, S. Green, A. Casey, J.P. Conroy, J.M. Regan, R. Shah, N. Maestrini, E. Bacchelli, E. Minopoli, F. Stoppioni, V. Battaglia, A. Igliozzi, R. Parrini, B. Tancredi, R. Oliveira, G. Almeida, J. Duque, F. Vicente, A. Correia, C. Magalhaes, T.R. Gillberg, C. Nygren, G. De Jonge, M. Van Engeland, H. Vorstman, J.A.S. Wittemeyer, K. Baird, G. Bolton, P.F. Rutter, M.L. Green, J. Lamb, J.A. Pickles, A. Parr, J.R. Le Couteur, A. Berney, T. McConachie, H. Wallace, S. Coutanche, M. Foley, S. White, K. Monaco, A.P. Holt, R. Farrar, P. Pagnamenta, A.T. Mirza, G.K. Ragoussis, J. Sousa, I. Sykes, N. Wing, K. Hallmayer, J. Cantor, R.M. Nelson, S.F. Geschwind, D.H. Abrahams, B.S. Volkmar, F. Pericak-Vance, M.A. Cuccaro, M.L. Gilbert, J. Cook, E.H. Guter, S.J. Jacob, S. Nurnberger, J.I., Jr. McDougle, C.J. Posey, D.J. Lord, C. Corsello, C. Hus, V. Kolevzon, A. Soorya, L. Parkhomenko, E. Leventhal, B.L. Dawson, G. Vieland, V.J. Hakonarson, H. Glessner, J.T. Kim, C. Wang, K. Schellenberg, G.D. Devlin, B. Klei, L. Minshew, N. Sutcliffe, J.S. Haines, J.L. Lund, S.C. Thomson, S. Coon, H. Miller, J. McMahon, W.M. Munson, J. Estes, A. Wijsman, E.M. Autism Genome Project

Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings. © 2011 Macmillan Publishers Limited All rights reserved.

Published
2011

6. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, R. Klei, L. Pinto, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Sykes, N. Pagnamenta, A.T. Almeida, J. Bacchelli, E. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Carson, A.R. Casallo, G. Casey, J. Chu, S.H. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Dawson, G. de Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Melhem, N.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Wing, K. Wittemeyer, K. Wood, S. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Betancur, C. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Miller, J. Monaco, A.P. Nurnberger Jr., J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Scherer, S.W. Sutcliffe, J.S. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Devlin, B. Ennis, S. Hallmayer, J.

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 3 10-28. 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 × 10-28 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. © The Author 2010. Published by Oxford University Press. All rights reserved.

Published
2010

7. Functional impact of global rare copy number variation in autism spectrum disorders

Author

Pinto, D. Pagnamenta, A.T. Klei, L. Anney, R. Merico, D. Regan, R. Conroy, J. Magalhaes, T.R. Correia, C. Abrahams, B.S. Almeida, J. Bacchelli, E. Bader, G.D. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Bolshakova, N. Bölte, S. Bolton, P.F. Bourgeron, T. Brennan, S. Brian, J. Bryson, S.E. Carson, A.R. Casallo, G. Casey, J. Chung, B.H.Y. Cochrane, L. Corsello, C. Crawford, E.L. Crossett, A. Cytrynbaum, C. Dawson, G. De Jonge, M. Delorme, R. Drmic, I. Duketis, E. Duque, F. Estes, A. Farrar, P. Fernandez, B.A. Folstein, S.E. Fombonne, E. Freitag, C.M. Gilbert, J. Gillberg, C. Glessner, J.T. Goldberg, J. Green, A. Green, J. Guter, S.J. Hakonarson, H. Heron, E.A. Hill, M. Holt, R. Howe, J.L. Hughes, G. Hus, V. Igliozzi, R. Kim, C. Klauck, S.M. Kolevzon, A. Korvatska, O. Kustanovich, V. Lajonchere, C.M. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventhal, B.L. Lionel, A.C. Liu, X.-Q. Lord, C. Lotspeich, L. Lund, S.C. Maestrini, E. Mahoney, W. Mantoulan, C. Marshall, C.R. McConachie, H. McDougle, C.J. McGrath, J. McMahon, W.M. Merikangas, A. Migita, O. Minshew, N.J. Mirza, G.K. Munson, J. Nelson, S.F. Noakes, C. Noor, A. Nygren, G. Oliveira, G. Papanikolaou, K. Parr, J.R. Parrini, B. Paton, T. Pickles, A. Pilorge, M. Piven, J. Ponting, C.P. Posey, D.J. Poustka, A. Poustka, F. Prasad, A. Ragoussis, J. Renshaw, K. Rickaby, J. Roberts, W. Roeder, K. Roge, B. Rutter, M.L. Bierut, L.J. Rice, J.P. Salt, J. Sansom, K. Sato, D. Segurado, R. Sequeira, A.F. Senman, L. Shah, N. Sheffield, V.C. Soorya, L. Sousa, I. Stein, O. Sykes, N. Stoppioni, V. Strawbridge, C. Tancredi, R. Tansey, K. Thiruvahindrapduram, B. Thompson, A.P. Thomson, S. Tryfon, A. Tsiantis, J. Van Engeland, H. Vincent, J.B. Volkmar, F. Wallace, S. Wang, K. Wang, Z. Wassink, T.H. Webber, C. Weksberg, R. Wing, K. Wittemeyer, K. Wood, S. Wu, J. Yaspan, B.L. Zurawiecki, D. Zwaigenbaum, L. Buxbaum, J.D. Cantor, R.M. Cook, E.H. Coon, H. Cuccaro, M.L. Devlin, B. Ennis, S. Gallagher, L. Geschwind, D.H. Gill, M. Haines, J.L. Hallmayer, J. Miller, J. Monaco, A.P. Nurnberger Jr, J.I. Paterson, A.D. Pericak-Vance, M.A. Schellenberg, G.D. Szatmari, P. Vicente, A.M. Vieland, V.J. Wijsman, E.M. Scherer, S.W. Sutcliffe, J.S. Betancur, C.

Subjects
mental disorders
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 1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable ( ∼90%)3, the underlying genetic determinants are still largely unknown.Hereweanalysed the genome-wide characteristics of rare (

Published
2010

8. A genome-wide linkage and association scan reveals novel loci for autism

Author

Weiss, L.A. Arking, D.E. Daly, M.J. Chakravarti, A. Brune, C.W. West, K. O'Connor, A. Hilton, G. Tomlinson, R.L. West, A.B. Cook Jr., E.H. Green, T. Chang, S.-C. Gabriel, S. Gates, C. Hanson, E.M. Kirby, A. Korn, J. Kuruvilla, F. McCarroll, S. Morrow, E.M. Neale, B. Purcell, S. Sasanfar, R. Sougnez, C. Stevens, C. Altshuler, D. Gusella, J. Santangelo, S.L. Sklar, P. Tanzi, R. Anney, R. Bailey, A.J. Baird, G. Battaglia, A. Berney, T. Betancur, C. Bölte, S. Bolton, P.F. Brian, J. Bryson, S.E. Buxbaum, J.D. Cabrito, I. Cai, G. Cantor, R.M. Coon, H. Conroy, J. Correia, C. Corsello, C. Crawford, E.L. Cuccaro, M.L. Dawson, G. De Jonge, M. Devlin, B. Duketis, E. Ennis, S. Estes, A. Farrar, P. Fombonne, E. Freitag, C.M. Gallagher, L. Geschwind, D.H. Gilbert, J. Gill, M. Gillberg, C. Goldberg, J. Green, A. Green, J. Guter, S.J. Haines, J.L. Hallmayer, J.F. Hus, V. Klauck, S.M. Korvatska, O. Lamb, J.A. Laskawiec, M. Leboyer, M. Le Couteur, A. Leventha, B.L. Liu, X.-Q. Lord, C. Lotspeich, L.J. Maestrini, E. Magalhaes, T. Mahoney, W. Mantoulan, C. McConachie, H. McDougle, C.J. McMahon, W.M. Marshall, C.R. Miller, J. Minshew, N.J. Monaco, A.P. Munson, J. Nurnberger Jr., J.I. Oliveira, G. Pagnamenta, A. Papanikolaou, K. Parr, J.R. Paterson, A.D. Pericak-Vance, M.A. Pickles, A. Pinto, D. Piven, J. Posey, D.J. Poustka, A. Poustka, F. Regan, R. Reichert, J. Renshaw, K. Roberts, W. Roge, B. Rutter, M.L. Salt, J. Schellenberg, G.D. Scherer, S.W. Sheffield, V. Sutcliffe, J.S. Szatmari, P. Tansey, K. Thompson, A.P. Tsiantis, J. Van Engeland, H. Vicente, A.M. Vieland, V.J. Volkmar, F. Wallace, S. Wassink, T.H. Wijsman, E.M. Wing, K. Wittemeyer, K. Yaspan, B.L. Zwaigenbaum, L. Yoo, S.-Y. Hill, R.S. Mukaddes, N.M. Balkhy, S. Gascon, G. Al-Saad, S. Hashmi, A. Ware, J. Joseph, R.M. LeClair, E. Partlow, J.N. Barry, B. Walsh, C.A. Pauls, D. Moilanen, I. Ebeling, H. Mattila, M.-L. Kuusikko, S. Jussila, K. Ignatius, J. Tolouei, A. Ghadami, M. Rostami, M. Hosseinipour, A. Valujerdi, M. Andresen, K. Winkloski, B. Haddad, S. Kunkel, L. Kohane, Z. Tran, T. Won Kong, S. O'Neil, S.B. Hundley, R. Holm, I. Peters, H. Baroni, E. Cangialose, A. Jackson, L. Albers, L. Becker, R. Bridgemohan, C. Friedman, S. Munir, K. Nazir, R. Palfrey, J. Schonwald, A. Simmons, E. Rappaport, L.A. Gauthier, J. Mottron, L. Joober, R. Rouleau, G. Rehnstrom, K. Von Wendt, L. Peltonen, L.

Abstract

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Published
2009

9. Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Author

Szatmari, P, Paterson, AD, Zwaigenbaum, L, Roberts, W, Brian, J, Liu, XQ, Vincent, JB, Skaug, JL, Thompson, AP, Senman, L, Feuk, L, Qian, C, Bryson, SE, Jones, MB, Marshall, CR, Scherer, SW, Vieland, VJ, Bartlett, C, Mangin, LV, Goedken, R, Segre, A, Pericak-Vance, MA, Cuccaro, ML, Gilbert, JR, Wright, HH, Abramson, RK, Betancur, C, Bourgeron, T, Gillberg, C, Leboyer, M, Buxbaum, JD, Davis, KL, Hollander, E, Silverman, JM, Hallmayer, J, Lotspeich, L, Sutcliffe, JS, Haines, JL, Folstein, SE, Piven, J, Wassink, TH, Sheffield, V, Geschwind, DH, Bucan, M, Brown, WT, Cantor, RM, Constantino, JN, Gilliam, TC, Herbert, M, LaJonchere, C, Ledbetter, DH, Lese-Martin, C, Miller, J, Nelson, S, Samango-Sprouse, CA, Spence, S, State, M, Tanzi, RE, Coon, H, Dawson, G, Devlin, B, Estes, A, Flodman, P, Klei, L, McMahon, WM, Minshew, N, Munson, J, Korvatska, E, Rodier, PM, Schellenberg, GD, Smith, M, Spence, MA, Stodgell, C, Tepper, PG, Wijsman, EM, Yu, CE, Rogé, B, Mantoulan, C, Wittemeyer, K, Poustka, A, Felder, B, Klauck, SM, Schuster, C, Poustka, F, Bölte, S, Feineis-Matthews, S, Herbrecht, E, Schmötzer, G, Tsiantis, J, Papanikolaou, K, Maestrini, E, and Bacchelli, E

Subjects
mental disorders
Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs. © 2007 Nature Publishing Group.

Published
2007

10. Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Author

Szatmari, P. Paterson, A.D. Zwaigenbaum, L. Roberts, W. Brian, J. Liu, X.-Q. Vincent, J.B. Skaug, J.L. Thompson, A.P. Senman, L. Feuk, L. Qian, C. Bryson, S.E. Jones, M.B. Marshall, C.R. Scherer, S.W. Vieland, V.J. Bartlett, C. Mangin, L.V. Goedken, R. Segre, A. Pericak-Vance, M.A. Cuccaro, M.L. Gilbert, J.R. Wright, H.H. Abramson, R.K. Betancur, C. Bourgeron, T. Gillberg, C. Leboyer, M. Buxbaum, J.D. Davis, K.L. Hollander, E. Silverman, J.M. Hallmayer, J. Lotspeich, L. Sutcliffe, J.S. Haines, J.L. Folstein, S.E. Piven, J. Wassink, T.H. Sheffield, V. Geschwind, D.H. Bucan, M. Brown, W.T. Cantor, R.M. Constantino, J.N. Gilliam, T.C. Herbert, M. LaJonchere, C. Ledbetter, D.H. Lese-Martin, C. Miller, J. Nelson, S. Samango-Sprouse, C.A. Spence, S. State, M. Tanzi, R.E. Coon, H. Dawson, G. Devlin, B. Estes, A. Flodman, P. Klei, L. McMahon, W.M. Minshew, N. Munson, J. Korvatska, E. Rodier, P.M. Schellenberg, G.D. Smith, M. Spence, M.A. Stodgell, C. Tepper, P.G. Wijsman, E.M. Yu, C.-E. Rogé, B. Mantoulan, C. Wittemeyer, K. Poustka, A. Felder, B. Klauck, S.M. Schuster, C. Poustka, F. Bölte, S. Feineis-Matthews, S. Herbrecht, E. Schmötzer, G. Tsiantis, J. Papanikolaou, K. Maestrini, E. Bacchelli, E. Blasi, F. Carone, S. Toma, C. Van Engeland, H. De Jonge, M. Kemner, C. Koop, F. Langemeijer, M. Hijimans, C. Staal, W.G. Baird, G. Bolton, P.F. Rutter, M.L. Weisblatt, E. Green, J. Aldred, C. Wilkinson, J.-A. Pickles, A. Le Couteur, A. Berney, T. McConachie, H. Bailey, A.J. Francis, K. Honeyman, G. Hutchinson, A. Parr, J.R. Wallace, S. Monaco, A.P. Barnby, G. Kobayashi, K. Lamb, J.A. Sousa, I. Sykes, N. Cook, E.H. Guter, S.J. Leventhal, B.L. Salt, J. Lord, C. Corsello, C. Hus, V. Weeks, D.E. Volkmar, F. Tauber, M. Fombonne, E. Shih, A.

Subjects
mental disorders
Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs. © 2007 Nature Publishing Group.

Published
2007

11. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author

Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., Vorstman, J., Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, Sven, Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Casey, J., Conroy, J., Correia, C., Corsello, C., Crawford, E., De jonge, M., Delorme, R., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Gilbert, J., Gillberg, C., Glessner, J., Green, A., Green, J., Guter, S., Heron, E., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Jacob, S., Kenny, G., Kim, C., Kolevzon, A., Kustanovich, V., Lajonchere, C., Lamb, J., Law-Smith, M., Leboyer, M., Le couteur, A., Leventhal, B., Liu, X., Lombard, F., Lord, C., Lotspeich, L., Lund, S., Magalhaes, T., Mantoulan, C., McDougle, C., Melhem, N., Merikangas, A., Minshew, N., Mirza, G., Munson, J., Noakes, C., Nygren, G., Papanikolaou, K., Pagnamenta, A., Parrini, B., Paton, T., Pickles, A., Posey, D., Poustka, F., Ragoussis, J., Regan, R., Roberts, W., Roeder, K., Roge, B., Rutter, M., Schlitt, S., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stoppioni, V., Sykes, N., Tancredi, R., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., and Vorstman, J.

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.

Published
2012

12. Early developmental regression in autism spectrum disorder: Evidence from an international multiplex sample

Author

Parr, J., Le Couteur, A., Baird, G., Rutter, M., Pickles, A., Fombonne, E., Bailey, A., Wallace, S., Wittemeyer, K., Monaco, A., Barnby, G., Bolton, P., Moore, J., Murin, M., McConachie, H., Berney, T., Docherty, Z., Abbs, S., Ogilvie, C., Warburton, P., Lamb, J., Green, J., Bolton, B., Packer, R., Haracopos, D., Pedersen, L., Isager, T., Brondum-Nielsen, K., Roge, B., Tauber, M., Mantoulan, C., Poustka, F., Bölte, Sven, Feineis-Matthews, S., Rühl, D., Schmötzer, G., Poustka, A., Klauck, S., Tsiantis, J., Papanikolaou, K., Maestrini, E., Van Engeland, H., De Jonge, M., Lord, C., Corsello, C., Cook, E., Salt, J., Guter, S., Leventhal, B., Volkmar, F., Koenig, K., Parr, J., Le Couteur, A., Baird, G., Rutter, M., Pickles, A., Fombonne, E., Bailey, A., Wallace, S., Wittemeyer, K., Monaco, A., Barnby, G., Bolton, P., Moore, J., Murin, M., McConachie, H., Berney, T., Docherty, Z., Abbs, S., Ogilvie, C., Warburton, P., Lamb, J., Green, J., Bolton, B., Packer, R., Haracopos, D., Pedersen, L., Isager, T., Brondum-Nielsen, K., Roge, B., Tauber, M., Mantoulan, C., Poustka, F., Bölte, Sven, Feineis-Matthews, S., Rühl, D., Schmötzer, G., Poustka, A., Klauck, S., Tsiantis, J., Papanikolaou, K., Maestrini, E., Van Engeland, H., De Jonge, M., Lord, C., Corsello, C., Cook, E., Salt, J., Guter, S., Leventhal, B., Volkmar, F., and Koenig, K.

Abstract

The characteristics of early developmental regression (EDR) were investigated in individuals with ASD from affected relative pairs recruited to the International Molecular Genetic Study of Autism Consortium (IMGSAC). Four hundred and fifty-eight individuals with ASD were recruited from 226 IMGSAC families. Regression before age 36 months occurred in 23.9% of individuals. The observed concordance rate for EDR within sibling pairs (18.9%) was not significantly above the rate expected under independence (13.5%, p = 0.10). The rate of regression in individuals with ASD from multiplex families was similar to that reported in singleton and epidemiological samples. Regression concordance data were not supportive of a separate familial influence on EDR, other than as a part of autism itself. © Springer Science+Business Media, LLC 2010.

Published
2011

14. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, R., primary, Klei, L., additional, Pinto, D., additional, Regan, R., additional, Conroy, J., additional, Magalhaes, T. R., additional, Correia, C., additional, Abrahams, B. S., additional, Sykes, N., additional, Pagnamenta, A. T., additional, Almeida, J., additional, Bacchelli, E., additional, Bailey, A. J., additional, Baird, G., additional, Battaglia, A., additional, Berney, T., additional, Bolshakova, N., additional, Bolte, S., additional, Bolton, P. F., additional, Bourgeron, T., additional, Brennan, S., additional, Brian, J., additional, Carson, A. R., additional, Casallo, G., additional, Casey, J., additional, Chu, S. H., additional, Cochrane, L., additional, Corsello, C., additional, Crawford, E. L., additional, Crossett, A., additional, Dawson, G., additional, de Jonge, M., additional, Delorme, R., additional, Drmic, I., additional, Duketis, E., additional, Duque, F., additional, Estes, A., additional, Farrar, P., additional, Fernandez, B. A., additional, Folstein, S. E., additional, Fombonne, E., additional, Freitag, C. M., additional, Gilbert, J., additional, Gillberg, C., additional, Glessner, J. T., additional, Goldberg, J., additional, Green, J., additional, Guter, S. J., additional, Hakonarson, H., additional, Heron, E. A., additional, Hill, M., additional, Holt, R., additional, Howe, J. L., additional, Hughes, G., additional, Hus, V., additional, Igliozzi, R., additional, Kim, C., additional, Klauck, S. M., additional, Kolevzon, A., additional, Korvatska, O., additional, Kustanovich, V., additional, Lajonchere, C. M., additional, Lamb, J. A., additional, Laskawiec, M., additional, Leboyer, M., additional, Le Couteur, A., additional, Leventhal, B. L., additional, Lionel, A. C., additional, Liu, X.-Q., additional, Lord, C., additional, Lotspeich, L., additional, Lund, S. C., additional, Maestrini, E., additional, Mahoney, W., additional, Mantoulan, C., additional, Marshall, C. R., additional, McConachie, H., additional, McDougle, C. J., additional, McGrath, J., additional, McMahon, W. M., additional, Melhem, N. M., additional, Merikangas, A., additional, Migita, O., additional, Minshew, N. J., additional, Mirza, G. K., additional, Munson, J., additional, Nelson, S. F., additional, Noakes, C., additional, Noor, A., additional, Nygren, G., additional, Oliveira, G., additional, Papanikolaou, K., additional, Parr, J. R., additional, Parrini, B., additional, Paton, T., additional, Pickles, A., additional, Piven, J., additional, Posey, D. J., additional, Poustka, A., additional, Poustka, F., additional, Prasad, A., additional, Ragoussis, J., additional, Renshaw, K., additional, Rickaby, J., additional, Roberts, W., additional, Roeder, K., additional, Roge, B., additional, Rutter, M. L., additional, Bierut, L. J., additional, Rice, J. P., additional, Salt, J., additional, Sansom, K., additional, Sato, D., additional, Segurado, R., additional, Senman, L., additional, Shah, N., additional, Sheffield, V. C., additional, Soorya, L., additional, Sousa, I., additional, Stoppioni, V., additional, Strawbridge, C., additional, Tancredi, R., additional, Tansey, K., additional, Thiruvahindrapduram, B., additional, Thompson, A. P., additional, Thomson, S., additional, Tryfon, A., additional, Tsiantis, J., additional, Van Engeland, H., additional, Vincent, J. B., additional, Volkmar, F., additional, Wallace, S., additional, Wang, K., additional, Wang, Z., additional, Wassink, T. H., additional, Wing, K., additional, Wittemeyer, K., additional, Wood, S., additional, Yaspan, B. L., additional, Zurawiecki, D., additional, Zwaigenbaum, L., additional, Betancur, C., additional, Buxbaum, J. D., additional, Cantor, R. M., additional, Cook, E. H., additional, Coon, H., additional, Cuccaro, M. L., additional, Gallagher, L., additional, Geschwind, D. H., additional, Gill, M., additional, Haines, J. L., additional, Miller, J., additional, Monaco, A. P., additional, Nurnberger, J. I., additional, Paterson, A. D., additional, Pericak-Vance, M. A., additional, Schellenberg, G. D., additional, Scherer, S. W., additional, Sutcliffe, J. S., additional, Szatmari, P., additional, Vicente, A. M., additional, Vieland, V. J., additional, Wijsman, E. M., additional, Devlin, B., additional, Ennis, S., additional, and Hallmayer, J., additional

Published
2010
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16. Individual common variants exert weak effects on the risk for autism spectrum disorderspi

Author

Naisha Shah, William M. McMahon, Barbara Parrini, Jeremy R. Parr, Thomas Bourgeron, Vanessa Hus, Gudrun Nygren, Sabine M. Klauck, John B. Vincent, Nadine M. Melhem, Jillian P. Casey, Christina Corsello, Jonathan L. Haines, Andrew D. Paterson, Raffaella Tancredi, Alistair T. Pagnamenta, Jonathan Green, Richard Delorme, Geraldine Dawson, Andrew Pickles, Carine Mantoulan, Alexander Kolevzon, Bridget A. Fernandez, Frederico Duque, Inês Sousa, Tara Paton, Kathryn Roeder, Joana Almeida, Richard Anney, Margaret A. Pericak-Vance, Joachim Hallmayer, Gerard D. Schellenberg, Sabata C. Lund, Rita M. Cantor, Daniel H. Geschwind, Janine A. Lamb, Annette Estes, Sven Bölte, Hakon Hakonarson, Gillian Hughes, Gillian Baird, John I. Nurnberger, Jessica Brian, Bernie Devlin, Roberta Igliozzi, Vera Stoppioni, Jiannis Ragoussis, Peter Szatmari, Ghazala Mirza, Eric Fombonne, Thomas H. Wassink, Emily L. Crawford, Nuala Sykes, Danielle Zurawiecki, Graham Kenny, David J. Posey, Elena Maestrini, Vlad Kustanovich, Elena Bacchelli, Veronica J. Vieland, Stephen W. Scherer, Guiomar Oliveira, Simon Wallace, John R. Gilbert, Latha Soorya, Sean Brennan, Tiago R. Magalhaes, Hilary Coon, Elizabeth A. Heron, Sabine Schlitt, Fritz Poustka, Astrid M. Vicente, Patrick Bolton, Linda Lotspeich, Nancy J. Minshew, Val C. Sheffield, Bennett L. Leventhal, Xiao-Qing Liu, Andrew Green, Joseph D. Buxbaum, Shawn Wood, Susan E. Folstein, Sean Ennis, Catarina Correia, James S. Sutcliffe, Carolyn Noakes, Ann Le Couteur, Marion Leboyer, Ann P. Thompson, Christine M. Freitag, Fred R. Volkmar, Katerina Papanikolaou, Dalila Pinto, Agatino Battaglia, Frances Lombard, Joseph Piven, Maretha de Jonge, Michael Rutter, Clara Lajonchere, Kerstin Wittemeyer, Herman van Engeland, Michael L. Cuccaro, Richard Holt, Lonnie Zwaigenbaum, Louise Gallagher, Jeff Munson, Ana Tryfon, John Tsiantis, Lambertus Klei, Christopher Gillberg, Penny Farrar, Joseph T. Glessner, Ellen M. Wijsman, Anthony P. Monaco, Wendy Roberts, Nadia Bolshakova, Cecilia Kim, Judith Miller, Stephen J. Guter, Susanne Thomson, Catherine Lord, Anthony J. Bailey, Miriam Law-Smith, Michael Gill, Christopher J. McDougle, Bernadette Rogé, Alison K. Merikangas, Jacob A. S. Vorstman, Suma Jacob, Judith Conroy, Kirsty Wing, Regina Regan, Jennifer L. Howe, Stanley F. Nelson, Edwin H. Cook, Catalina Betancur, Eftichia Duketis, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The Centre for Applied Genomics, Toronto, University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Newcomen Centre, Guy's Hospital [London], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Child and Adolescent Psychiatry, Institute of psychiatry, Molecular and Cellular Neurobiology, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Psychiatry, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Speech and Hearing Sciences [Washington], University of Washington [Seattle], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], University of Miami School of Medicine, John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Research Unit on Children's Psychosocial Maladjustment, Université Laval [Québec] (ULaval)-Department of Psychology, University of Gothenburg (GU), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Manchester Academic Health Sciences Centre, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Autism Genetic Resource Exchange, Autism Speaks, Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Centre de Référence du Syndrome de Prader-Willi, CHU Toulouse [Toulouse], Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Psychiatry and Behavioral Sciences, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Social, Genetic and Developmental Psychiatry Centre, Department of Pediatrics, University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Neuropsichiatria Infantile, Ospedale Santa Croce, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, University of Toronto, Child Study Centre, Yale University School of Medicine, University of Oxford [Oxford]-Warneford Hospital, University of Alberta, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), The Institute of Psychiatry-King‘s College London, Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California-University of California [Los Angeles] (UCLA), University of California-University of California, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Carolina Institute for Developmental Disabilities, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Stanford School of Medicine [Stanford], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Children’s Hospital of Philadelphia (CHOP )-Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Yale School of Medicine [New Haven, Connecticut] (YSM), King‘s College London-The Institute of Psychiatry, University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu XQ, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman J, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI Jr, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, Devlin B, University of Oxford, Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Oxford-Warneford Hospital, University of Pennsylvania, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Betancur, Catalina, and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
Male, CNTNAP2, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Nerve Tissue Proteins, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Language Development, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, autism spectrum disorders (ASDs), Gene Frequency, Risk Factors, mental disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Allele, GENOME-WIDE ASSOCIATION, Child, Molecular Biology, Allele frequency, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Association Studies Articles, Membrane Proteins, General Medicine, medicine.disease, Genetic architecture, Child Development Disorders, Pervasive, common variant, Perturbações do Desenvolvimento Infantil e Saúde Mental, Autism, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

International audience; 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.

Published
2012

17. A genome-wide scan for common alleles affecting risk for autism

Author

Veronica J. Vieland, Stephen W. Scherer, Elizabeth A. Heron, Barbara Parrini, Jeremy R. Parr, Louise Gallagher, Jeff Munson, Annemarie Poustka, Susan E. Folstein, Irene Drmic, Gudrun Nygren, John P. Rice, Jeff Salt, Simon Wallace, Geraldine Dawson, Daniel H. Geschwind, Annette Estes, Sean Brennan, Alistair T. Pagnamenta, Nancy J. Minshew, Christina Corsello, Jonathan Green, William M. McMahon, Christopher Gillberg, Kathryn Roeder, Lambertus Klei, Anath C. Lionel, Bridget A. Fernandez, Thomas Bourgeron, Ellen M. Wijsman, Gerard D. Schellenberg, Wendy Roberts, Jeremy Goldberg, Frederico Duque, Ghazala Mirza, Sean Ennis, Joana Almeida, Nadine M. Melhem, Jillian P. Casey, Roberta Igliozzi, Ricardo Segurado, Carine Mantoulan, Katy Renshaw, Kai Wang, Andrew D. Paterson, Raffaella Tancredi, Matthew Nicholas Hill, Richard Anney, Christian R. Marshall, Anthony P. Monaco, Linda Lotspeich, Marion Leboyer, Richard Holt, Andrew Pickles, Vlad Kustanovich, William M. Mahoney, Jessica Brian, Inês Sousa, Peter Szatmari, Vanessa Hus, Janine A. Lamb, Hakon Hakonarson, Lonnie Zwaigenbaum, John Tsiantis, David J. Posey, Olena Korvatska, Guillermo Casallo, Rita M. Cantor, Bhooma Thiruvahindrapduram, Nadia Bolshakova, Sven Bölte, Alison K. Merikangas, Brian L. Yaspan, Cecilia Kim, Andrew Crossett, Fritz Poustka, Danielle Zurawiecki, Agatino Battaglia, Sabata C. Lund, Ann P. Thompson, Bennett L. Leventhal, Jessica Rickaby, Zhouzhi Wang, John I. Nurnberger, Astrid M. Vicente, Maretha de Jonge, Tiago R. Magalhaes, Michael L. Cuccaro, Val C. Sheffield, Nuala Sykes, Elena Maestrini, Guiomar Oliveira, Joseph D. Buxbaum, Fred R. Volkmar, Shawn Wood, Magdalena Laskawiec, Katherine Sansom, Herman van Engeland, Jane McGrath, Thomas H. Wassink, Su H. Chu, Elena Bacchelli, Carolyn Noakes, Ann Le Couteur, Catarina Correia, Ohsuke Migita, Bernie Devlin, Hilary Coon, Gillian Baird, Joseph Piven, Tom Berney, Ana Tryfon, Abdul Noor, Patrick Bolton, Latha Soorya, Vera Stoppioni, Stephen J. Guter, Joseph T. Glessner, Michael Gill, Christopher J. McDougle, Anthony J. Bailey, Margaret A. Pericak-Vance, Joachim Hallmayer, Christine M. Freitag, Penny Farrar, Kirsty Wing, Katherine E. Tansey, Bernadette Rogé, Michael Rutter, Christina Strawbridge, Brett S. Abrahams, Kerstin Wittemeyer, Laura J. Bierut, Tara Paton, Emily L. Crawford, Jonathan L. Haines, Alexander Kolevzon, Gillian Hughes, Lili Senman, James S. Sutcliffe, John B. Gilbert, Katerina Papanikolaou, Andrew R. Carson, Lynne E Cochrane, Regina Regan, Judith Miller, Susanne Thomson, Helen McConachie, Daisuke Sato, Richard Delorme, Jiannis Ragoussis, Eric Fombonne, Clara Lajonchere, Judith Conroy, Dalila Pinto, Aparna Prasad, Naisha Shah, Stanley F. Nelson, Sabine M. Klauck, Catalina Betancur, John B. Vincent, Eftichia Duketis, Jennifer L. Howe, Edwin H. Cook, Xiao-Qing Liu, Catherine Lord, Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Department of Neurology, University of California [Los Angeles] (UCLA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry, University of Oxford [Oxford]-Warneford Hospital, Newcomen Centre, Guy's Hospital [London], Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Child and Adolescent Mental Health, Newcastle University [Newcastle], Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Child and Adolescent Psychiatry, Institute of psychiatry, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Autism Research Unit, University of Toronto-The Hospital for sick children [Toronto] (SickKids), Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Scientific Affairs, Autism Speaks, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Speech and Hearing Sciences [Washington], University of Washington [Seattle], Disciplines of Genetics and Medicine, Memorial University of Newfoundland [St. John's], John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), University of Gothenburg (GU), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario], Manchester Academic Health Sciences Centre, Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Department of Medicine, Autism Genetic Resource Exchange, Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nathan Kline Institute for Psychiatric Research (NKI), Nathan Kline Institute for Psychiatric Research, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU)-NYU Child Study Center, Centre d'Etudes et de Recherches en PsychoPathologie, Université Toulouse - Jean Jaurès (UT2J), Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Departments of Psychiatry and Neurology, Department of Psychiatry and Behavioral Sciences, Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), Centre for Addiction and Mental Health, Clarke Institute, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Institutes of Neuroscience and Health and Society, Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Carolina Institute for Developmental Disabilities, Social, Genetic and Developmental Psychiatry Centre, Washington University in Saint Louis (WUSTL), Howard Hughes Medical-Institute Carver College of Medicine-University of Iowa [Iowa City], Neuropsichiatria Infantile, Ospedale Santa Croce, Child Study Centre, Yale University School of Medicine, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], University of Alberta, Physiopathologie des Maladies du Système Nerveux Central, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Departments of Biostatistics and Medicine, This research was primarily supported by Autism Speaks (USA), the Health Research Board (HRB, Ireland), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health [HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH057881, MH061009, MH06359, MH066673, MH077930, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261], the Canadian Institutes for Health Research (CIHR), Assistance Publique-Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant: Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), GlaxoSmithKline-CIHR Pathfinder Chair (Canada), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health [convention 181 of 19.10.2001], the John P Hussman Foundation (USA), McLaughlin Centre (Canada), Netherlands Organization for Scientific Research [Rubicon 825.06.031], Ontario Ministry of Research and Innovation (Canada), Royal Netherlands Academy of Arts and Sciences [TMF/DA/5801], the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award [075491/Z/04 UK]. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004422)., University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Yale School of Medicine [New Haven, Connecticut] (YSM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of Oxford-Warneford Hospital, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), Université de Toulouse (UT)-Université de Toulouse (UT), University of Pennsylvania, Betancur, Catalina, Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, and Hallmayer J.

Subjects
Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Genotype, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Databases, Genetic, Copy-number variation, MESH: Genetic Variation, Genetics (clinical), MESH: Databases, Genetic, Genetics, 0303 health sciences, education.field_of_study, MESH: Polymorphism, Single Nucleotide, Association Studies Articles, MESH: Genetic Predisposition to Disease, General Medicine, MESH: European Continental Ancestry Group, Autism spectrum disorders, MESH: DNA Copy Number Variations, Genotyping, DNA Copy Number Variations, Genotype, Population, MESH: Autistic Disorder, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Genetic variation, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Autistic Disorder, SNP association, education, Molecular Biology, Alleles, MESH: Genome, Human, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genome, Human, MESH: Alleles, Haplotype, Genetic Variation, Genetic architecture, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, 030217 neurology & neurosurgery, Genome-Wide Association Study
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. Author has checked copyright TS 14.06.13 The subscript characters from the abstract have not copied across properly. TS

Published
2010

18. A genome-wide linkage and association scan reveals novel loci for autism

Author

Zak Kohane, Jeremy Goldberg, Carine Mantoulan, Shaun Purcell, Jessica Brian, Magdalena Laskawiec, Christopher A. Walsh, Irma Moilanen, Ridha Joober, Peter Szatmari, Olena Korvatska, Kerim Munir, James F. Gusella, Rudolph E. Tanzi, David L. Pauls, Generoso G. Gascon, Christine Stevens, Linda Lotspeich, John I. Nurnberger, Ramzi Nazir, Jonathan Green, Brian L. Yaspan, Marion Leboyer, Ann P. Thompson, Shun-Chiao Chang, Carolyn Bridgemohan, Louise Gallagher, Jeff Munson, Michael Gill, Guiqing Cai, Fritz Poustka, Regina Regan, Aislyn Cangialose, Gerard D. Schellenberg, Christopher J. McDougle, Christina Corsello, Wendy Roberts, Thomas H. Wassink, Majid Ghadami, Ellen M. Hanson, Benjamin M. Neale, Stacey Gabriel, Lonnie Zwaigenbaum, John Tsiantis, Hanna Ebeling, Sabine M. Klauck, Elaine LeClair, Bernie Devlin, Steven A. McCarroll, Ashley O'Connor, Andrew Pickles, Emily L. Crawford, Katja Jussila, Helen McConachie, Christopher Gillberg, Brenda E. Barry, Lou Kunkel, Seung Yun Yoo, Jennifer N. Partlow, Stephanie Brewster O'Neil, Ingrid A. Holm, Judith Miller, Guy A. Rouleau, Val C. Sheffield, Catherine Lord, Judith S. Palfrey, Ellen M. Wijsman, Astrid M. Vicente, Azam Hosseinipour, Ronald E. Becker, James S. Sutcliffe, Fred R. Volkmar, Marja Leena Mattila, Katerina Papanikolaou, Jennifer Reichert, Edwin H. Cook, Pamela Sklar, Elena Maestrini, Hilary Coon, Sek Won Kong, Stephen A. Haddad, Todd Green, Gillian Baird, Andrew Kirby, Patrick Bolton, Robert Sean Hill, Eric M. Morrow, Tom Berney, Jonathan L. Haines, Maryam Valujerdi, Casey Gates, David J. Posey, Karola Rehnström, Alistair T. Pagnamenta, Christine M. Freitag, Eric Fombonne, Janice Ware, Christian R. Marshall, Janine A. Lamb, Lauren A. Weiss, Agatino Battaglia, Nancy J. Minshew, Roksana Sasanfar, Elizabeth Baroni, Maretha de Jonge, Lennart von Wendt, Gina Hilton, Dalila Pinto, Nahit Motavalli Mukaddes, Ala Tolouei, Catalina Betancur, Michael Rutter, Tram Tran, Eftichia Duketis, Laurent Mottron, Margaret A. Pericak-Vance, Kristen West, Joachim Hallmayer, Kirsty Wing, Kerstin Wittemeyer, Rachel J. Hundley, Herman van Engeland, Judith Conroy, Mark J. Daly, Asif Hashmi, Michael L. Cuccaro, Geraldine Dawson, Sanna Kuusikko, Richard Anney, Anthony P. Monaco, Brian Winkloski, Samira Al-Saad, Dan E. Arking, Veronica J. Vieland, Stephen W. Scherer, Soher Balkhy, Kara Andresen, Rebecca L. Tomlinson, Joseph D. Buxbaum, Aravinda Chakravarti, Xiao-Qing Liu, Lindsay Jackson, Jaakko Ignatius, Catarina Correia, Leonard Rappaport, Heather Peters, Julie Gauthier, John R. Gilbert, Jeremy R. Parr, Carrie Sougnez, Katherine E. Tansey, Bennett L. Leventha, Annemarie Poustka, Daniel H. Geschwind, Annette Estes, Leena Peltonen, Maryam Rostami, Jeff Salt, David Altshuler, Simon Wallace, Susan E. Bryson, William M. Mahoney, Katy Renshaw, Robert M. Joseph, Lisa H. Albers, Inês Cabrito, Sean Ennis, Vanessa Hus, Guiomar Oliveira, Ann Le Couteur, Joseph Piven, Sandra L. Friedman, Penny Farrar, Joshua M. Korn, Sven Bölte, Camille W. Brune, Esau Simmons, Susan L. Santangelo, Andrew D. Paterson, Rita M. Cantor, Andrew B. West, Finny G Kuruvilla, Tiago R. Magalhaes, Andrew Green, Alison Schonwald, Stephen J. Guter, Anthony J. Bailey, Bernadette Rogé, William M. McMahon, Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Johns Hopkins University (JHU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Génétique de l'autisme = Genetics of Autism (NPS-01), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Betancur, Catalina, University of Helsinki, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), WEISS LA, ARKING DE, and GENE DISCOVERY PROJECT OF JOHNS HOPKINS & THE AUTISM CONSORTIUM, DALY MJ, CHAKRAVARTI A, BRUNE CW, WEST K, O'CONNOR A, HILTON G, TOMLINSON RL, WEST AB, COOK EH JR, CHAKRAVARTI A, WEISS LA, GREEN T, CHANG SC, GABRIEL S, GATES C, HANSON EM, KIRBY A, KORN J, KURUVILLA F, MCCARROLL S, MORROW EM, NEALE B, PURCELL S, SASANFAR R, SOUGNEZ C, STEVENS C, ALTSHULER D, GUSELLA J, SANTANGELO SL, SKLAR P, TANZI R, DALY MJ, ANNEY R, BAILEY AJ, BAIRD G, BATTAGLIA A, BERNEY T, BETANCUR C, BÖLTE S, BOLTON PF, BRIAN J, BRYSON SE, BUXBAUM JD, CABRITO I, CAI G, CANTOR RM, COOK EH JR, COON H, CONROY J, CORREIA C, CORSELLO C, CRAWFORD EL, CUCCARO ML, DAWSON G, DE JONGE M, DEVLIN B, DUKETIS E, ENNIS S, ESTES A, FARRAR P, FOMBONNE E, FREITAG CM, GALLAGHER L, GESCHWIND DH, GILBERT J, GILL M, GILLBERG C, GOLDBERG J, GREEN A, GREEN J, GUTER SJ, HAINES JL, HALLMAYER JF, HUS V, KLAUCK SM, KORVATSKA O, LAMB JA, LASKAWIEC M, LEBOYER M, COUTEUR AL, LEVENTHAL BL, LIU XQ, LORD C, LOTSPEICH LJ, MAESTRINI E, MAGALHAES T, MAHONEY W, MANTOULAN C, MCCONACHIE H, MCDOUGLE CJ, MCMAHON WM, MARSHALL CR, MILLER J, MINSHEW NJ, MONACO AP, MUNSON J, NURNBERGER JI JR, OLIVEIRA G, PAGNAMENTA A, PAPANIKOLAOU K, PARR JR, PATERSON AD, PERICAK-VANCE MA, PICKLES A, PINTO D, PIVEN J, POSEY DJ, POUSTKA A, POUSTKA F, REGAN R, REICHERT J, RENSHAW K, ROBERTS W, ROGE B, RUTTER ML, SALT J, SCHELLENBERG GD, SCHERER SW, SHEFFIELD V, SUTCLIFFE JS, SZATMARI P, TANSEY K, THOMPSON AP, TSIANTIS J, VAN ENGELAND H, VICENTE AM, VIELAND VJ, VOLKMAR F, WALLACE S, WASSINK TH, WIJSMAN EM, WING K, WITTEMEYER K, YASPAN BL, ZWAIGENBAUM L, MORROW EM, YOO SY, HILL RS, MUKADDES NM, BALKHY S, GASCON G, AL-SAAD S, HASHMI A, WARE J, JOSEPH RM, LECLAIR E, PARTLOW JN, BARRY B, WALSH CA, PAULS D, MOILANEN I, EBELING H, MATTILA ML, KUUSIKKO S, JUSSILA K, IGNATIUS J, SASANFAR R, TOLOUEI A, GHADAMI M, ROSTAMI M, HOSSEINIPOUR A, VALUJERDI M, SANTANGELO SL, ANDRESEN K, WINKLOSKI B, HADDAD S, KUNKEL L, KOHANE Z, TRAN T, KONG SW, O'NEIL SB, HANSON EM, HUNDLEY R, HOLM I, PETERS H, BARONI E, CANGIALOSE A, JACKSON L, ALBERS L, BECKER R, BRIDGEMOHAN C, FRIEDMAN S, MUNIR K, NAZIR R, PALFREY J, SCHONWALD A, SIMMONS E, RAPPAPORT LA, GAUTHIER J, MOTTRON L, JOOBER R, FOMBONNE E, ROULEAU G, REHNSTROM K, VON WENDT L, PELTONEN L.

Subjects
Perturbação Autística, Internationality, Genetic Linkage, Genome-wide association study, MESH: Semaphorins, Semaphorins, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0302 clinical medicine, Neurodevelopmental disorder, Heritability of autism, MESH: Nerve Tissue Proteins, Association mapping, Genetics, 0303 health sciences, Multidisciplinary, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Brain, Chromosome Mapping, Chromosomes, Human, Pair 5, MESH: Membrane Proteins, MESH: Chromosomes, Human, Pair 5, MESH: Autistic Disorder, MESH: Genetic Linkage, Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, MESH: Brain, Genetic linkage, medicine, Humans, Genetic Predisposition to Disease, Autistic Disorder, MESH: Sample Size, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Membrane Proteins, medicine.disease, Sample Size, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, MESH: Internationality, Autism, MESH: Chromosome Mapping, Predisposição Genética para Doença, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Member of the Autism Genome Project Consortium: Astrid M. Vicente Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Published
2009

19. Mapping autism risk loci using genetic linkage and chromosomal rearrangements

Author

Peter, Szatmari, Andrew D, Paterson, Lonnie, Zwaigenbaum, Wendy, Roberts, Jessica, Brian, Xiao-Qing, Liu, John B, Vincent, Jennifer L, Skaug, Ann P, Thompson, Lili, Senman, Lars, Feuk, Cheng, Qian, Susan E, Bryson, Marshall B, Jones, Christian R, Marshall, Stephen W, Scherer, Veronica J, Vieland, Christopher, Bartlett, La Vonne, Mangin, Rhinda, Goedken, Alberto, Segre, Margaret A, Pericak-Vance, Michael L, Cuccaro, John R, Gilbert, Harry H, Wright, Ruth K, Abramson, Catalina, Betancur, Thomas, Bourgeron, Christopher, Gillberg, Marion, Leboyer, Joseph D, Buxbaum, Kenneth L, Davis, Eric, Hollander, Jeremy M, Silverman, Joachim, Hallmayer, Linda, Lotspeich, James S, Sutcliffe, Jonathan L, Haines, Susan E, Folstein, Joseph, Piven, Thomas H, Wassink, Val, Sheffield, Daniel H, Geschwind, Maja, Bucan, W Ted, Brown, Rita M, Cantor, John N, Constantino, T Conrad, Gilliam, Martha, Herbert, Clara, Lajonchere, David H, Ledbetter, Christa, Lese-Martin, Janet, Miller, Stan, Nelson, Carol A, Samango-Sprouse, Sarah, Spence, Matthew, State, Rudolph E, Tanzi, Hilary, Coon, Geraldine, Dawson, Bernie, Devlin, Annette, Estes, Pamela, Flodman, Lambertus, Klei, William M, McMahon, Nancy, Minshew, Jeff, Munson, Elena, Korvatska, Patricia M, Rodier, Gerard D, Schellenberg, Moyra, Smith, M Anne, Spence, Chris, Stodgell, Ping Guo, Tepper, Ellen M, Wijsman, Chang-En, Yu, Bernadette, Rogé, Carine, Mantoulan, Kerstin, Wittemeyer, Annemarie, Poustka, Bärbel, Felder, Sabine M, Klauck, Claudia, Schuster, Fritz, Poustka, Sven, Bölte, Sabine, Feineis-Matthews, Evelyn, Herbrecht, Gabi, Schmötzer, John, Tsiantis, Katerina, Papanikolaou, Elena, Maestrini, Elena, Bacchelli, Francesca, Blasi, Simona, Carone, Claudio, Toma, Herman, Van Engeland, Maretha, de Jonge, Chantal, Kemner, Frederieke, Koop, Frederike, Koop, Marjolein, Langemeijer, Marjolijn, Langemeijer, Channa, Hijmans, Channa, Hijimans, Wouter G, Staal, Gillian, Baird, Patrick F, Bolton, Michael L, Rutter, Emma, Weisblatt, Jonathan, Green, Catherine, Aldred, Julie-Anne, Wilkinson, Andrew, Pickles, Ann, Le Couteur, Tom, Berney, Helen, McConachie, Anthony J, Bailey, Kostas, Francis, Gemma, Honeyman, Aislinn, Hutchinson, Jeremy R, Parr, Simon, Wallace, Anthony P, Monaco, Gabrielle, Barnby, Kazuhiro, Kobayashi, Janine A, Lamb, Ines, Sousa, Nuala, Sykes, Edwin H, Cook, Stephen J, Guter, Bennett L, Leventhal, Jeff, Salt, Catherine, Lord, Christina, Corsello, Vanessa, Hus, Daniel E, Weeks, Fred, Volkmar, Maïté, Tauber, Eric, Fombonne, Andy, Shih, Kacie J, Meyer, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Centre for Applied Genomics, Toronto, University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Department of Pediatrics, University of Alberta, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, Department of Psychiatry, University of Toronto, Departments of Pediatrics and Psychology, Dalhousie University [Halifax], Department of Neural and Behavioral Sciences, Pennsylvania State University (Penn State), Penn State System-Penn State System, Department of Molecular Genetics [Toronto], Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, Department of Pathology and Laboratory Medicine, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Department of Computer Science, University of Iowa [Iowa City], John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], W.S. Hall Psychiatric Institute, University of South Carolina [Columbia], Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Institute of Child Health, University College of London [London] (UCL), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Neuroscience, PennState Meteorology Department, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Department of Psychiatry and Behavioral Sciences [Stanford], Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Johns Hopkins University (JHU), Carolina Institute for Developmental Disabilities, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], University of Iowa [Iowa City]-Howard Hughes Medical-Institute Carver College of Medicine, Department of Neurology, UCLA School of Medicine, Department of Genetics, University of Pennsylvania [Philadelphia]-School of Medicine, N.Y.S. Institute for Basic Research in Developmental Disabilities, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Washington University in Saint Louis (WUSTL), University of Chicago, Harvard Medical School [Boston] (HMS), Autism Genetic Resource Exchange, Autism Speaks, Emory University [Atlanta, GA], Developmental Brain and Behaviour Unit, University of Southampton, Cure Autism Now, Institute of Human Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, Children's National Medical Center, The George Washington University (GW), Massachusetts General Hospital, Massachusetts General Hospital [Boston], Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris [Pisa], Autism Speaks and the Department of Psychiatry, Department of Speech and Hearing Sciences [Washington], University of Washington [Seattle], University of California [Irvine] (UCI), University of California-University of California, Department of Psychiatry and Behavioral Sciences, Department of OB/GYN, University of Rochester Medical Center, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Department of Epidemiology, University of Pittsburgh (PITT), Departments of Biostatistics and Medicine, Department of Medicine, Octogone Unité de Recherche Interdisciplinaire (Octogone), Université Toulouse - Jean Jaurès (UT2J), Centre de Référence du Syndrome de Prader-Willi, CHU Toulouse [Toulouse], University of Oxford [Oxford]-Warneford Hospital, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, University Department of Child Psychiatry, National and Kapodistrian University of Athens (NKUA), Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Medical Genetics Laboratory, Policlinico S. Orsola-Malpighi, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Department of Neurocognition, Maastricht University [Maastricht], Newcomen Centre, Guy's Hospital [London], Department of Child and Adolescent Psychiatry, Institute of psychiatry, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), The Institute of Psychiatry-King‘s College London, University of Cambridge Clinical School, University of Cambridge [UK] (CAM), Manchester Academic Health Sciences Centre, Department of Medicine, Manchester, University of Manchester [Manchester]-School of Epidemiology and Health Science, Newcastle University [Newcastle]-Institute of Health & Society (Child & Adolescent Psychiatry), Child and Adolescent Mental Health, Newcastle University [Newcastle], Institutes of Neuroscience and Health and Society, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Centre for Integrated Genomic Medical Research, Manchester, University of Manchester [Manchester], Institute for Juvenile Research-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Institute for Juvenile Research, University of Illinois [Chicago] (UIC), Department of Disability and Human Development, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Autism and Communicative Disorders Centre, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Human Genetics Department, SFU Discrete Mathematics Group (SFU-DMG), Simon Fraser University (SFU.ca), Child Study Centre, Yale University School of Medicine, Centre d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Scientific Affairs, Autism Genome Project Consortium, RS: FPN CN II, Cognitive Neuroscience, MUMC+: HZC Klinische Neurofysiologie (5), The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, University of California (UC)-University of California (UC)-Semel Institute, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), King‘s College London-The Institute of Psychiatry, Yale School of Medicine [New Haven, Connecticut] (YSM), Betancur, Catalina, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania-School of Medicine, University of Pennsylvania, Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Oxford-Warneford Hospital, University of Oxford, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT), Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Roge B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bolte S, Feineis-Matthews S, Herbrecht E, Schmotzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijimans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, and Shih A.

Subjects
Male, genetic structures, Genetic Linkage, Neurexin, [SDV.GEN] Life Sciences [q-bio]/Genetics, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Heritability of autism, Copy-number variation, MESH: Genetic Variation, Genetics, 0303 health sciences, medicine.diagnostic_test, MESH: Genetic Testing, MESH: Genetic Predisposition to Disease, Chromosome Mapping, 3. Good health, Female, MESH: Genetic Linkage, MESH: Autistic Disorder, Epigenetics of autism, Biology, Article, 03 medical and health sciences, Genetic linkage, mental disorders, medicine, Humans, MESH: Chromosome Aberrations, Family, Genetic Predisposition to Disease, Genetic Testing, Autistic Disorder, MESH: Family, 030304 developmental biology, Genetic testing, Chromosome Aberrations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genetic Variation, medicine.disease, Genetic architecture, MESH: Male, MESH: Lod Score, Autism, Lod Score, MESH: Chromosome Mapping, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Published
2007

20. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Author

Veronica J. Vieland, Stephen W. Scherer, Alison K. Merikangas, Naisha Shah, Edwin H. Cook, William M. McMahon, Kirsty Wing, Sabata C. Lund, Jacob A. S. Vorstman, Judith Conroy, Sabine M. Klauck, John B. Vincent, Astrid M. Vicente, Carine Mantoulan, Barbara Parrini, Jeremy R. Parr, Herman van Engeland, Jane McGrath, Guiomar Oliveira, Jonathan Green, James S. Sutcliffe, Peter Szatmari, Ann Le Couteur, Katerina Papanikolaou, Joseph Piven, Andrew Pickles, Gillian Baird, Inês Sousa, Gerard D. Schellenberg, Catarina Correia, Bennett L. Leventhal, Helen McConachie, Joseph T. Glessner, Fritz Poustka, Alistair T. Pagnamenta, Marion Leboyer, Nuala Sykes, Elena Maestrini, Penny Farrar, Maïté Tauber, Suzanne Foley, Richard Holt, Lonnie Zwaigenbaum, David J. Posey, John Tsiantis, Alexander Kolevzon, Agatino Battaglia, Maretha de Jonge, Hilary Coon, Gillian Hughes, John R. Gilbert, Patrick Bolton, Louise Gallagher, Jeff Munson, Kathy White, Michael L. Cuccaro, Annemarie Poustka, Daniel H. Geschwind, Richard Delorme, Annette Estes, Christine M. Freitag, Jillian P. Casey, Joana Almeida, Dalila Pinto, Simon Wallace, Sean Brennan, Stephen J. Guter, Stanley F. Nelson, Michael Rutter, Ghazala Mirza, Anthony J. Bailey, Christina Corsello, Kerstin Wittemeyer, Christian R. Marshall, Janine A. Lamb, Catherine Lord, Hakon Hakonarson, Jiannis Ragoussis, Catalina Betancur, Geraldine Dawson, Eftichia Duketis, Sean Ennis, Fiorella Minopoli, Christopher Gillberg, Vera Stoppioni, Bridget A. Fernandez, Frederico Duque, Eric Fombonne, Ellen M. Wijsman, Bernadette Rogé, Vanessa Hus, Susan E. Folstein, Jonathan L. Haines, Denis C. Shields, Tiago R. Magalhaes, Andrew Green, Thomas Bourgeron, Brian L. Yaspan, Ann P. Thompson, Gudrun Nygren, Judith Miller, Susanne Thomson, Roberta Igliozzi, Ana Filipa Sequeira, Kai Wang, Brett S. Abrahams, John I. Nurnberger, Michael Gill, Thomas H. Wassink, Christopher J. McDougle, Marc N. Coutanche, Anthony P. Monaco, Nadia Bolshakova, Cecilia Kim, Raffaella Tancredi, Rita M. Cantor, Phil Cali, Fred R. Volkmar, Tom Berney, Margaret A. Pericak-Vance, Joachim Hallmayer, Joseph D. Buxbaum, Elena Bacchelli, Latha Soorya, Richard Anney, Regina Regan, University of Bologna, Open University of Israël, IRCCS Fondazione Stella Maris [Pisa], Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Goethe-University Frankfurt am Main, Memorial University of Newfoundland [St. John's], McGill University = Université McGill [Montréal, Canada], Johns Hopkins University (JHU), Autism Research Centre and Section of Developmental Psychiatry, University of Cambridge [UK] (CAM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Psychiatrie génétique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mondor de Recherche Biomédicale, The Hospital for sick children [Toronto] (SickKids), University of Toronto, Australian Resources Research Centre, Kensington, Sécurité et Qualité des Produits d'Origine Végétale (SQPOV), Avignon Université (AU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital des Enfants, CHU Toulouse [Toulouse], School of Chemistry, Dalhousie University [Halifax], DLR Institut für Planetenforschung, Deutsches Zentrum für Luft- und Raumfahrt [Berlin] (DLR), Department of Human Genetics, University of Chicago, University of Alberta, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), University of Koblenz-Landau, McMaster University [Hamilton, Ontario], The authors acknowledge the families participating in the study and the main funders of the Autism Genome Project Consortium (AGP): Autism Speaks (USA), the Health Research Board (HRB, Ireland), The Medical Research Council (MRC, UK), Genome Canada/Ontario Genomics Institute, and the Hilibrand Foundation (USA). Additional support for individual groups was provided by the US National Institutes of Health (NIH grants HD055751, HD055782, HD055784, HD35465, MH52708, MH55284, MH57881, MH061009, MH06359, MH066673, MH080647, MH081754, MH66766, NS026630, NS042165, NS049261), the Canadian Institute for Advanced Research (CIFAR), the Canadian Institutes for Health Research (CIHR), Assistance Publique–Hôpitaux de Paris (France), Autistica, Canada Foundation for Innovation/Ontario Innovation Trust, Deutsche Forschungsgemeinschaft (grant Po 255/17-4) (Germany), EC Sixth FP AUTISM MOLGEN, Fundação Calouste Gulbenkian (Portugal), Fondation de France, Fondation FondaMental (France), Fondation Orange (France), Fondation pour la Recherche Médicale (France), Fundação para a Ciência e Tecnologia (Portugal), the Hospital for Sick Children Foundation and University of Toronto (Canada), INSERM (France), Institut Pasteur (France), the Italian Ministry of Health (convention 181 of 19.10.2001), the John P. Hussman Foundation (USA), McLaughlin Centre (Canada), Ontario Ministry of Research and Innovation (Canada), the Seaver Foundation (USA), the Swedish Science Council, The Centre for Applied Genomics (Canada), the Utah Autism Foundation (USA) and the Wellcome Trust core award 075491/Z/04 (UK). We acknowledge support from the Autism Genetic Resource Exchange (AGRE) and Autism Speaks. We gratefully acknowledge the resources provided by the AGRE consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI). We wish to acknowledge the National Children’s Research Centre Our Lady’s Children’s Hospital Crumlin Ireland for providing additional support and the Wellcome Trust Case–Control Consortium for providing data sets that were used as part of this study. J.P.C is supported by an EMBARK postgraduate award from the Irish Research Council for Science, Engineering and Technology (IRCSET)., The AGRE Consortium, Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI Jr, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S., McGill University, Institut National de la Recherche Agronomique (INRA)-Avignon Université (AU), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Bologna/Università di Bologna, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Candidate gene, Genome-wide association study, Linkage Disequilibrium, MESH: Child Development Disorders, Pervasive, Cohort Studies, MESH: Genotype, 0302 clinical medicine, MESH: Child, Cluster Analysis, Genetics(clinical), Copy-number variation, Child, MESH: Cohort Studies, Genetics (clinical), Original Investigation, SNPS, Genetics, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Nuclear Family, MESH: Polymorphism, Single Nucleotide, Homozygote, MESH: Genetic Predisposition to Disease, Middle Aged, Autism spectrum disorder (ASD), 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: DNA Copy Number Variations, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Homozygote, Adult, DNA Copy Number Variations, Genotype, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Nuclear Family, 03 medical and health sciences, HOMOZYGOSITY MAPPING, mental disorders, medicine, Humans, Genetic Predisposition to Disease, ddc:610, AUTISM, GENOME-WIDE ASSOCIATION, education, 030304 developmental biology, MESH: Humans, Genetic heterogeneity, Haplotype, MESH: Adult, MESH: Haplotypes, medicine.disease, MESH: Cluster Analysis, MESH: Male, Haplotypes, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, MESH: Genome-Wide Association Study, Autism, MESH: Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
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. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users.

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21. A study of voice and non-voice processing in Prader-Willi syndrome.

Author

Strenilkov K, Debladis J, Salles J, Valette M, Mantoulan C, Thuilleaux D, Laurier V, Molinas C, Barone P, and Tauber M

Subjects
Bayes Theorem, Humans, Uniparental Disomy, Autism Spectrum Disorder genetics, Prader-Willi Syndrome genetics
Abstract

Background: Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder of genetic origin. It manifests itself in endocrine and cognitive problems, including highly pronounced hyperphagia and severe obesity. In many cases, impaired acquisition of social and communication skills leads to autism spectrum features, and individuals with this syndrome are occasionally diagnosed with autism spectrum disorder (ASD) using specific scales. Given that communicational skills are largely based on vocal communication, it is important to study human voice processing in PWS. We were able to examine a large number of participants with PWS (N = 61) recruited from France's national reference center for PWS and other hospitals. We tested their voice and nonvoice recognition abilities, as well as their ability to distinguish between voices and nonvoices in a free choice task. We applied the hierarchical drift diffusion model (HDDM) with Bayesian estimation to compare decision-making in participants with PWS and controls., Results: We found that PWS participants were impaired on both voice and nonvoice processing, but displayed a compensatory ability to perceive voices. Participants with uniparental disomy had poorer voice and nonvoice perception than participants with a deletion on chromosome 15. The HDDM allowed us to demonstrate that participants with PWS need to accumulate more information in order to make a decision, are slower at decision-making, and are predisposed to voice perception, albeit to a lesser extent than controls., Conclusions: The categorization of voices and nonvoices is generally preserved in participants with PWS, though this may not be the case for the lowest IQ.

Published
2020
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22. Face processing and exploration of social signals in Prader-Willi syndrome: a genetic signature.

Author

Debladis J, Valette M, Strenilkov K, Mantoulan C, Thuilleaux D, Laurier V, Molinas C, Barone P, and Tauber M

Subjects
Adult, Autism Spectrum Disorder genetics, Facial Recognition physiology, Female, Genotype, Humans, Interpersonal Relations, Male, Prader-Willi Syndrome genetics
Abstract

Background: Faces are critical social cues that must be perfectly processed in order to engage appropriately in everyday social interactions. In Prader-Willi Syndrome (PWS), a rare genetic disorder characterized by cognitive and behavioural difficulties including autism spectrum disorder, the literature referring to face processing is sparse. Given reports of poor social interactions in individuals with PWS, we sought to assess their face and emotion recognition skills during eyetracking recordings., Results: Compared with controls, patients with PWS performed more poorly on face/emotion recognition. We observed atypical facial exploration by patients with maternal disomy. These patients looked preferentially at the mouth region, whereas patients with a deletion and controls were more attracted to the eye region. During social scenes, the exploration became more atypical as the social content increased., Conclusions: Our comprehensive study brings new insights into the face processing of patients with PWS. Atypical facial exploration was only displayed by patients with the maternal disomy subtype, corresponding to their higher rate of autism spectrum disorder. This finding strongly argues in favor of early identification of this genetic subgroup in order to optimize care by implementing tailored interventions for each patient as soon as possible.

Published
2019
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23. New Interview and Observation Measures of the Broader Autism Phenotype: Description of Strategy and Reliability Findings for the Interview Measures.

Author

Parr JR, De Jonge MV, Wallace S, Pickles A, Rutter ML, Le Couteur AS, van Engeland H, Wittemeyer K, McConachie H, Roge B, Mantoulan C, Pedersen L, Isager T, Poustka F, Bolte S, Bolton P, Weisblatt E, Green J, Papanikolaou K, Baird G, and Bailey AJ

Subjects
Adolescent, Adult, Aged, Child, Child, Preschool, Factor Analysis, Statistical, Female, Humans, Male, Middle Aged, Netherlands, Reproducibility of Results, Social Behavior, United Kingdom, Young Adult, Autistic Disorder diagnosis, Interview, Psychological methods, Interview, Psychological standards
Abstract

Clinical genetic studies confirm the broader autism phenotype (BAP) in some relatives of individuals with autism, but there are few standardized assessment measures. We developed three BAP measures (informant interview, self-report interview, and impression of interviewee observational scale) and describe the development strategy and findings from the interviews. International Molecular Genetic Study of Autism Consortium data were collected from families containing at least two individuals with autism. Comparison of the informant and self-report interviews was restricted to samples in which the interviews were undertaken by different researchers from that site (251 UK informants, 119 from the Netherlands). Researchers produced vignettes that were rated blind by others. Retest reliability was assessed in 45 participants. Agreement between live scoring and vignette ratings was very high. Retest stability for the interviews was high. Factor analysis indicated a first factor comprising social-communication items and rigidity (but not other repetitive domain items), and a second factor comprised mainly of reading and spelling impairments. Whole scale Cronbach's alphas were high for both interviews. The correlation between interviews for factor 1 was moderate (adult items 0.50; childhood items 0.43); Kappa values for between-interview agreement on individual items were mainly low. The correlations between individual items and total score were moderate. The inclusion of several factor 2 items lowered the overall Cronbach's alpha for the total set. Both interview measures showed good reliability and substantial stability over time, but the findings were better for factor 1 than factor 2. We recommend factor 1 scores be used for characterising the BAP., (© 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.)

Published
2015
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24. Prader-Willi syndrome as a model of human hyperphagia.

Author

Tauber M, Diene G, Mimoun E, Çabal-Berthoumieu S, Mantoulan C, Molinas C, Muscatelli F, and Salles JP

Subjects
Feeding Behavior, Humans, Brain metabolism, Dopamine metabolism, Ghrelin metabolism, Hyperphagia metabolism, Prader-Willi Syndrome metabolism
Abstract

Prader-Willi syndrome (PWS), first described in 1956, is considered as a paradigm of a neurodevelopmental disorder with severe and early obesity with hyperphagia and impaired satiety. The improved knowledge in the natural history and recent data on genetics offer new perspectives for understanding the metabolic and endocrine dysfunctions and possibly for treatment. Natural history of the disease has been described due to the early diagnosis performed in the first months of life and various nutritional phases have been described. In addition, there is clear evidence that the abnormal feeding behavior is included in the behavioral problems. Brain imaging studies have shown that some brain regions may be important in PWS. The role of SNORD116 gene cluster is detailed and its links with circadian rhythm and brain and hypothalamus development. Pathophysiology of the abnormal ghrelin levels and of OT dysfunction is documented. While no effect on appetite and weight regulation has been reported with ghrelin antagonists, OT has been shown to improve some of the behavioral problems in adults. We discuss our hypothesis of an abnormal ghrelin/OT/dopamine pathway which may explain the switch of nutritional phases and behavior. These new aspects offer an opportunity for therapeutic use and possible early intervention., (© 2014 S. Karger AG, Basel.)

Published
2014
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25. Individual common variants exert weak effects on the risk for autism spectrum disorders.

Author

Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu XQ, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI Jr, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, and Devlin B

Subjects
Alleles, Child, Child Development Disorders, Pervasive physiopathology, Female, Gene Frequency, Genotype, Humans, Language Development, Male, Polymorphism, Single Nucleotide, Risk Factors, Child Development Disorders, Pervasive genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Membrane Proteins genetics, Nerve Tissue Proteins genetics
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.

Published
2012
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26. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Author

Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI Jr, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, and Ennis S

Subjects
Adult, Child, Cluster Analysis, Cohort Studies, DNA Copy Number Variations, Female, Genotype, Homozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Nuclear Family, Polymorphism, Single Nucleotide, Child Development Disorders, Pervasive genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Haplotypes genetics
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.

Published
2012
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27. Oxytocin may be useful to increase trust in others and decrease disruptive behaviours in patients with Prader-Willi syndrome: a randomised placebo-controlled trial in 24 patients.

Author

Tauber M, Mantoulan C, Copet P, Jauregui J, Demeer G, Diene G, Rogé B, Laurier V, Ehlinger V, Arnaud C, Molinas C, and Thuilleaux D

Subjects
Adolescent, Adult, Double-Blind Method, Female, Humans, Male, Placebos, Prader-Willi Syndrome psychology, Young Adult, Oxytocin therapeutic use, Prader-Willi Syndrome drug therapy
Abstract

Background: Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder with hypothalamic dysfunction, early morbid obesity with hyperphagia, and specific psychiatric phenotypes including cognitive and behavioural problems, particularly disruptive behaviours and frequent temper outbursts that preclude socialization. A deficit in oxytocin (OT)-producing neurons of the hypothalamic paraventricular nucleus has been reported in these patients., Methods: In a double-blind, randomised, placebo-controlled study, 24 adult patients with PWS received a single intranasal administration of 24 IU of OT or placebo and were tested 45 min later on social skills. Behaviours were carefully monitored and scored using an in-house grid as follows: over the two days before drug administration, on the half-day following administration, and over the subsequent two days. All patients were in a dedicated PWS centre with more than ten years of experience. Patients are regularly admitted to this controlled environment., Results: Patients with PWS who received a single intranasal administration of OT displayed significantly increased trust in others (P = 0.02) and decreased sadness tendencies (P = 0.02) with less disruptive behaviour (P = 0.03) in the two days following administration than did patients who received placebo. In the half-day following administration, we observed a trend towards less conflict with others (p = 0.07) in the OT group compared with the placebo group. Scores in tests assessing social skills were not significantly different between the two groups., Conclusions: This study needs to be reproduced and adapted. It nevertheless opens new perspectives for patients with PWS and perhaps other syndromes with behavioural disturbances and obesity., Trial Registration Number: ClinicalTrials.gov: NCT01038570.

Published
2011
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28. PET scan perfusion imaging in the Prader-Willi syndrome: new insights into the psychiatric and social disturbances.

Author

Mantoulan C, Payoux P, Diene G, Glattard M, Rogé B, Molinas C, Sevely A, Zilbovicius M, Celsis P, and Tauber M

Subjects
Adolescent, Cerebrovascular Circulation physiology, Cerebrovascular Disorders diagnostic imaging, Cerebrovascular Disorders etiology, Child, Child Behavior Disorders etiology, Child Behavior Disorders psychology, Female, Humans, Image Processing, Computer-Assisted, Intelligence Tests, Magnetic Resonance Imaging, Male, Mental Disorders etiology, Neuropsychological Tests, Positron-Emission Tomography, Psychotropic Drugs therapeutic use, Regression, Psychology, Social Behavior Disorders etiology, Young Adult, Mental Disorders diagnostic imaging, Mental Disorders psychology, Prader-Willi Syndrome diagnostic imaging, Prader-Willi Syndrome psychology, Social Behavior Disorders diagnostic imaging, Social Behavior Disorders psychology
Abstract

The Prader-Willi syndrome (PWS), a rare multisystem genetic disease, leads to severe disabilities, such as morbid obesity, endocrine dysfunctions, psychiatric disorders, and social disturbances. We explored the whole brain of patients with PWS to detect abnormalities that might explain the behavioral and social disturbances, as well as the psychiatric disorders of these patients. Nine patients with PWS (six males, three females; mean age 16.4 years) underwent a positron emission tomography (PET) scan with H(2)(15)O as a tracer to measure regional cerebral blood flow (rCBF). The images were compared with those acquired from nine controls (six males, three females; mean age 21.2 years). A morphologic magnetic resonance imaging (MRI) was also performed in PWS patients, and their cognitive and behavioral skills were assessed with Wechsler Intelligence Scale for Children III and the Child Behavior Check List (CBCL). The MRI images showed no evident anatomic abnormalities, whereas PET scans revealed hypoperfused brain regions in PWS patients compared with controls, particularly in the anterior cingulum and superior temporal regions. We observed a significant relationship (P<0.05) between rCBF in the hypoperfused regions and CBCL scores. The functional consequences of these perfusion abnormalities in specific brain regions might explain the behavioral and social problems observed in these individuals.

Published
2011
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29. Functional impact of global rare copy number variation in autism spectrum disorders.

Author

Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, and Betancur C

Subjects
Case-Control Studies, Cell Movement, Child, Child Development Disorders, Pervasive pathology, Cytoprotection, Europe ethnology, Genome-Wide Association Study, Humans, Signal Transduction, Social Behavior, Child Development Disorders, Pervasive genetics, Child Development Disorders, Pervasive physiopathology, DNA Copy Number Variations genetics, Gene Dosage genetics, Genetic Predisposition to Disease genetics
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.

Published
2010
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30. Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Author

Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijmans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, and Meyer KJ

Subjects
Autistic Disorder diagnosis, Family, Female, Genetic Variation, Humans, Lod Score, Male, Risk Factors, Autistic Disorder genetics, Chromosome Aberrations, Chromosome Mapping, Genetic Linkage, Genetic Predisposition to Disease, Genetic Testing methods
Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Published
2007
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