Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy population

BMC Neuroscience

Peter L Hurd²  Bernard J Crespi¹ 

[1]Department of Biology, Simon Fraser University, 8888 University Drive, Burnaby V5A 1S6, , BC, Canada

[2]Department of Psychology, and Neuroscience and Mental Health Institute, University of Alberta, 116 St. and 85 Avenue, Edmonton T6G 2R3, AB, Canada

关键词: GTF2I gene;    Autism;    Williams syndrome;    Anxiety;    Social behavior;   

Others  :  1090502
DOI  :  10.1186/s12868-014-0127-1

 received in 2014-08-01, accepted in 2014-11-13,  发布年份 2014

【 摘 要 】

Background

Individuals with Williams syndrome, a neurogenetic condition caused by deletion of a set of genes at chromosomal location 7q11.23, exhibit a remarkable suite of traits including hypersociality with high, nonselective friendliness and low social anxiety, expressive language relatively well-developed but under-developed social-communication skills overall, and reduced visual-spatial abilities. Deletions and duplications of the Williams-syndrome region have also been associated with autism, and with schizophrenia, two disorders centrally involving social cognition. Several lines of evidence have linked the gene GTF2I (General Transcription Factor IIi) with the social phenotypes of Williams syndrome, but a role for this gene in sociality within healthy populations has yet to be investigated.

Results

We genotyped a large set of healthy individuals for two single-nucleotide polymorphisms in the GTF2I gene that have recently been significantly associated with autism, and thus apparently exhibit functional effects on autism-related social phenotypes. GTF2I genotypes for these SNPs showed highly significant association with low social anxiety combined with reduced social-communication abilities, which represents a metric of the Williams-syndrome cognitive profile as described from previous studies.

Conclusions

These findings implicate the GTF2I gene in the neurogenetic basis of social communication and social anxiety, both in Williams syndrome and among individuals in healthy populations.

【 授权许可】

   
2014 Crespi and Hurd; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Mervis CB, Klein-Tasman BP: Williams syndrome: cognition, personality, and adaptive behavior. Ment Retard Dev Disabil Res Rev 2000, 6:148-158.
• [2]Dykens EM: Anxiety, fears, and phobias in persons with Williams syndrome. Dev Neuropsychol 2003, 23:291-316.
• [3]Martens MA, Wilson SJ, Reutens DC: Research review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype. J Child Psychol Psychiatry 2008, 49:576-608.
• [4]Schubert C: The genomic basis of the Williams-Beuren syndrome. Cell Mol Life Sci 2009, 66:1178-1197.
• [5]Morris CA: The behavioral phenotype of Williams syndrome: a recognizable pattern of neurodevelopment. Am J Med Genet C Semin Med Genet 2010, 154C:427-431.
• [6]Järvinen AM, Bellugi U: What does Williams syndrome reveal about the determinants of social behavior? Front Hum Neurosci 2013, 7:321.
• [7]Järvinen A, Korenberg JR, Bellugi U: The social phenotype of Williams syndrome. Curr Opin Neurobiol 2013, 23:414-422.
• [8]Somerville MJ, Mervis CB, Young EJ, Seo EJ, del Campo M, Bamforth S, Peregrine E, Loo W, Lilley M, Pérez-Jurado LA, Morris CA, Scherer SW, Osborne LR: Severe expressive-language delay related to duplication of the Williams-Beuren locus. New Engl J Med 2005, 353:1694-1701.
• [9]Mervis CB, Dida J, Lam E, Crawford-Zelli NA, Young EJ, Henderson DR, Onay T, Morris CA, Woodruff-Borden J, Yeomans J, Osborne LR: Duplication of GTF2I results in separation anxiety in mice and humans. Am J Hum Genet 2012, 90:1064-1070.
• [10]Dixit A, McKee S, Mansour S, Mehta SG, Tanteles GA, Anastasiadou V, Patsalis PC, Martin K, McCullough S, Suri M, Sarkar A: 7q11.23 Microduplication: a recognizable phenotype. Clin Genet 2013, 83:155-161.
• [11]Meyer-Lindenberg A, Hariri AR, Munoz KE, Mervis CB, Mattay VS, Morris CA, Berman KF: Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci 2005, 8:991-993.
• [12]Meyer-Lindenberg A, Mervis CB, Berman KF: Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci 2006, 7:380-393.
• [13]Jabbi M, Kippenhan JS, Kohn P, Marenco S, Mervis CB, Morris CA, Meyer-Lindenberg A, Berman KF: The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and function. Proc Natl Acad Sci USA 2012, 109:E860-E866.
• [14]Young EJ, Lipina T, Tam E, Mandel A, Clapcote SJ, Bechard AR, Chambers J, Mount HTJ, Fletcher PJ, Roder JC, Osborne LR: Reduced fear and aggression and altered serotonin metabolism in Gtf2ird1-targeted mice. Genes Brain Behav 2008, 7:224-234.
• [15]Palmer SJ, Taylor KM, Santucci N, Widagdo J, Chan YKA, Yeo JL, Adams M, Gunning PW, Hardeman EC: GTF2IRD2 from the Williams-Beuren critical region encodes a mobile-element-derived fusion protein that antagonizes the action of its related family members. J Cell Sci 2012, 125:5040-5050.
• [16]Li HH, Roy M, Kuscuoglu U, Spencer CM, Halm B, Harrison KC, Bayle JH, Splendore A, Ding F, Meltzer LA, Wright E, Paylor R, Deisseroth K, Francke U: Induced chromosome deletions cause hypersociability and other features of Williams-Beuren syndrome in mice. EMBO Mol Med 2009, 1:50-65.
• [17]Sakurai T, Dorr NP, Takahashi N, McInnes LA, Elder GA, Buxbaum JD: Haploinsufficiency of Gtf2i, a gene deleted in Williams syndrome, leads to increases in social interactions. Autism Res 2011, 4:28-39.
• [18]Malenfant P, Liu X, Hudson ML, Qiao Y, Hrynchak M, Riendeau N, Hildebrand MJ, Cohen IL, Chudley AE, Forster-Gibson C, Mickelson ECR, Rajcan-Separovic E, Lewis MES, Holden JJA: Association of GTF2i in the Williams-Beuren syndrome critical region with autism spectrum disorders. J Autism Dev Disord 2012, 42:1459-1469.
• [19]Klein-Tasman BP, Mervis CB, Lord C, Phillips KD: Socio-communicative deficits in young children with Williams syndrome: performance on the autism diagnostic observation schedule. Child Neuropsychol 2007, 13:444-467.
• [20]Klein-Tasman BP, Phillips KD, Lord C, Mervis CB, Gallo FJ: Overlap with the autism spectrum in young children with Williams syndrome. J Dev Behav Pediatr 2009, 30:289-299.
• [21]Tordjman S, Anderson GM, Botbol M, Toutain A, Sarda P, Carlier M, Saugier-Veber P, Baumann C, Cohen D, Lagneaux C, Tabet AC, Verloes A: Autistic disorder in patients with Williams-Beuren syndrome: a reconsideration of the Williams-Beuren syndrome phenotype. PLoS One 2012, 7:e30778.
• [22]Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PBS, Choi M, Crawford EL, Davis L, Davis Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, et al.: Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011, 70:863-885.
• [23]Mulle JG, Pulver AE, McGrath JA, Wolyniec PS, Dodd AF, Cutler DJ, Sebat J, Malhotra D, Nestadt G, Conrad DF, Hurles M, Barnes CP, Ikeda M, Iwata N, Levinson DF, Gejman PV, Sanders AR, Duan J, Mitchell AA, Peter I, Sklar P, O’Dushlaine CT, Grozeva D, O’Donovan MC, Owen MJ, Hultman CM, Kähler AK, Sullivan PF, Kirov G, et al.: Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. Biol Psychiatry 2013, 75:371-377.
• [24]Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E: The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord 2001, 31:5-17.
• [25]Cohen AS, Matthews RA, Najolia GM, Brown LA: Toward a more psychometrically sound brief measure of schizotypal traits: introducing the SPQ-brief revised. J Pers Disord 2010, 24:516-537.
• [26]Reilly J, Losh M, Bellugi U, Wulfeck B: “Frog, where are you?” Narratives in children with specific language impairment, early focal brain injury, and Williams syndrome. Brain Lang 2004, 88:229-247.
• [27]Reilly J, Bernicot J, Vicari S, Lacroix A, Bellugi U: Narratives in Children With Williams Syndrome: A Cross Linguistic Perspective. In Perspectives on Language and Language Development: Essays in Honor of Ruth A. Berman. Edited by Ravid D, Shyldkrot HBZ. Kluwer, Dordrecht, the Netherlands; 2005:303-312.
• [28]Fishman I, Yam A, Bellugi U, Mills D: Language and sociability: insights from Williams syndrome. J Neurodev Disord 2011, 3:185-192.
• [29]Dai L, Carter CS, Ying J, Bellugi U, Pournajafi-Nazarloo H, Korenberg JR: Oxytocin and vasopressin are dysregulated in Williams syndrome, a genetic disorder affecting social behavior. PLoS One 2012, 7:e38513.
• [30]Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, Bjornsdottir G, Walters GB, Jonsdottir GA, Doyle OM, Tost H, Grimm O, Kristjansdottir S, Snorrason H, Davidsdottir SR, Gudmundsson LJ, Jonsson GF, Stefansdottir B, Helgadottir I, Haraldsson M, Jonsdottir B, Thygesen JH, Schwarz AJ, Didriksen M, Stensbøl TB, Brammer M, Kapur S, Halldorsson JG, Hreidarsson S, Saemundsen E, et al.: CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 2014, 505:361-366.
• [31]Burkett K, Graham J, McNeney B: hapassoc: software for likelihood inference of trait associations with SNP haplotypes and other attributes. J Stat Softw 2006, 16:1-19.
• [32]Scheeren AM, Koot HM, Begeer S: Social interaction style of children and adolescents with high-functioning autism spectrum disorder. J Autism Dev Disord 2012, 42:2046-2055.
• [33]Danoff SK, Taylor HE, Blackshaw S, Desiderio S: TFII-I, a candidate gene forWilliams syndrome cognitive profile: parallels between regional expression in mouse brain and human phenotype. Neuroscience 2004, 123:931-938.
• [34]Collette JC, Chen XN, Mills DL, Galaburda AM, Reiss AL, Bellugi U, Korenberg JR: William’s syndrome: gene expression is related to parental origin and regional coordinate control. J Hum Genet 2009, 54:193-198.
• [35]Crespi BJ: The Strategies of the Genes: Genomic Conflicts, Attachment Theory, and Development of the Social Brain. In Brain, Behavior and Epigenetics. Edited by Petronis A, Mill J. Springer-Verlag, Heidelberg, Berlin; 2011:143-168.
• [36]Preuss TM, Cáceres M, Oldham MC, Geschwind DH: Human brain evolution: insights from microarrays. Nat Rev Genet 2004, 5:850-860.
• [37]Sikela JM: The jewels of our genome: the search for the genomic changes underlying the evolutionarily unique capacities of the human brain. PLoS Genet 2006, 2:e80.