The ultimate goal of this component is to establish the genetic architecture of Williams syndrome and to use this to dissect genetic contributions to the neural systems underlying human cognition and social behavior. The overarching premise is that humans with cognition and well-defined genetic anomalies provide incisive models for understanding uniquely human social behavior. In the past grant period, we generated the genetic toolkit and defined the common deletion and rare variants with high resolution genomic arrays. We used these tools to associate a single gene, GTF2I, with altered social behavior, two genes with visual spatial function and neuroanatomy, and a small set of genes with mild cognitive deficits. We used quantitative transcriptional analysis to reveal parent-of-origin effects, to show the synaptic protein STX1A is related to WS cognition and to suggest gene networks perturbed. We established a new approach to link WS genes to primate brain systems, colocalizing GTF2IRD1 in hypothalamic neurons, leading to our hypothesis that oxytocin-vasopressin dysregulation underlies WS social behavior. In the next grant period, we will employ a high resolution approach in the WS region and genomewide, and use genetic hypotheses to dissect cognitive, social and neural imaging data, to elucidate the role of WS genes and modifiers in establishing and maintaining the neural systems for WS.
In Aim 1 we will determine the genomic structure of the PPG WS cohort and identify new atypical deletions.
In Aim 2 we will determine the role of WS region DNA sequence in social-emotional phenotypes and the role of genes related to social behavior as modifiers of WS phenotypes.
In Aim 3 we will determine the role of transcript levels of WS and non-WS genes to WS social-emotional phenotypes.
In Aim 4 we will determine the transcriptional networks perturbed in WS using cell line and neuron models. Elucidating the links between genes, emotion and social behavior in WS may provide fundamental insight into the genetic mechanisms and neural circuits for human behavior.

Public Health Relevance

Understanding human social behavior and emotion is one of the greatest challenges for modern biomedicine. Mental dysfunction affects the lives of many millions of Americans and there is a pressing need to develop new ways to treat it. The results of our study will provide unprecedented integration of the genetic and brain processes responsible for human behavior and keys to novel treatments

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Salk Institute for Biological Studies
La Jolla
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