Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP

Science Translational Medicine

Volumn 2, Issue 56, 2010, Pages

  Scott Van Zeeland, Ashley A ^a,b   Abrahams, Brett S ^a,c   Alvarez Retuerto, Ana I ^a   Sonnenblick, Lisa I ^a   Rudie, Jeffrey D ^a   Ghahremani, Dara ^a   Mumford, Jeanette A ^a   Poldrack, Russell A ^a   Dapretto, Mirella ^a   Geschwind, Daniel H ^a   Bookheimer, Susan Y ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b SCRIPPS TRANSLATIONAL SCIENCE INSTITUTE   (United States)

^c ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CONTACTIN ASSOCIATED PROTEIN LIKE 2; NEUREXIN; UNCLASSIFIED DRUG; CNTNAP2 PROTEIN, HUMAN; MEMBRANE PROTEIN; NERVE PROTEIN;

ARTICLE; AUTISM; BRAIN FUNCTION; CHILD; CLINICAL ARTICLE; CNTNAP2 GENE; CONTROLLED STUDY; FRONTAL LOBE; FUNCTIONAL MAGNETIC RESONANCE IMAGING; GENE; GENE EXPRESSION; GENETIC ASSOCIATION; GENETIC PREDISPOSITION; GENETIC RISK; GENETIC VARIABILITY; GENOTYPE; HUMAN; PHENOTYPE; PRIORITY JOURNAL; GENETICS; NERVE TRACT; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOLOGY; RISK FACTOR;

AUTISTIC DISORDER; FRONTAL LOBE; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MAGNETIC RESONANCE IMAGING; MEMBRANE PROTEINS; NERVE TISSUE PROTEINS; NEURAL PATHWAYS; RISK FACTORS;

EID: 78149301263     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3001344     Document Type: Article

References (41)

1. B. S. Abrahams, D. H. Geschwind, Genetics of autism, in Human Genetics: Problems and Approaches, M. R. Speicher, S. E. Antonarakis, A. G. Motulsky, Eds. (Springer-Verlag, Heidelberg, 2010).
2. A. J. Verkerk, C. A. Mathews, M. Joosse, B. H. Eussen, P. Heutink, B. A. Oostra; Tourette Syndrome Association International Consortium for Genetics, Cntnap2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82, 1-9 (2003).
3. K. A. Strauss, E. G. Puffenberger, M. J. Huentelman, S. Gottlieb, S. E. Dobrin, J.M. Parod, D. A. Stephan, D. H. Morton, Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N. Engl. J. Med. 354, 1370-1377 (2006).
4. M. Alarcón, B. S. Abrahams, J. L. Stone, J. A. Duvall, J. V. Perederiy, J. M. Bomar, J. Sebat, M. Wigler, C. L. Martin, D. H. Ledbetter, S. F. Nelson, R. M. Cantor, D. H. Geschwind, Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 82, 150-159 (2008).
5. D. E. Arking, D. J. Cutler, C. W. Brune, T. M. Teslovich, K. West, M. Ikeda, A. Rea, M. Guy, S. Lin, E. H. Cook Jr., A. Chakravarti, A common genetic variant in the neurexin super-family member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82, 160-164 (2008).
6. S. C. Vernes, D. F. Newbury, B. S. Abrahams, L. Winchester, J. Nicod, M. Groszer, M. Alarcón, P. L. Oliver, K. E. Davies, D. H. Geschwind, A. P. Monaco, S. E. Fisher, A functional genetic link between distinct developmental language disorders. N. Engl. J. Med. 359, 2337-2345 (2008).
7. B. S. Abrahams, D. Tentler, J. V. Perederiy, M. C. Oldham, G. Coppola, D. H. Geschwind, Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc. Natl. Acad. Sci. U.S.A. 104, 17849-17854 (2007).
8. K. McNealy, J. C. Mazziotta, M. Dapretto, Cracking the language code: Neural mechanisms underlying speech parsing. J. Neurosci. 26, 7629-7639 (2006).
9. B. J. Knowlton, J. A. Mangels, L. R. Squire, A neostriatal habit learning system in humans. Science 273, 1399-1402 (1996).
10. R. A. Poldrack, V. Prabhakaran, C. A. Seger, J. D. Gabrieli, Striatal activation during acquisition of a cognitive skill. Neuropsychology 13, 564-574 (1999).
11. + channels in myelinated axons depends on Caspr2 and TAG-1. J. Cell Biol. 162, 1149-1160 (2003).
12. G. Corfas, M. O. Velardez, C. P. Ko, N. Ratner, E. Peles, Mechanisms and roles of axon-Schwann cell interactions. J. Neurosci. 24, 9250-9260 (2004).
13. G. C. Tan, T. F. Doke, J. Ashburner, N. W. Wood, R. S. Frackowiak, Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2. NeuroImage 53, 1030-1042 (2010).
14. D. Badre, M. D'Esposito, Is the rostro-caudal axis of the frontal lobe hierarchical? Nat. Rev. Neurosci. 10, 659-669 (2009).
15. D. Badre, M. D'Esposito, Functional magnetic resonance imaging evidence for a hierarchical organization of the prefrontal cortex. J. Cogn. Neurosci. 19, 2082-2099 (2007).
16. E. Koechlin, C. Ody, F. Kouneiher, The architecture of cognitive control in the human pre-frontal cortex. Science 302, 1181-1185 (2003).
17. S. Bookheimer, Functional MRI of language: New approaches to understanding the cortical organization of semantic processing. Annu. Rev. Neurosci. 25, 151-188 (2002).
18. G. Rizzolatti, L. Craighero, The mirror-neuron system. Annu. Rev. Neurosci. 27, 169-192 (2004).
19. W. B. Groen, M. P. Zwiers, R. J. van der Gaag, J. K. Buitelaar, The phenotype and neural correlates of language in autism: An integrative review. Neurosci. Biobehav. Rev. 32, 1416-1425 (2008).
20. M. Dapretto, M. S. Davies, J. H. Pfeifer, A. A. Scott, M. Sigman, S. Y. Bookheimer, M. Iacoboni, Understanding emotions in others: Mirror neuron dysfunction in children with autism spectrum disorders. Nat. Neurosci. 9, 28-30 (2006).
21. N. Hadjikhani, R. M. Joseph, J. Snyder, H. Tager-Flusberg, Anatomical differences in the mirror neuron system and social cognition network in autism. Cereb. Cortex 16, 1276-1282 (2006).
22. L. M. Oberman, E. M. Hubbard, J. P. McCleery, E. L. Altschuler, V. S. Ramachandran, J. A. Pineda, EEG evidence for mirror neuron dysfunction in autism spectrum disorders. Brain Res. Cogn. Brain Res. 24, 190-198 (2005).
23. L. Q. Uddin, M. S. Davies, A. A. Scott, E. Zaidel, S. Y. Bookheimer, M. Iacoboni, M. Dapretto, Neural basis of self and other representation in autism: An fMRI study of self-face recognition. PLoS One 3, e3526 (2008).
24. E. Courchesne, K. Pierce, Brain overgrowth in autism during a critical time in development: Implications for frontal pyramidal neuron and interneuron development and connectivity. Int. J. Dev. Neurosci. 23, 153-170 (2005).
25. D. H. Geschwind, P. Levitt, Autism spectrum disorders: Developmental disconnection syndromes. Curr. Opin. Neurobiol. 17, 103-111 (2007).
26. B. J. Casey, J. T. Nigg, S. Durston, New potential leads in the biology and treatment of attention deficit-hyperactivity disorder. Curr. Opin. Neurol. 20, 119-124 (2007).
27. K. H. Karlsgodt, D. Sun, A. M. Jimenez, E. S. Lutkenhoff, R. Willhite, T. G. van Erp, T. D. Cannon, Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia. Dev. Psychopathol. 20, 1297-1327 (2008).
28. A. A. Scott-Van Zeeland, M. Dapretto, D. G. Ghahremani, R. A. Poldrack, S. Y. Bookheimer, Reward processing in autism. Autism Res. 3, 53-67 (2010).
29. M. E. Raichle, A. M. MacLeod, A. Z. Snyder, W. J. Powers, D. A. Gusnard, G. L. Shulman, A default mode of brain function. Proc. Natl. Acad. Sci. U.S.A. 98, 676-682 (2001).
30. D. C. Glahn, A. M. Winkler, P. Kochunov, L. Almasy, R. Duggirala, M. A. Carless, J. C. Curran, R. L. Olvera, A. R. Laird, S. M. Smith, C. F. Beckmann, P. T. Fox, J. Blangero, Genetic control over the resting brain. Proc. Natl. Acad. Sci. U.S.A. 107, 1223-1228 (2010).
31. S. J. Broyd, C. Demanuele, S. Debener, S. K. Helps, C. J. James, E. J. S. Sonuga-Barke, Default-mode brain dysfunction in mental disorders: A systematic review. Neurosci. Biobehav. Rev. 33, 279-296 (2009).
32. M. R. Herbert, D. A. Ziegler, C. K. Deutsch, L. M. O'Brien, D. N. Kennedy, P. A. Filipek, A. I. Bakardjiev, J. Hodgson, M. Takeoka, N. Makris, V. S. Caviness Jr., Brain asymmetries in autism and developmental language disorder: A nested whole-brain analysis. Brain 128, 213-226 (2005).
33. N. U. Dosenbach, B. Nardos, A. L. Cohen, D. A. Fair, J. D. Power, J. A. Church, S. M. Nelson, G. S. Wig, A. C. Vogel, C. N. Lessov-Schlaggar, K. A. Barnes, J. W. Dubis, E. Feczko, R. S. Coalson, J. R. Pruett Jr., D. M. Barch, S. E. Petersen, B. L. Schlaggar, Prediction of individual brain maturity using fMRI. Science 329, 1358-1361 (2010).
34. D. H. Geschwind, Autism: Many genes, common pathways? Cell 135, 391-395 (2008).
35. E. Courchesne, E. Redcay, J. T. Morgan, D. P. Kennedy, Autism at the beginning: Microstructural and growth abnormalities underlying the cognitive and behavioral phenotype of autism. Dev. Psychopathol. 17, 577-597 (2005).
36. D. E. Arking, D. J. Cutler, C. W. Brune, T. M. Teslovich, K. West, M. Ikeda, A. Rea, M. Guy, S. Lin, E. H. Cook Jr., A. Chakravarti, A common genetic variant in the neurexin super-family member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82, 160-164 (2008).
37. D. A. Fair, A. L. Cohen, J. D. Power, N. U. Dosenbach, J. A. Church, F. M. Miezin, B. L. Schlaggar, S. E. Petersen, Functional brain networks develop from a "local to distributed" organization. PLoS Comput. Biol. 5, e1000381 (2009).
38. I. I. Gottesman, T. D. Gould, The endophenotype concept in psychiatry: Etymology and strategic intentions. Am. J. Psychiatry 160, 636-645 (2003).
39. J. Elia, X. Gai, H. M. Xie, J. C. Perin, E. Geiger, J. T. Glessner, M. D'arcy, R. deBerardinis, E. Frackelton, C. Kim, F. Lantieri, B. M. Muganga, L. Wang, T. Takeda, E. F. Rappaport, S. F. Grant, W. Berrettini, M. Devoto, T. H. Shaikh, H. Hakonarson, P. S. White, Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol. Psychiatry 15, 637-646 (2010).
40. J. I. Friedman, T. Vrijenhoek, S. Markx, I. M. Janssen, W. A. van der Vliet, B. H. Faas, N. V. Knoers, W. Cahn, R. S. Kahn, L. Edelmann, K. L. Davis, J. M. Silverman, H. G. Brunner, A. G. van Kessel, C. Wijmenga, R. A. Ophoff, J. A. Veltman, CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol. Psychiatry 13, 261-266 (2008).
41. Acknowledgments: We thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, Ahmanson Foundation, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Dickinson Family Foundation, Robson Family, and Northstar Fund. We thank K. McNealy for providing replication data. Funding: This work was in part supported by grants from the National Institute of Child Health and Human Development (P01 HD035470, P50 HD055784, and R01 HD065280-01), the National Alliance for Autism Research, Autism Speaks, and Whitehall Foundation, as well as by the Training Program in Neurobehavioral Genetics (T32 MH073526), and a National Research Service Award predoctoral fellowship (F31 MH079645). The project described was in part also supported by grants (RR12169, RR13642, and RR00865, UL1 RR025774) from the National Center for Research Resources (NCRR), a component of the NIH, and R01-hd065280 and P50-hd055784-03s1 from the NIH (to S.Y.B.); its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. Author contributions: A.A.S.-V.Z., S.Y.B., M.D., and D.H.G. developed the initial idea and design of the study. A.A.S.-V.Z., D.H.G., and R.A.P. developed the fMRI task. J.A.M. contributed to statistical analysis of the data. B.S.A., A.I.A.-R., A.A.S.-V.Z., J.D.R., and L.I.S. performed genotyping and genetic analyses. B.S.A., S.Y.B., M.D., D.H.G., and A.A.S.-V.Z. interpreted the findings and contributed to the manuscript. All authors revised and commented on drafts of the manuscript. Competing interests: The authors declare that they have no competing interests.