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


METHODS
Association study of a genetic variant with quantitative traits.


METHODS
Autism research centers at the University of North Carolina (UNC), Chapel Hill, and the University of Washington (UW), Seattle.


METHODS
Forty-four male children, 2 to 4 years old, with autism participating in longitudinal brain magnetic resonance imaging studies.


METHODS
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(2,23) = 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(1,24) = 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: F(1,38) = 11.73, P = .002). Effect sizes of 5-HTTLPR genotype on total cortical and frontal lobe gray matter volumes were 10% and 16%, respectively.


CONCLUSIONS
The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism.
Wassink
Thomas H
TH
Department of Psychiatry, The University of Iowa, USA.
Hazlett
Heather C
HC
Epping
Eric A
EA
Arndt
Stephan
S
Dager
Stephen R
SR
Schellenberg
Gerard D
GD
Dawson
Geraldine
G
Piven
Joseph
J
D000367:Age Factors; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology*; D002531:Cerebellum / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology*; D002675:Child, Preschool; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006984:Hypertrophy / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D011110:Polymorphism, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012737:Sex Factors
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins