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Quantitative Linkage for Autism Spectrum Disorders Symptoms in Attention-Deficit/Hyperactivity Disorder: Significant Locus on Chromosome 7q11

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Abstract

We studied 261 ADHD probands and 354 of their siblings to assess quantitative trait loci associated with autism spectrum disorder symptoms (as measured by the Children’s Social Behavior Questionnaire (CSBQ)) using a genome-wide linkage approach, followed by locus-wide association analysis. A genome-wide significant locus for the CSBQ subscale addressing social interaction was found on chromosome 7q11, with suggestive signals supporting this locus on three other CSBQ subscales. We identified two other suggestive loci for the CSBQ total scale and individual subscales on chromosomes 4q35 and 7p12. Fine-mapping the significantly linked locus resulted in interesting candidate genes, although their association was not significant after permutation testing.

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References

  • Abecasis, G. R., Cherny, S. S., Cookson, W. O., & Cardon, L. R. (2002). Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nature Genetics, 30, 97–101.

    Article  PubMed  Google Scholar 

  • Abecasis, G. R., & Wigginton, J. E. (2005). Handling marker–marker linkage disequilibrium: pedigree analysis with clustered markers. American Journal of Human Genetics, 77, 754–767.

    Article  PubMed Central  PubMed  Google Scholar 

  • Allen-Brady, K., Miller, J., Matsunami, N., Stevens, J., Block, H., Farley, M., et al. (2009a). A high-density SNP genome-wide linkage scan in a large autism extended pedigree. Molecular Psychiatry, 14, 590–600. doi:10.1038/mp.2008.

    Article  PubMed  Google Scholar 

  • Allen-Brady, K., Robison, R., Cannon, D., Varvil, T., Villalobos, M., Pingree, C., et al. (2009b). Genome-wide linkage in Utah autism pedigrees. Molecular Psychiatry, 14, 590–600. doi:10.1038/mp.2008.

    Article  PubMed  Google Scholar 

  • Almasy, L., & Blangero, J. (1998). Multipoint quantitative-trait linkage analysis in general pedigrees. American Journal of Human Genetics, 62, 1198–1211.

    Article  PubMed Central  PubMed  Google Scholar 

  • American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders, 4 edn. Washington, DC.

  • Asherson, P., Zhou, K., Anney, R. J., Franke, B., Buitelaar, J., Ebstein, R., et al. (2008). A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16. Molecular Psychiatry, 13, 514–521. doi:10.1038/sj.mp.4002140.

    Article  PubMed  Google Scholar 

  • Bakker, S. C., van der Meulen, E. M., Buitelaar, J. K., Sandkuijl, L. A., Pauls, D. L., Monsuur, A. J., et al. (2003). A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. American Journal of Human Genetics, 72, 1251–1260.

    Article  PubMed Central  PubMed  Google Scholar 

  • Berg, J. S., Brunetti-Pierri, N., Peters, S. U., Kang, S. H., Fong, C. T., Salamone, J., et al. (2007). Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genetics in Medicine, 9, 427–441.

    Article  PubMed  Google Scholar 

  • Berument, S. K., Rutter, M., Lord, C., Pickles, A., & Bailey, A. (1999). Autism screening questionnaire: diagnostic validity. British Journal of Psychiatry, 175, 444–451.

    Article  PubMed  Google Scholar 

  • Brookes, K., Xu, X., Chen, W., Zhou, K., Neale, B., Lowe, N., et al. (2006). The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Molecular Psychiatry, 11, 934–953.

    Article  PubMed  Google Scholar 

  • Conners, K. (1996). Rating scales in ADHD. Durham, NC: Duke University Medical Center.

    Google Scholar 

  • Constantino, J. N. (2011). The quantitative nature of autistic social impairment. Pediatric Research, 69, 55R–62R.

    Article  PubMed Central  PubMed  Google Scholar 

  • Constantino, J. N., & Todd, R. D. (2000). Genetic structure of reciprocal social behavior. American Journal of Psychiatry, 157, 2043–2045.

    Article  PubMed  Google Scholar 

  • Constantino, J. N., & Todd, R. D. (2003). Autistic traits in the general population: a twin study. Archives of General Psychiatry, 60, 524–530.

    Article  PubMed  Google Scholar 

  • Constantino, J. N., & Todd, R. D. (2005). Intergenerational transmission of subthreshold autistic traits in the general population. Biological Psychiatry, 57, 655–660.

    Article  PubMed  Google Scholar 

  • Depienne, C., Heron, D., Betancur, C., Benyahia, B., Trouillard, O., Bouteiller, D., et al. (2007). Autism, language delay and mental retardation in a patient with 7q11 duplication. Journal of Medical Genetics, 44, 452–458.

    Article  PubMed Central  PubMed  Google Scholar 

  • Epstein, M. P., Duren, W. L., & Boehnke, M. (2000). Improved inference of relationship for pairs of individuals. American Journal of Human Genetics, 67, 1219–1231.

    Article  PubMed Central  PubMed  Google Scholar 

  • Faraone, S. V., Doyle, A. E., Lasky-Su, J., Sklar, P. B., D’Angelo, E., Gonzalez-Heydrich, J., et al. (2008). Linkage analysis of attention deficit hyperactivity disorder. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 147B, 1387–1391.

    Article  Google Scholar 

  • Goodman, R. (1997). The strengths and difficulties questionnaire: A research note. Journal of Child Psychology and Psychiatry, 38, 581–586.

    Google Scholar 

  • Happé, F., & Ronald, A. (2008). The ‘fractionable autism triad’: A review of evidence from behavioural, genetic, cognitive and neural research. Neuropsychology Review, 18, 287–304.

    Article  PubMed  Google Scholar 

  • Hartman, C. A., Luteijn, E., Moorlag, H., de Bildt, A., & Minderaa, R. B. (2007). Vragenlijst voor inventarisatie van sociaal gedrag van kinderen VISK. Herziene handleiding 2007. Amsterdam: Harcourt Test Publishers.

  • Hartman, C. A., Luteijn, E., Serra, M., & Minderaa, R. (2006). Refinement of the Children’s Social Behavior Questionnaire CSBQ: An instrument that describes the diverse problems seen in milder forms of PDD. Journal of Autism and Developmental Disorders, 36, 325–342.

    Article  PubMed  Google Scholar 

  • Kong, A., Gudbjartsson, D. F., Sainz, J., Jonsdottir, G. M., Gudjonsson, S. A., Richardsson, B., et al. (2002). A high-resolution recombination map of the human genome. Nature Genetics, 31, 241–247.

    PubMed  Google Scholar 

  • Krug, D. A., Arick, J. R., & Almond, P. J. (1980). Behavior checklist for identifying severely handicapped individuals with high levels of autistic behavior. Journal of Child Psychology and Psychiatry and Allied Disciplines, 21, 221–229.

    Article  Google Scholar 

  • Kuntsi, J., Neale, B. M., Chen, W., Faraone, S. V., & Asherson, P. (2006). The IMAGE project: methodological issues for the molecular genetic analysis of ADHD. Behavioral and Brain Functions, 2, 27.

    Article  PubMed Central  PubMed  Google Scholar 

  • Lander, E., & Kruglyak, L. (1995). Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nature Genetics, 11, 241–247.

    Article  PubMed  Google Scholar 

  • Ligthart, L., Nyholt, D. R., Hottenga, J. J., Distel, M. A., Willemsen, G., & Boomsma, D. I. (2008). A genome-wide linkage scan provides evidence for both new and previously reported loci influencing common migraine. Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 147B, 1186–1195.

    Article  Google Scholar 

  • Luteijn, E. F., Serra, M., Jackson, S., Steenhuis, M. P., Althaus, M., Volkmar, F., et al. (2000). How unspecified are disorders of children with a pervasive developmental disorder not otherwise specified? A study of social problems in children with PDD-NOS and ADHD. European Child and Adolescent Psychiatry, 9, 168–179.

    Article  PubMed  Google Scholar 

  • Neale, B. M., Lasky-Su, J., Anney, R., Franke, B., Zhou, K., Maller, J. B., et al. (2008). Genome-wide association scan of attention deficit hyperactivity disorder. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 147B, 1337–1344.

    Article  Google Scholar 

  • Nijmeijer, J. S., Hoekstra, P. J., Minderaa, R. B., Buitelaar, J. K., Altink, M. E., Buschgens, C. J., et al. (2008a). PDD Symptoms in ADHD, an Independent Familial Trait? Journal of Abnormal Child Psychology, 37, 443–453.

    Article  Google Scholar 

  • Nijmeijer, J. S., Minderaa, R. B., Buitelaar, J. K., Mulligan, A., Hartman, C. A., & Hoekstra, P. J. (2008b). Attention-deficit/hyperactivity disorder and social dysfunctioning. Clinical Psychology Review, 28, 692–708.

    Article  PubMed  Google Scholar 

  • O’Connell, J. R., & Weeks, D. E. (1998). PedCheck: a program for identification of genotype incompatibilities in linkage analysis. American Journal of Human Genetics, 63, 259–266.

    Article  PubMed Central  PubMed  Google Scholar 

  • Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D., et al. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559–575.

    Article  PubMed Central  PubMed  Google Scholar 

  • Reiersen, A. M., Constantino, J. N., Grimmer, M., Martin, N. G., & Todd, R. D. (2008). Evidence for shared genetic influences on self-reported ADHD and autistic symptoms in young adult Australian twins. Twin Research and Human Genetics, 11, 579–585.

    Article  PubMed Central  PubMed  Google Scholar 

  • Reiersen, A. M., Constantino, J. N., Volk, H. E., & Todd, R. D. (2007). Autistic traits in a population-based ADHD twin sample. Journal of Child Psychology and Psychiatry and Allied Disciplines, 48, 464–472.

    Article  Google Scholar 

  • Rommelse, N. N., Franke, B., Geurts, H. M., Hartman, C. A., & Buitelaar, J. K. (2010). Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder. European Child and Adolescent Psychiatry, 19, 281–295.

    Article  PubMed Central  PubMed  Google Scholar 

  • Ronald, A., Happé, F., Bolton, P., Butcher, L. M., Price, T. S., Wheelwright, S., et al. (2006a). Genetic heterogeneity between the three components of the autism spectrum: a twin study. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 691–699.

    Article  PubMed  Google Scholar 

  • Ronald, A., Happé, F., Price, T. S., Baron-Cohen, S., & Plomin, R. (2006b). Phenotypic and genetic overlap between autistic traits at the extremes of the general population. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 1206–1214.

    Article  PubMed  Google Scholar 

  • Ronald, A., Simonoff, E., Kuntsi, J., Asherson, P., & Plomin, R. (2008). Evidence for overlapping genetic influences on autistic and ADHD behaviours in a community twin sample. Journal of Child Psychology and Psychiatry and Allied Disciplines, 49, 535–542.

    Article  Google Scholar 

  • Sham, P. C., Purcell, S., Cherny, S. S., & Abecasis, G. R. (2002). Powerful regression-based quantitative-trait linkage analysis of general pedigrees. American Journal of Human Genetics, 71, 238–253.

    Article  PubMed Central  PubMed  Google Scholar 

  • Spiker, D., Lotspeich, L. J., Dimiceli, S., Myers, R. M., & Risch, N. (2002). Behavioral phenotypic variation in autism multiplex families: Evidence for a continuous severity gradient. American Journal of Medical Genetics, 114, 129–136.

    Article  PubMed  Google Scholar 

  • Sultana, R., Yu, C. E., Yu, J., Munson, J., Chen, D., Hua, W., et al. (2002). Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics, 80, 129–134.

    Article  PubMed  Google Scholar 

  • Taylor, E., Schachar, R., Thorley, G., & Wieselberg, M. (1986). Conduct disorder and hyperactivity: I. Separation of hyperactivity and antisocial conduct in British child psychiatric patients. British Journal of Psychiatry, 149, 760–767.

    Article  PubMed  Google Scholar 

  • Vandeweyer, G., Van der Aa, N., Reyniers, E., & Kooy, R. F. (2012). The contribution of CLIP2 haploinsufficiency to the clinical manifestations of the Williams-Beuren syndrome. American Journal of Human Genetics, 8, 1071–1078. doi:10.1016/j.ajhg.2012.04.020.

    Article  Google Scholar 

  • Waldman, I. D., & Gizer, I. R. (2006). The genetics of attention deficit hyperactivity disorder. Clinical Psychology Review, 26, 396–432.

    Article  PubMed  Google Scholar 

  • Wigginton, J. E., & Abecasis, G. R. (2005). PEDSTATS: Descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics, 21, 3445–3447.

    Article  PubMed  Google Scholar 

  • Yang, M. S., & Gill, M. (2007). A review of gene linkage, association and expression studies in autism and an assessment of convergent evidence. International Journal of Developmental Neuroscience, 25, 69–85.

    Article  PubMed  Google Scholar 

  • Zhou, K., Asherson, P., Sham, P., Franke, B., Anney, R. J., Buitelaar, J., et al. (2008a). Linkage to chromosome 1p36 for attention-deficit/hyperactivity disorder traits in school and home settings. Biological Psychiatry, 64, 571–576.

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhou, K., Dempfle, A., Arcos-Burgos, M., Bakker, S. C., Banaschewski, T., Biederman, J., et al. (2008b). Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 147B, 1392–1398.

    Article  Google Scholar 

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Acknowledgments

The IMAGE project is a multi-site, international effort supported by NIH Grants R01MH081803 and R01MH62873 to S.V. Faraone. Site Principal Investigators are Philip Asherson, Tobias Banaschewski, Jan Buitelaar, Richard P. Ebstein, Stephen V. Faraone, Michael Gill, Ana Miranda, Fernando Mulas, Robert D. Oades, Herbert Roeyers, Aribert Rothenberger, Joseph Sergeant, Edmund Sonuga-Barke, and Hans-Christoph Steinhausen. Senior coinvestigators are Margaret Thompson, Pak Sham, Peter McGuffin, Robert Plomin, Ian Craig and Eric Taylor. Chief Investigators at each site are Rafaela Marco, Nanda Rommelse, Wai Chen, Henrik Uebel, Hanna Christiansen, Ueli Mueller, Marieke Altink, Barbara Franke, Lamprini Psychogiou. We thank all the families who kindly participated in this research.

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Authors and Affiliations

  1. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Judith S. Nijmeijer, Ruud B. Minderaa, Pieter J. Hoekstra & Catharina A. Hartman

  2. Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Alejandro Arias-Vásquez, Marieke E. Altink, Ellen A. Fliers & Barbara Franke

  3. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Alejandro Arias-Vásquez, Cathelijne J. M. Buschgens, Ellen A. Fliers, Barbara Franke & Jan K. Buitelaar

  4. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Nanda N. J. Rommelse, Cathelijne J. M. Buschgens & Jan K. Buitelaar

  5. Karakter, Child and Adolescent Psychiatry University Medical Center Nijmegen, Nijmegen, The Netherlands

    Nanda N. J. Rommelse, Marieke E. Altink & Jan K. Buitelaar

  6. Youth Department, Lucertis, Parnassia-BAVO-Group, Rotterdam, The Netherlands

    Ellen A. Fliers

  7. Department of Clinical Neuropsychology, Vrije Universiteit University Amsterdam, Amsterdam, The Netherlands

    Joseph A. Sergeant

  8. Department of Child and Adolescent Psychiatry, University of Groningen, Hanzeplein 1, PO Box 660, 9700 AR, Groningen, The Netherlands

    Judith S. Nijmeijer

  9. Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Nanda N. J. Rommelse

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  1. Judith S. Nijmeijer
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  2. Alejandro Arias-Vásquez
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  3. Nanda N. J. Rommelse
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  4. Marieke E. Altink
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  5. Cathelijne J. M. Buschgens
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  6. Ellen A. Fliers
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  7. Barbara Franke
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  8. Ruud B. Minderaa
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  9. Joseph A. Sergeant
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  10. Jan K. Buitelaar
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  11. Pieter J. Hoekstra
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  12. Catharina A. Hartman
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Corresponding author

Correspondence to Judith S. Nijmeijer.

Additional information

Judith S. Nijmeijer/Alejandro Arias-Vásquez and Pieter J. Hoekstra/Catharina A. Hartman shared first and last authorship, respectively.

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Nijmeijer, J.S., Arias-Vásquez, A., Rommelse, N.N.J. et al. Quantitative Linkage for Autism Spectrum Disorders Symptoms in Attention-Deficit/Hyperactivity Disorder: Significant Locus on Chromosome 7q11. J Autism Dev Disord 44, 1671–1680 (2014). https://doi.org/10.1007/s10803-014-2039-4

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