Poster No:
878
Submission Type:
Abstract Submission
Authors:
Michael Gregory1, Mbemba Jabbi2, Shane Kippenhan1, Tiffany Nash1, Madeline Garvey1, Carolyn Mervis3, Daniel Eisenberg1, Shau-Ming Wei1, Philip Kohn1, Bhaskar Kolachana1, Peter Schmidt1, Karen Berman1
Institutions:
1NIMH, National Institutes of Health, Bethesda, MD, 2University of Texas, Austin, TX, 3University of Louisville, Louisville, KY
First Author:
Co-Author(s):
Tiffany Nash
NIMH, National Institutes of Health
Bethesda, MD
Philip Kohn
NIMH, National Institutes of Health
Bethesda, MD
Karen Berman
NIMH, National Institutes of Health
Bethesda, MD
Introduction:
The insula, located deep within the lateral sulcus, subserves a multitude of neurofunctional domains including sensorimotor, chemosensory, cognition, and socio-emotional processing (1). Anterior portions of the insula mediate socio-emotional processes, including empathy, social cognition, emotional experience, and simulating others' mental states (2). Williams syndrome (WS), a rare neurodevelopmental disorder caused by hemideletion of ~26 genes at the 7q11.23 chromosomal locus, offers a valuable opportunity to understand how genetic changes affect brain development and translate into complex behaviors because both the genetics and neurobehavioral phenotypes are well-circumscribed and well-defined. The neurobehavioral profile of WS includes increased sociability, overfriendliness, and empathy (3), characteristics that have been related to structural and functional changes of the anterior insula (Ai) (4). Additionally, GTF2I, a gene in the 7q11.23 WS Critical Region (WSCR), has also been linked to the WS social phenotype (4,5,6). Here, we test whether Ai structure and function are altered in children and adolescents with WS, and if so, which, if any, WSCR genes are associated with Ai structure by conducting a region-wide association study ("mini-GWAS") restricted to just the WSCR. Further, as GTF2I has been linked to brain myelination (7), we specifically examined whether development of myelin underlying the insular cortex was related to GTF2I variation.
Methods:
First, we compared Ai gray matter volume (GMV) from longitudinal scans of 30 children and adolescents with WS (79 visits, age=12.6±4.7 years, 10 males) to 74 typically developing individuals ([TDs]; 197 visits, age=12.4±3.3 years, 27 males) using linear mixed-effects modeling, controlling for age and sex. Next, we compared Ai regional cerebral blood flow (rCBF) derived with ASL MRI of 13 individuals with WS (18 visits, age=15.1±5.5 years, 1 male) and 25 TDs (44 visits, age=15.3±5.5 years, 2 males) using linear mixed-effects modeling, controlling for age and sex. Then, to investigate the genetic underpinnings of insular structure, we tested whether GMV of the Ai was related to genetic variation in the WSCR in 222 healthy adults using a mini-GWAS of just this genetic region, and we sought replication of the findings in a second, independent sample of 265 healthy adults from the Human Connectome Project (HCP). Finally, using longitudinal mcDESPOT imaging of myelin water fraction (MWF) from 134 TDs (423 visits, age=12.9±2.9 years, 68 males), we tested whether genetic variation predicting GTF2I cortical expression was related to the development of MWF with mixed-effect spline modeling. Imaging analyses were FDR-corrected for multiple comparisons, and mini-GWAS analyses were Bonferroni-corrected for the number of LD-independent signals in the WSCR.
Results:
GMV of two distinct portions of the bilateral Ai were altered in children with WS: a superior portion with less GMV and an inferior area with greater GMV (both p-FDR<0.001). rCBF of bilateral Ai clusters that overlapped the areas of decreased GMV was significantly lower in individuals with WS (both p-FDR<0.01). In the discovery group of healthy adults, Ai GMV related to SNPs spanning the initiation site of GTF2I (peak SNP p=4.37x10-4), a finding replicated in the HCP sample (peak SNP p=1.3x10-3). Finally, GTF2I expression scores related to development of MWF in the bilateral anterior temporal lobe white matter directly projecting to Ai: individuals predisposed to greater GTF2I expression had increased myelin as they approached adulthood (p<0.001).
Conclusions:
These results provide evidence of a GTF2I-related neurogenetic mechanism important in insular cortex structural and functional organization. Given the associations of GTF2I with the social phenotype of WS and with myelination, our results linking Ai structure, function, and myelination with GTF2I variation underscore a critical role in the behavioral and brain alterations of WS.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism) 2
Emotion, Motivation and Social Neuroscience:
Social Cognition
Genetics:
Genetic Modeling and Analysis Methods
Neurogenetic Syndromes 1
Novel Imaging Acquisition Methods:
Multi-Modal Imaging
Keywords:
Cerebral Blood Flow
Myelin
STRUCTURAL MRI
Other - GWAS; Williams syndrome; ASL; mcDESPOT; GTF2I; Insula
1|2Indicates the priority used for review
Provide references using author date format
1. Uddin L. (2017), Structure and function of the human insula. J Clin Neurophysiol. 34(4): 300–306.
2. Lamm C. (2010), The role of anterior insular cortex in social emotions. Brain Struct Funct. 214(5-6):579-91.
3. Mervis CB. (2000), Williams syndrome: cognition, personality, and adaptive behavior. Ment Retard Dev Disabil Res Rev. 6(2):148-58.
4. Jabbi M. (2012), The Williams syndrome chromosome 7q11.23 hemideletion confers hypersocial, anxious personality coupled with altered insula structure and function. Proc Natl Acad Sci. 109(14):E860-6.
5. Jarvinen A. (2013), The Social Phenotype of Williams Syndrome. Curr Opin Neurobiol. 23(3): 414–422.
6. Crespi B. (2014), Cognitive-behavioral phenotypes of Williams syndrome are associated with genetic variation in the GTF2I gene, in a healthy population. BMC Neurosci. 15:127.
7. Barak B. (2019), Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug. Nat Neurosci. 22(5):700-708.