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

Abstract

BackgroundIndividuals 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.ResultsWe 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.ConclusionsThese 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.

A Common Polymorphism in a Williams Syndrome Gene Predicts Amygdala Reactivity and Extraversion in Healthy Adults

“…While our current results along with those of Crespi and Hurd (7) are consistent with the hyper-social phenotype of WS, the molecular mechanisms through which these associations occur is unclear. One intriguing possible molecular pathway through which GTF2I rs13227433 genotype may affect neural and behavioral socioemotional phenotypes is serotonin signaling, which plays an important role in modulating corticolimbic circuit function, including amygdala reactivity (31-33).…”

“…However, results were similar when using a genotyped proxy SNP in high linkage disequilibrium with rs4717907 and rs13227433 (see Supplementary Analyses), increasing confidence in our results and the quality of imputation. An additional limitation of the present study is that the DNS battery did not include a measure specific to social anxiety or a measure of social abilities similar to the Autism Spectrum Quotient used in prior research examining these GTF2I genotypes (7), and so we were unable to construct a WS profile similar to that examined by Crespi and Hurd. However, given that extraversion is negatively correlated with social anxiety (12), individuals who reported relatively higher levels of extraversion in the DNS likely also had low social anxiety.…”

“…There were a small number of participants homozygous for the minor C allele (Caucasian n=22, African American n=2, Asian n=3), therefore we created a binary variable grouping participants as A allele homozygotes or C allele carriers (see also Supplementary Analyses supporting this grouping). Genotype was dummy-coded so that the AA genotype (previously associated with a higher WS profile score and lower social anxiety (7)) was the group of interest (C allele carriers = 0; AA = 1). Population stratification reflecting genetic heterogeneity associated with ancestry was examined using identity by state (IBS) analysis in PLINK of the whole genome SNPs, extracting the first four multidimensional scaling (MDS) components for inclusion as covariates in all genotype analyses (26).…”

“…Specifically, two GTF2I SNPs in high linkage disequilibrium, rs13227433 and rs4717907, have been associated with individual differences on a composite WS profile score, including reduced communication abilities as rated on the Autism Spectrum Quotient scale, and also reduced social anxiety (7). Moreover, GTF2I -deficient mice evidence increased social interaction but not alterations in learning and memory or general anxiety, suggesting that deletion of GTF2I may play a specific role in the social phenotype of WS (8).…”

Imaging Genetics and Genomics in Psychiatry: A Critical Review of Progress and Potential

“…For example, Williams Syndrome, which is characterized by a host of physical and personality characteristics, including excessive sociality is attributable to a microdeletion that typically occurs during the formation of germline cells in people with no history of the disorder (48,49). Common variation within the genes (e.g., GTF2I ) spanning the microdeletion region have become candidates that are informing phenotypes related to sociability (22,50). Intermediate phenotypes can also represent stable trait differences that while not entirely heritable per se, are dependent upon experience arising as the product gene by environment interactions (e.g., FKBP5 (20,51,52); Supplemental Material).…”