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
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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)