Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism

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 quan titative 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 (F-2,F-23=7.29, P=.004) and of 3 lobe-based subregions in the UNC sample of 29 children (frontal lobe gray matter: F-2,(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: F-1,(24)= 14. 11, P=.001; frontal lobe gray matter: F-1,F-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: F-1,(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 polyinorphism 5-HTTLPR influences cerebral cortical gray, matter volumes in young male children with autism.