Common functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents.
Disrupted-in-schizophrenia-1 (DISC1), contains two common non-synonymous single-nucleotide polymorphisms (SNPs)--Leu607Phe and Ser704Cys--that modulate (i) facets of DISC1 molecular functioning important for cortical development, (ii) fronto-temporal cortical anatomy in adults and (iii) risk for diverse psychiatric phenotypes that often emerge during childhood and adolescence, and are associated with altered fronto-temporal cortical development. It remains unknown, however, if Leu607Phe and Ser704Cys influence cortical maturation before adulthood, and whether each SNP shows unique or overlapping effects. Therefore, we related genotype at Leu607Phe and Ser704Cys to cortical thickness (CT) in 255 typically developing individuals aged 9-22 years on whom 598 magnetic resonance imaging brain scans had been acquired longitudinally. Rate of cortical thinning varied with DISC1 genotype. Specifically, the rate of cortical thinning was attenuated in Phe-carrier compared with Leu-homozygous groups (in bilateral superior frontal and left angular gyri) and accelerated in Ser-homozygous compared with Cys-carrier groups (in left anterior cingulate and temporal cortices). Both SNPs additively predicted fixed differences in right lateral temporal CT, which were maximal between Phe-carrier/Ser-homozygous (thinnest) vs Leu-homozygous/Cys-carrier (thickest) groups. Leu607Phe and Ser704Cys genotype interacted to predict the rate of cortical thinning in right orbitofrontal, middle temporal and superior parietal cortices, wherein a significantly reduced rate of CT loss was observed in Phe-carrier/Cys-carrier participants only. Our findings argue for further examination of Leu607Phe and Ser704Cys interactions at a molecular level, and suggest that these SNPs might operate (in concert with other genetic and environmental factors) to shape risk for diverse phenotypes by impacting on the early maturation of fronto-temporal cortices.
Raznahan
A
A
Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA. raznahana@mail.nih.gov
Lee
Y
Y
Long
R
R
Greenstein
D
D
Clasen
L
L
Addington
A
A
Rapoport
J L
JL
Giedd
J N
JN
D000293:Adolescent; D041923:Adolescent Development / Q000502:physiology*; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000254:growth & development*; D002648:Child; D002657:Child Development / Q000502:physiology*; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D059906:Neuroimaging / Q000379:methods / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D055815:Young Adult
C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins