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

Brain Structure and Function, Oct 2015

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.

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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

Brain Struct Funct 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 Jiayuan Xu 0 1 2 Wen Qin 0 1 2 Bing Liu 0 1 2 Tianzi Jiang 0 1 2 Chunshui Yu 0 1 2 0 Brainnetome Center, Institute of Automation, Chinese Academy of Sciences , Beijing 100190 , China 1 Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital , No. 154, Anshan Road, Heping District, Tianjin 300052 , China 2 National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences , Beijing 100190 , China 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 voxelbased analysis. We found a significant non-additive COMT 9 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 9 DRD2 interaction in the rsFC between the right dACC and precuneus, displaying a U-shape modulation by dopamine signaling. Moreover, this J. Xu and W. Qin were contributed equally to this work. Catechol-O-methyltransferase; Dopamine D2 receptor; Functional magnetic resonance imaging; Gray matter volume; Resting-state functional connectivity - As an important neurotransmitter, dopamine is involved in the modulation of the cognitive and emotional processing (Girault and Greengard 2004; Seamans and Yang 2004). The dopamine system affects human behaviors via modulating brain structural and functional properties in a nonlinear manner (Williams and Goldman-Rakic 1995, 1998; Seamans and Yang 2004; Bertolino et al. 2009). The dopamine signaling in the brain depends on both the availability of dopamine and the efficiency of dopamine receptors. The availability of dopamine can be modulated by the catechol-O-methyltransferase (COMT), which catalyzes the degradation of synaptic dopamine, especially in the prefrontal cortex (PFC) (Ma¨nnist o¨ and Kaakkola 1999; Seamans and Yang 2004). COMT gene contains a functional polymorphism (rs4680, G [ A), resulting in a decrease in enzymatic activity in A-allele carriers (Ma¨nnisto¨ and Kaakkola 1999), through which COMT polymorphism can modulate structure and function of the brain that affect individuals’ behavioral performance. The efficiency of dopamine receptors is also modulated by genetic variation. A functional polymorphism (rs1076560, G [ T) of the dopamine D2 receptor (DRD2) gene can modulate DRD2 efficiency by modifying the ratios of its two isoforms (Zhang et al. 2007). According to the genotypes of COMT rs4680 and DRD2 rs1076560, one can approximately estimate the dopamine signaling in the brain. The COMT rs4680-GG subjects have greater COMT activity and lower dopamine signaling than the A-allele carriers (Matsumoto et al. 2003). For the DRD2 rs1076560, GG genotype has greater expression of D2S (inhibiting dopamine release) and lower dopamine signaling than T-allele carriers (Zhang et al. 2007). Consequently, individuals with the rs4680-GG/rs1076560-GG status may have the lowest dopamine signaling; in contrast, individuals with the rs4680-A-allele/rs1076560-TT status may have the highest dopamine signaling. In this frame, we can explore the non-linear modulation of the dopamine system on structure and function of the brain by observing combined effects between COMT and DRD2 genotypes. The effects of the common genetic variants of COMT and DRD2 on behavioral performance and brain structural and functional properties have been originally described in populations with European ancestry (Bruder et al. 2005; Egan et al. 2001; Mattay et al. 2003; Meyer-Lindenberg et al. 2006; Zhang et al. 2007). This knowledge has been subsequently translated to Asia populations (Li et al. 2009; Liu et al. 2010; Ohnishi et al. 2006; Zhang et al. 2007; Zheng et al. 2012). However, most of these studies focus on the respective effects of COMT or DRD2 (Taylor et al. 2007; Cerasa et al. 2008, 2009, 2010; Honea et al. 2009; Li et al. 2009; Ehrlich et al. 2010; Liu et al. 2010). Only a few studies have focused on COMT 9 DRD2 interactions on behavioral performance (Reuter et al. 2005, 2007; Xu et al. 2007). A recent study has explored COMT 9 DRD2 interactions on functional connectivity density (FCD) in healthy subjects and found completely inversed nonlinear modulation patterns of the dopamine s (...truncated)


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Jiayuan Xu, Wen Qin, Bing Liu, Tianzi Jiang, Chunshui Yu. 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, Brain Structure and Function, 2016, pp. 3891-3901, Volume 221, Issue 8, DOI: 10.1007/s00429-015-1134-4