Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Brain Structure and Function
Published in: Brain Structure and Function 8/2016

Open Access 01-11-2016 | Original Article

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

Authors: Jiayuan Xu, Wen Qin, Bing Liu, Tianzi Jiang, Chunshui Yu

Published in: Brain Structure and Function | Issue 8/2016

Login to get access

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.
Appendix
Available only for authorised users
Literature
Akil M, Kolachana BS, Rothmond DA, Hyde TM, Weinberger DR, Kleinman JE (2003) Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 23:2008–2013PubMed
Beck AT, Steer RA, Ball R, Ranieri WF (1996) Comparison of beck depression inventories-IA and-II in psychiatric outpatients. J Pers Assess 67:588–597CrossRefPubMed
Bertolino A, Fazio L, Di Giorgio A, Blasi G, Romano R, Taurisano P, Caforio G, Sinibaldi L, Ursini G, Popolizio T (2009) Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans. J Neurosci 29:1224–1234CrossRefPubMedPubMedCentral
Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, Gilliam TC (2005) Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiatry 58:901–907CrossRefPubMed
Cerasa A, Cherubini A, Quattrone A, Gioia MC, Tarantino P, Annesi G, Assogna F, Caltagirone C, Spalletta G (2010) Met158 variant of the catechol-O-methyltransferase genotype is associated with thicker cortex in adult brain. Neuroscience 167:809–814CrossRefPubMed
Cerasa A, Gioia MC, Labate A, Liguori M, Lanza P, Quattrone A (2008) Impact of catechol-O-methyltransferase Val108/158 met genotype on hippocampal and prefrontal gray matter volume. NeuroReport 19:405–408CrossRefPubMed
Cerasa A, Gioia MC, Tarantino P, Labate A, Arabia G, Annesi G, Lanza P, Di Palma G, Blasi V, Quattrone A (2009) The DRD2 TaqIA polymorphism associated with changed midbrain volumes in healthy individuals. Genes Brain Behav 8:459–463CrossRefPubMed
Chao-Gan Y, Yu-Feng Z (2010) DPARSF: a MATLAB toolbox for “pipeline” data analysis of resting-state fMRI. Front Syst Neurosci 4:13PubMedPubMedCentral
Cloninger CR, Svrakic DM, Przybeck TR (1993) A psychobiological model of temperament and character. Arch Gen Psychiatry 50:975–990CrossRefPubMed
Coffeen U, López-Avila A, Ortega-Legaspi JM, Ángel R, López-Muñoz FJ, Pellicer F (2008) Dopamine receptors in the anterior insular cortex modulate long-term nociception in the rat. Eur J Pain 12:535–543CrossRefPubMed
Contreras M, Ceric F, Torrealba F (2007) Inactivation of the interoceptive insula disrupts drug craving and malaise induced by lithium. Science 318:655–658CrossRefPubMed
DeMille MM, Kidd JR, Ruggeri V, Palmatier MA, Goldman D, Odunsi A, Okonofua F, Grigorenko E, Schulz LO, Bonne-Tamir B, Lu RB, Parnas J, Pakstis AJ, Kidd KK (2002) Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. Hum Genet 111:521–537CrossRefPubMed
Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98:6917–6922CrossRefPubMedPubMedCentral
Ehrlich S, Morrow EM, Roffman JL, Wallace SR, Naylor M, Bockholt HJ, Lundquist A, Yendiki A, Ho BC, White T, Manoach DS, Clark VP, Calhoun VD, Gollub RL, Holt DJ (2010) The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults. NeuroImage 53:992–1000CrossRefPubMed
Fumagalli F, Racagni G, Colombo E, Riva M (2003) BDNF gene expression is reduced in the frontal cortex of dopamine transporter knockout mice. Mol Psychiatry 8:898–899CrossRefPubMed
Goldman-Rakic PS (1998) The cortical dopamine system: role in memory and cognition. Adv Pharmacol (San Diego, Calif) 42:707–711CrossRef
Gong Y (1989) Manual of Wechsler Memory Scale-China Revised. Hunan Mapping, Changsha
Heaton R (1999) Wisconsin Card Sorting Test (computer version 3 for Windows research edition). Psychological Assessment Resources, Odessa, FL
Henseler I, Falkai P, Gruber O (2009) A systematic fMRI investigation of the brain systems subserving different working memory components in schizophrenia. Eur J Neurosci 30:693–702CrossRefPubMed
Honea R, Verchinski BA, Pezawas L, Kolachana BS, Callicott JH, Mattay VS, Weinberger DR, Meyer-Lindenberg A (2009) Impact of interacting functional variants in COMT on regional gray matter volume in human brain. NeuroImage 45:44–51CrossRefPubMed
Ko JH, Ptito A, Monchi O, Cho SS, Van Eimeren T, Pellecchia G, Ballanger B, Rusjan P, Houle S, Strafella AP (2009) Increased dopamine release in the right anterior cingulate cortex during the performance of a sorting task: a [11C] FLB 457 PET study. NeuroImage 46:516–521CrossRefPubMedPubMedCentral
Küppers E, Beyer C (2001) Dopamine regulates brain-derived neurotrophic factor (BDNF) expression in cultured embryonic mouse striatal cells. NeuroReport 12:1175–1179CrossRefPubMed
Larsen KE, Fon EA, Hastings TG, Edwards RH, Sulzer D (2002) Methamphetamine-induced degeneration of dopaminergic neurons involves autophagy and upregulation of dopamine synthesis. J Neurosci 22:8951–8960PubMed
Li J, Yu C, Li Y, Liu B, Liu Y, Shu N, Song M, Zhou Y, Zhu W, Li K, Jiang T (2009) COMT val158met modulates association between brain white matter architecture and IQ. Am J Med Genet B Neuropsychiatr Genet 150B:375–380CrossRefPubMed
Liu B, Song M, Li J, Liu Y, Li K, Yu C, Jiang T (2010) Prefrontal-related functional connectivities within the default network are modulated by COMT val158met in healthy young adults. J Neurosci 30:64–69CrossRefPubMed
MacLeod CM (1991) Half a century of research on the Stroop effect: an integrative review. Psychol Bull 109:163–203CrossRefPubMed
Männistö PT, Kaakkola S (1999) Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51:593–628PubMed
Matsumoto M, Weickert C, Akil M, Lipska B, Hyde T, Herman M, Kleinman J, Weinberger D (2003) Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116:127–137CrossRefPubMed
Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100:6186–6191CrossRefPubMedPubMedCentral
Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR (2006) Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 11(867–877):797CrossRef
Mukherjee N, Kidd KK, Pakstis AJ, Speed WC, Li H, Tarnok Z, Barta C, Kajuna SL, Kidd JR (2010) The complex global pattern of genetic variation and linkage disequilibrium at catechol-O-methyltransferase. Mol Psychiatry 15:216–225CrossRefPubMed
Naqvi NH, Bechara A (2010) The insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making. Brain Struct Funct 214:435–450CrossRefPubMedPubMedCentral
Ohnishi T, Hashimoto R, Mori T, Nemoto K, Moriguchi Y, Iida H, Noguchi H, Nakabayashi T, Hori H, Ohmori M (2006) The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia. Brain 129:399–410CrossRefPubMed
Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113CrossRefPubMed
Owen AM, McMillan KM, Laird AR, Bullmore E (2005) N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp 25:46–59CrossRefPubMed
Palmatier MA, Kang AM, Kidd KK (1999) Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 46:557–567CrossRefPubMed
Polli FE, Barton JJ, Thakkar KN, Greve DN, Goff DC, Rauch SL, Manoach DS (2008) Reduced error-related activation in two anterior cingulate circuits is related to impaired performance in schizophrenia. Brain 131:971–986CrossRefPubMed
Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE (2012) Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage 59:2142–2154CrossRefPubMed
Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE (2013) Steps toward optimizing motion artifact removal in functional connectivity MRI; a reply to Carp. NeuroImage 76:439–441CrossRefPubMed
Reuter M, Peters K, Schroeter K, Koebke W, Lenardon D, Bloch B, Hennig J (2005) The influence of the dopaminergic system on cognitive functioning: a molecular genetic approach. Behav Brain Res 164:93–99CrossRefPubMed
Reuter M, Schmitz A, Corr P, Hennig J (2007) Molecular genetics support Gray’s personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system. Int J Neuropsychopharmacol 9:155–166
Sambataro F, Fazio L, Taurisano P, Gelao B, Porcelli A, Mancini M, Sinibaldi L, Ursini G, Masellis R, Caforio G (2013) DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding. Schizophr Bull 39:206–216CrossRefPubMed
Santiago M, Matarredona ER, Granero L, Cano J, Machado A (2000) Neurotoxic relationship between dopamine and iron in the striatal dopaminergic nerve terminals. Brain Res 858:26–32CrossRefPubMed
Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58CrossRefPubMed
Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, Reiss AL, Greicius MD (2007) Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 27:2349–2356CrossRefPubMedPubMedCentral
Suhara T, Okubo Y, Yasuno F, Sudo Y, Inoue M, Ichimiya T, Nakashima Y, Nakayama K, Tanada S, Suzuki K (2002) Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia. Arch Gen Psychiatry 59:25–30CrossRefPubMed
Suhara T, Yasuno F, Sudo Y, Yamamoto M, Inoue M, Okubo Y, Suzuki K (2001) Dopamine D2 receptors in the insular cortex and the personality trait of novelty seeking. NeuroImage 13:891–895CrossRefPubMed
Takahashi H, Higuchi M, Suhara T (2006) The role of extrastriatal dopamine D2 receptors in schizophrenia. Biol Psychiatry 59:919–928CrossRefPubMed
Taylor WD, Züchner S, Payne ME, Messer DF, Doty TJ, MacFall JR, Beyer JL, Krishnan KRR (2007) The COMT Val158Met polymorphism and temporal lobe morphometry in healthy adults. Psychiatry Res 155:173–177CrossRefPubMedPubMedCentral
Thomas G, Sinville R, Sutton S, Farquar H, Hammer RP, Soper SA, Cheng YW, Barany F (2004) Capillary and microelectrophoretic separations of ligase detection reaction products produced from low-abundant point mutations in genomic DNA. Electrophoresis 25:1668–1677CrossRefPubMed
Thompson PM, Hayashi KM, Simon SL, Geaga JA, Hong MS, Sui Y, Lee JY, Toga AW, Ling W, London ED (2004) Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci 24:6028–6036CrossRefPubMed
Tian T, Qin W, Liu B, Jiang T, Yu C (2013) Functional connectivity in healthy subjects is nonlinearly modulated by the COMT and DRD2 polymorphisms in a functional system-dependent manner. J Neurosci 33:17519–17526CrossRefPubMed
Wang D, Liu B, Qin W, Wang J, Zhang Y, Jiang T, Yu C (2013) KIBRA gene variants are associated with synchronization within the default-mode and executive control networks. NeuroImage 69:213–222CrossRefPubMed
Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine Dl receptors in prefrontal cortex. Nature 376:572–575CrossRefPubMed
Williams SM, Goldman-Rakic PS (1998) Widespread origin of the primate mesofrontal dopamine system. Cereb Cortex 8:321–345CrossRefPubMed
Woodward ND, Zald DH, Ding Z, Riccardi P, Ansari MS, Baldwin RM, Cowan RL, Li R, Kessler RM (2009) Cerebral morphology and dopamine D2/D3receptor distribution in humans: a combined [18F] fallypride and voxel-based morphometry study. NeuroImage 46:31–38CrossRefPubMedPubMedCentral
Xu H, Kellendonk CB, Simpson EH, Keilp JG, Bruder GE, Polan HJ, Kandel ER, Gilliam TC (2007) DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability. Schizophr Res 90:104–107CrossRefPubMed
Xu M, Moratalla R, Gold LH, Hiroi N, Koob GF, Graybiel AM, Tonegawa S (1994) Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell 79:729–742CrossRefPubMed
Yi P, Chen Z, Zhao Y, Guo J, Fu H, Zhou Y, Yu L, Li L (2009) PCR/LDR/capillary electrophoresis for detection of single-nucleotide differences between fetal and maternal DNA in maternal plasma. Prenat Diagn 29:217–222CrossRefPubMed
Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee M-LT, Xiao T, Papp A, Wang D (2007) Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci USA 104:20552–20557CrossRefPubMedPubMedCentral
Zheng C, Shen Y, Xu Q (2012) Rs1076560, a functional variant of the dopamine D2 receptor gene, confers risk of schizophrenia in Han Chinese. Neurosci Lett 518:41–44CrossRefPubMed
Metadata
Title
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
Authors
Jiayuan Xu
Wen Qin
Bing Liu
Tianzi Jiang
Chunshui Yu
Publication date
01-11-2016
Publisher
Springer Berlin Heidelberg
Published in
Brain Structure and Function / Issue 8/2016
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI
https://doi.org/10.1007/s00429-015-1134-4

Other articles of this Issue 8/2016

Brain Structure and Function 8/2016 Go to the issue

Original Article

Task-specific preparatory neural activations in low-interference contexts

Original Article

Modulation effect of the SORL1 gene on functional connectivity density in healthy young adults

Original Article

The extreme capsule fiber complex in humans and macaque monkeys: a comparative diffusion MRI tractography study

Original Article

Hippocampal size is related to short-term true and false memory, and right fusiform size is related to long-term true and false memory

Original Article

Abnormal cross-network functional connectivity in chronic pain and its association with clinical symptoms

Original Article

Non-invasive mapping of calculation function by repetitive navigated transcranial magnetic stimulation