International Meeting for Autism Research: Genotype-Phenotype Associations In Response to the Intruder Paradigm for Humans

Genotype-Phenotype Associations In Response to the Intruder Paradigm for Humans

Thursday, May 12, 2011
Elizabeth Ballroom E-F and Lirenta Foyer Level 2 (Manchester Grand Hyatt)
3:00 PM
P. D. Chamberlain1, N. K. Jamison1, K. Taylor2, R. J. Robison3, P. Wilson3, T. Newton1, S. van Tassell4, O. Johnston5, M. Christensen4, J. D. Higley4 and M. South1,4, (1)Neuroscience, Brigham Young University, Provo, UT, (2)Psychiatry, Virginia Commonwealth University, Richmond, VA, (3)Psychiatry Research Clinic, University of Utah School of Medicine, Salt Lake City, UT, (4)Psychology, Brigham Young University, Provo, UT, (5)School of Accountancy, Brigham Young University, Provo, UT
Background:  

Previous research correlating genotype and categorical diagnostic symptoms of autism spectrum disorders (ASD) have yielded largely inconclusive findings, in part due to variation of behaviors within the ASDs. Ecologically-valid dimensional behaviors may improve insight into underlying genetic and neuropathological processes, as opposed to mere categorical diagnostic designations.  We adapted a paradigm used in studies with rhesus monkeys that use a human intruder to provoke anxiety (Kalin, 2003).   This paradigm may provide a particularly useful translational model because of the similarity in related brain systems across species and because anxiety is a frequent debilitating symptom of those diagnosed with ASD.

Objectives:  

Our goal was to explore the relationship between known anxiety-related genetic single nucleotide polymorphisms (SNPs) and psychophysiological responses during anxiety-provoking situations.  Analysis of associations between allelic variations and such specific phenotypes provides better opportunity for understanding symptom heterogeneity found within ASD.

Methods:  

We adapted the Human Intruder Paradigm from studies of emotion regulation in monkeys (Kalin, 2003).  Participants were 38 children and adolescents diagnosed with an ASD (mean age = 13.3, mean Full Scale IQ = 108) and 36 typically developing controls (TYP group) matched for age and IQ. Each participant performed a simple computer task with a research assistant present while we measured their skin conductance response (SCR). During the first stage of the paradigm, the attending research assistant leaves the room for a short time, leaving the participant alone.  After the RA returns, an imposing male confederate enters the room and begins arguing with the RA until she agrees to leave with him to resolve their differences.  One minute later, the confederate intruder returns, this time without the RA.

We collected saliva samples for DNA extraction using Oragene kits. Genotyping was conducted using TaqManÒ, with ready SNP assays from Applied Biosystems for COMT, DAT1 (SLC6A3), 5-HT1B (HTR1B), HTR2A, SNAP25, BDNF, MAOA, and TPH2. T-test analyses included genotype status (± expected minor allele) as the independent variable and psychophysiological response amplitudes as dependent variables. 

Results:  

In the ASD but not the TYP group, SCR response during the Isolation phase was significantly affected by variation in the functional COMT Val158Met polymorphism (rs4680; Met tranformation = increased response), t(36) = 3.86, p < .001. Also in the ASD group but not the TYP group, the minor C allele of the HTR1B SNP also showed an increased response during Isolation that was marginally significant (p < .10).  In contrast, the TYP group but not the ASD group showed significant associations between MAOA status (major A allele has increased SCR activation) for the Intrusion and post-intruder Recovery phases. There were no significant associations between genotype variation and ASD symptoms scores measured by the ADOS. 

Conclusions:  

Our findings suggest that genotypes are more helpful in predicting specific behavioral variables, such as the response to a strange human intruder, than more general symptom categories. The development of relevant and rich behavioral measures of important dimensions such as anxiety can provide insight into the associations of genes, brain development, and behavior in autism.

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