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Interactions of genetic variants reveal inverse modulation patterns of dopamine system on brain gray matter volume and resting-state functional connectivity in healthy young adults.

ABSTRACT: Different genotypic combinations of COMT and DRD2 can generate multiple subgroups with different levels of dopamine signaling. Its modulations on brain properties can be investigated by analyzing the combined gene effects of COMT and DRD2. However, the inherent association between modulation patterns of the dopamine system on structural and functional properties of the brain remains unknown. In 294 healthy young adults, we investigated both additive and non-additive interactions of COMT and DRD2 on gray matter volume (GMV) and resting-state functional connectivity (rsFC) using a voxel-based analysis. We found a significant non-additive COMT × DRD2 interaction in the right dorsal anterior cingulate cortex (dACC), exhibiting an inverted U-shape modulation by dopamine signaling. We also found a significant non-additive COMT × DRD2 interaction in the rsFC between the right dACC and precuneus, displaying a U-shape modulation by dopamine signaling. Moreover, this rsFC was negatively correlated with the GMV of the right dACC. Although the additive interaction did not pass corrections for multiple comparisons, we also found a trend towards an inverse modulation pattern and a negative correlation between the GMV and rsFC of the right inferior frontal gyrus. No genotypic differences were detected in any assessments of the cognition, mood and personality. These findings suggest that healthy young adults without optimal dopamine signaling may maintain their normal behavioral performance via a functional compensatory mechanism in response to structural deficit due to genetic variation.

SUBMITTER: Xu J

PROVIDER: S-EPMC5065899 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Interactions of genetic variants reveal inverse modulation patterns of dopamine system on brain gray matter volume and resting-state functional connectivity in healthy young adults.

Xu Jiayuan J Qin Wen W Liu Bing B Jiang Tianzi T Yu Chunshui C

Brain structure & function 20151025 8

Different genotypic combinations of COMT and DRD2 can generate multiple subgroups with different levels of dopamine signaling. Its modulations on brain properties can be investigated by analyzing the combined gene effects of COMT and DRD2. However, the inherent association between modulation patterns of the dopamine system on structural and functional properties of the brain remains unknown. In 294 healthy young adults, we investigated both additive and non-additive interactions of COMT and DRD2 ...[more]

PMID: 26498330

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Project description:BackgroundDespite decades of research, there is continued uncertainty regarding whether autism is associated with a specific profile of gray matter (GM) structure. This inconsistency may stem from the widespread use of voxel-based morphometry (VBM) methods that combine indices of GM density and GM volume. If GM density or volume, but not both, prove different in autism, the traditional VBM approach of combining the two indices may obscure the difference. The present study measures GM density and volume separately to examine whether autism is associated with alterations in GM volume, density, or both.MethodsDifferences in MRI-based GM density and volume were examined in 6-25 year-olds with a diagnosis of autism spectrum disorder (n = 213, 80.8% male, IQ 47-154) and a typically developing (TD) sample (n = 190, 71.6% male, IQ 67-155). High-resolution T1-weighted anatomical images were collected on a single MRI scanner. Regional density and volume were estimated via whole-brain parcellation comprised of 1625 parcels. Parcel-wise analyses were conducted using generalized additive models while controlling the false discovery rate (FDR, q < 0.05). Volume differences in the 68-region Desikan-Killiany atlas derived from Freesurfer were also examined, to establish the generalizability of findings across methods.ResultsNo density differences were observed between the autistic and TD groups, either in individual parcels or whole brain mean density. Increased volume was observed in autism compared to the TD group when controlling for Age, Sex, and IQ, both at the level of the whole brain (total volume) and in 45 parcels (2.8% of total parcels). Parcels with greater volume included inferior, middle, and superior temporal gyrus, inferior and superior frontal gyrus, precuneus, and fusiform gyrus. Converging evidence from a standard Freesurfer pipeline also identified greater volume in a number of overlapping regions.LimitationsThe method for determining "density" is not a direct measure of neuronal density, and this study cannot reveal underlying cellular differences. While this study represents possibly the largest single-site sample of its kind, it is underpowered to detect very small differences.ConclusionsThese results provide compelling evidence that autism is associated with regional GM volumetric differences, which are more prominent than density differences. This underscores the importance of examining volume and density separately, and suggests that direct measures of volume (e.g. region-of-interest or tensor-based morphometry approaches) may be more sensitive to autism-relevant differences in neuroanatomy than concentration/density-based approaches.

Dataset Information

Interactions of genetic variants reveal inverse modulation patterns of dopamine system on brain gray matter volume and resting-state functional connectivity in healthy young adults.

Publications

Interactions of genetic variants reveal inverse modulation patterns of dopamine system on brain gray matter volume and resting-state functional connectivity in healthy young adults.

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