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Cerebral Cortical Gray Matter Overgrowth and Functional Variation of the Serotonin Transporter Gene in Autism
Thomas H. Wassink, MD;
Heather C. Hazlett, PhD;
Eric A. Epping, MD, PhD;
Stephan Arndt, PhD;
Stephen R. Dager, MD;
Gerard D. Schellenberg, PhD;
Geraldine Dawson, PhD;
Joseph Piven, MD
Arch Gen Psychiatry. 2007;64(6):709-717.
Context Autism is a heritable neurodevelopmental disorder characterized biologically by enlargement of the head and brain and abnormalities of serotonin neurotransmission.
Objective To evaluate whether 5-HTTLPR, a functional promoter polymorphism of the serotonin transporter gene SLC6A4, influences cerebral cortical structure volumes in young male children with autism.
Design Association study of a genetic variant with quantitative traits.
Setting Autism research centers at the University of North Carolina (UNC), Chapel Hill, and the University of Washington (UW), Seattle.
Participants Forty-four male children, 2 to 4 years old, with autism participating in longitudinal brain magnetic resonance imaging studies.
Main Outcome Measures Cerebral cortical and cerebellar gray and white matter volumes.
Results We found that 5-HTTLPR genotype influenced gray matter volumes of the cerebral cortex (F2,23 = 7.29, P = .004) and of 3 lobe-based subregions in the UNC sample of 29 children (frontal lobe gray matter: F2,23 = 6.36, P = .01). The 5-HTTLPR short allele appeared to be additively associated with increasing gray matter volumes, an observation affirmed by tests of linear genotype effects (cortical gray matter: F1,24 = 14.11, P = .001; frontal lobe gray matter: F1,24 = 13.20, P = .001). Genotype did not influence cerebellar volumes. Confirmation was pursued by means of the UW sample of 15 children. While effects were not significant in the UW sample alone, the patterns of adjusted means resembled those found in the UNC sample. Positive Cochran-Mantel-Haenszel test results supported the concordance of relationships across the 2 sites, and analyses of covariance of the combined sample that included a site covariate showed significant linear genotype effects on structure volumes (cortical gray matter: F1,38 = 5.73, P = .02; frontal lobe gray matter: F1,38 = 11.73, P = .002). Effect sizes of 5-HTTLPR genotype on total cortical and frontal lobe gray matter volumes were 10% and 16%, respectively.
Conclusion The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism.
Author Affiliations: Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine (Drs Wassink, Epping, and Arndt), and Department of Biostatistics, College of Public Health (Dr Arndt), The University of Iowa, Iowa City; Neurodevelopmental Disorders Research Center, Department of Psychiatry, University of North Carolina, Chapel Hill (Drs Hazlett and Piven); Autism Center, Center on Human Development and Disability, University of Washington, Seattle (Drs Dager, Schellenberg, and Dawson); Departments of Radiology and Bioengineering (Dr Dager), Psychiatry and Behavioral Sciences (Drs Dager and Dawson), Gerontology and Geriatric Medicine (Dr Schellenberg), Neurology (Dr Schellenberg), Pharmacology (Dr Schellenberg), and Psychology (Dr Dawson), University of Washington, Seattle; and Geriatrics Research Education and Clinical Center, Puget Sound Veterans Affairs Medical Center, Seattle (Dr Schellenberg).
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