Hostname: page-component-586b7cd67f-2brh9 Total loading time: 0 Render date: 2024-11-22T19:10:29.399Z Has data issue: false hasContentIssue false

Association between GLP-1 receptor gene polymorphisms with reward learning, anhedonia and depression diagnosis

Published online by Cambridge University Press:  26 March 2020

Hale Yapici-Eser*
Affiliation:
School of Medicine, Koç University, İstanbul, Turkey Research Center for Translational Medicine, Koç University,İstanbul, Turkey
Vivek Appadurai
Affiliation:
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Roskilde, Denmark
Candan Yasemin Eren
Affiliation:
Research Center for Translational Medicine, Koç University,İstanbul, Turkey
Dilek Yazici
Affiliation:
School of Medicine, Koç University, İstanbul, Turkey
Chia-Yen Chen
Affiliation:
Psychiatric and Neurodevelopmental Genetics Unit and Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA Department of Psychiatry, Harvard Medical School, Boston, MA, USA
Dost Öngür
Affiliation:
Department of Psychiatry, Harvard Medical School, Boston, MA, USA Schizophrenia and Bipolar Disorder Research Program, McLean Hospital, Belmont, MA, USA
Diego A. Pizzagalli
Affiliation:
Department of Psychiatry, Harvard Medical School, Boston, MA, USA Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, MA, USA
Thomas Werge
Affiliation:
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark Institute of Biological Psychiatry, Mental Health Center St. Hans, Mental Health Services Copenhagen, Roskilde, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Mei-Hua Hall
Affiliation:
Department of Psychiatry, Harvard Medical School, Boston, MA, USA Schizophrenia and Bipolar Disorder Research Program, McLean Hospital, Belmont, MA, USA Psychosis Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, USA
*
Author for correspondence: Hale Yapici-Eser, Email: [email protected]

Abstract

Background:

Glucagon-like peptide-1 receptors (GLP-1Rs) are widely expressed in the brain. Evidence suggests that they may play a role in reward responses and neuroprotection. However, the association of GLP-1R with anhedonia and depression diagnosis has not been studied. Here, we examined the association of GLP-1R polymorphisms with objective and subjective measures of anhedonia, as well as depression diagnosis.

Methods:

Objective [response bias assessed by the probabilistic reward task (PRT)] and subjective [Snaith-Hamilton Pleasure Scale (SHAPS)] measures of anhedonia, clinical variables and DNA samples were collected from 100 controls and 164 patients at McLean Hospital. An independent sample genotyped as part of the Psychiatric Genomics Consortium (PGC) was used to study the effect of putative GLP-1R polymorphisms linked to response bias in PRT on depression diagnosis.

Results:

The C allele in rs1042044 was significantly associated with increased PRT response bias, when controlling for age, sex, case-control status and PRT discriminability. AA genotype of rs1042044 showed higher anhedonia phenotype based on SHAPS scores. However, analysis of PGC major depressive disorder data showed no association between rs1042044 and depression diagnosis.

Conclusion:

Findings suggest a possible association of rs1042044 with anhedonia but no association with depression diagnosis.

Type
Original Article
Copyright
© Scandinavian College of Neuropsychopharmacology 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Allen, JG (1998) User’s guide, administration booklet, and scoresheet for the Structured Clinical Interview for DSM-IV Axis I Disorders, clinician version. Bulletin of the Menninger Clinic 62, 126126.Google Scholar
Auton, A, Abecasis, GR, Altshuler, DM, Durbin, RM, Bentley, DR, Chakravarti, A, Clark, AG, Donnelly, P, Eichler, EE and Flicek, P (2015) A global reference for human genetic variation. Nature 526, 6874.Google ScholarPubMed
Anderberg, RH, Richard, JE, Hansson, C, Nissbrandt, H, Bergquist, F and Skibicka, KP (2016) GLP-1 is both anxiogenic and antidepressant; divergent effects of acute and chronic GLP-1 on emotionality. Psychoneuroendocrinology 65, 5466.CrossRefGoogle ScholarPubMed
Aroda, VR (2018) A review of GLP-1 receptor agonists: evolution and advancement, through the lens of randomised controlled trials. Diabetes, Obesity and Metabolism 20 Suppl. 1, 2233.CrossRefGoogle ScholarPubMed
Brunetti, L, Orlando, G, Recinella, L, Leone, S, Ferrante, C, Chiavaroli, A, Lazzarin, F and Vacca, M (2008) Glucagon-like peptide 1 (7-36) amide (GLP-1) and exendin-4 stimulate serotonin release in rat hypothalamus. Peptides 29, 13771381.CrossRefGoogle ScholarPubMed
Chowen, JA, de Fonseca, FR, Alvarez, E, Navarro, M, Garcia-Segura, LM and Blazquez, E (1999) Increased glucagon-like peptide-1 receptor expression in glia after mechanical lesion of the rat brain. Neuropeptides 33, 212215.CrossRefGoogle ScholarPubMed
Clark-Elford, R, Nathan, PJ, Auyeung, B, Voon, V, Sule, A, Müller, U, Dudas, R, Sahakian, BJ, Phan, KL and Baron-Cohen, S (2014) The effects of oxytocin on social reward learning in humans. International Journal of Neuropsychopharmacology 17, 199209.CrossRefGoogle ScholarPubMed
Daniele, G, Iozzo, P, Molina-Carrion, M, Lancaster, J, Ciociaro, D, Cersosimo, E, Tripathy, D, Triplitt, C, Fox, P, Musi, N and DeFronzo, R (2015) Exenatide regulates cerebral glucose metabolism in brain areas associated with glucose homeostasis and reward system. Diabetes 64, 34063412.CrossRefGoogle ScholarPubMed
Delgado, MR, Miller, MM, Inati, S and Phelps, EA (2005) An fMRI study of reward-related probability learning. Neuroimage 24, 862873.CrossRefGoogle ScholarPubMed
de Luis, DA, Aller, R, Izaola, O and Bachiller, R (2015) Role of rs6923761 gene variant in glucagon-like peptide 1 receptor in basal GLP-1 levels, cardiovascular risk factor and serum adipokine levels in naive type 2 diabetic patients. Journal of Endocrinological Investigation 38, 143147.CrossRefGoogle ScholarPubMed
de Luis, DA, Pacheco, D, Aller, R and Izaola, O (2014a) Role of the rs6923761 gene variant in glucagon-like peptide 1 receptor gene on cardiovascular risk factors and weight loss after biliopancreatic diversion surgery. Annals of Nutrition and Metabolism 65, 259263.CrossRefGoogle ScholarPubMed
de Luis, DA, Pacheco, D, Aller, R, Izaola, O and Bachiller, R (2014b) Roles of rs 6923761 gene variant in glucagon-like peptide 1 receptor on weight, cardiovascular risk factor and serum adipokine levels in morbid obese patients. Nutricion Hospitalaria 29, 889893.Google ScholarPubMed
Detka, J, Ślusarczyk, J, Kurek, A, Kucharczyk, M, Adamus, T, Konieczny, P, Kubera, M, Basta-Kaim, A, Lasoń, W and Budziszewska, B (2019) Hypothalamic insulin and glucagon-like peptide-1 levels in an animal model of depression and their effect on corticotropin-releasing hormone promoter gene activity in a hypothalamic cell line. Pharmacological Reports 71, 338346.CrossRefGoogle Scholar
Dichter, GS, Damiano, CA and Allen, JA (2012) Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings. Journal of Neurodevelopmental Disorders 4, 19.CrossRefGoogle ScholarPubMed
Drucker, DJ (2006) The biology of incretin hormones. Cell Metabolism 3, 153165.CrossRefGoogle ScholarPubMed
Duman, RS and Aghajanian, GK (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 6872.CrossRefGoogle ScholarPubMed
Erbil, D, Eren, CY, Demirel, C, Kucuker, MU, Solaroglu, I and Eser, HY (2019) GLP-1’s role in neuroprotection: a systematic review. Brain Injury 185.Google ScholarPubMed
Erreger, K, Davis, AR, Poe, AM, Greig, NH, Stanwood, GD and Galli, A (2012) Exendin-4 decreases amphetamine-induced locomotor activity. Physiology & Behavior 106, 574578.CrossRefGoogle ScholarPubMed
Farr, OM, Sofopoulos, M, Tsoukas, MA, Dincer, F, Thakkar, B, Sahin-Efe, A, Filippaios, A, Bowers, J, Srnka, A, Gavrieli, A and Ko, BJ (2016) GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetologia 59, 954965.CrossRefGoogle ScholarPubMed
Franken, IHA, Rassin, E and Muris, P (2007) The assessment of anhedonia in clinical and non-clinical populations: further validation of the Snaith-Hamilton Pleasure Scale (SHAPS). Journal of Affective Disorders 99, 8389.CrossRefGoogle Scholar
Gold, MS, Blum, K, Febo, M, Baron, D, Modestino, EJ, Elman, I and Badgaiyan, RD (2018) Molecular role of dopamine in anhedonia linked to reward deficiency syndrome (RDS) and anti- reward systems. Front Biosci (Schol Ed) 10, 309325.Google ScholarPubMed
Graham, DL, Erreger, K, Galli, A and Stanwood, GD (2013) GLP-1 analog attenuates cocaine reward. Molecular Psychiatry 18, 961962.CrossRefGoogle ScholarPubMed
Hall, MH, Chen, CY, Cohen, BM, Spencer, KM, Levy, DL, Öngür, D and Smoller, JW (2015) Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics 168, 151161.CrossRefGoogle Scholar
Heppner, KM, Kirigiti, M, Secher, A, Paulsen, SJ, Buckingham, R, Pyke, C, Knudsen, LB, Vrang, N and Grove, KL (2015) Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. Endocrinology 156, 255267.CrossRefGoogle ScholarPubMed
Hernandez, NS, O’Donovan, B, Ortinski, PI and Schmidt, HD (2019) Activation of glucagon-like peptide-1 receptors in the nucleus accumbens attenuates cocaine seeking in rats. Addiction Biology 24, 170181.CrossRefGoogle ScholarPubMed
Howard, DM, Adams, MJ, Clarke, TK, Hafferty, JD, Gibson, J, Shirali, M, Coleman, JR, Hagenaars, SP, Ward, J, Wigmore, EM and Alloza, C (2019) Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nature Neuroscience 22, 343352.CrossRefGoogle ScholarPubMed
Howie, B, Marchini, J and Stephens, M (2011) Genotype imputation with thousands of genomes. G3-Genes Genomes Genetics 1, 457469.Google ScholarPubMed
Kappe, C, Tracy, LM, Patrone, C, Iverfeldt, K and Sjoholm, A (2012) GLP-1 secretion by microglial cells and decreased CNS expression in obesity. Journal of Neuroinflammation 9, 276.CrossRefGoogle ScholarPubMed
Koshal, P, Jamwal, S and Kumar, P (2018) Glucagon-like Peptide-1 (GLP-1) and neurotransmitters signaling in epilepsy: an insight review. Neuropharmacology 136, 271279.CrossRefGoogle Scholar
Krass, M, Rünkorg, K, Vasar, E and Volke, V. (2012) Acute administration of GLP-1 receptor agonists induces hypolocomotion but not anxiety in mice. Acta Neuropsychiatrica 24(5), 296300.CrossRefGoogle Scholar
Krass, M, Volke, A, Rünkorg, K, Wegener, G, Lund, S, Abildgaard, A, Vasar, E and Volke, V (2015) GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment. Acta Neuropsychiatrica 27(1), 2532.CrossRefGoogle ScholarPubMed
Lewandowski, KE, Whitton, AE, Pizzagalli, DA, Norris, LA, Ongur, D and Hall, MH (2016) Reward learning, neurocognition, social cognition, and symptomatology in psychosis. Frontiers in Psychiatry 7.CrossRefGoogle ScholarPubMed
Luijten, M, Schellekens, AF, Kuhn, S, Machielse, MW and Sescousse, G (2017) Disruption of Reward processing in addiction: an image-based meta-analysis of functional magnetic resonance imaging studies. JAMA Psychiatry 74, 387398.CrossRefGoogle ScholarPubMed
Malendowicz, LK, Nussdorfer, GG, Nowak, KW, Ziolkowska, A, Tortorella, C and Trejter, M. (2003). Exendin-4, a GLP-1 receptor agonist, stimulates pituitary-adrenocortical axis in the rat: investigations into the mechanism (s) underlying Ex4 effect. International Journal of Molecular Medicine 12(2), 237241.Google ScholarPubMed
Mansur, RB, Fries, GR, Trevizol, AP, Subramaniapillai, M, Lovshin, J, Lin, K, Vinberg, M, Ho, RC, Brietzke, E and McIntyre, RS (2019) The effect of body mass index on glucagon-like peptide receptor gene expression in the post mortem brain from individuals with mood and psychotic disorders. European Neuropsychopharmacology 29, 137146.CrossRefGoogle ScholarPubMed
Mistry, S, Harrison, JR, Smith, DJ, Escott-Price, V and Zammit, S (2018) The use of polygenic risk scores to identify phenotypes associated with genetic risk of bipolar disorder and depression: A systematic review. Journal of Affective Disorders 234, 148155.CrossRefGoogle ScholarPubMed
Nusslock, R and Alloy, LB (2017) Reward processing and mood-related symptoms: an RDoC and translational neuroscience perspective. Journal of Affective Disorders 216, 316.CrossRefGoogle ScholarPubMed
O’Connell, J, Sharp, K, Shrine, N, Wain, L, Hall, I, Tobin, M, Zagury, JF, Delaneau, O and Marchini, J (2016) Haplotype estimation for biobank-scale data sets. Nature Genetics 48, 817820.CrossRefGoogle ScholarPubMed
Peterson, DA, Lotz, DT, Halgren, E, Sejnowski, TJ and Poizner, H (2011) Choice modulates the neural dynamics of prediction error processing during rewarded learning. Neuroimage 54, 13851394.CrossRefGoogle ScholarPubMed
Pitsillou, E, Bresnehan, SM, Kagarakis, EA, Wijoyo, SJ, Liang, J, Hung, A and Karagiannis, TC (2019) The cellular and molecular basis of major depressive disorder: towards a unified model for understanding clinical depression. Molecular Biology Reports 47(1), 753770.CrossRefGoogle ScholarPubMed
Pizzagalli, DA, Iosifescu, D, Hallett, LA, Ratner, KG and Fava, M (2008) Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. Journal of Psychiatric Research 43, 7687.CrossRefGoogle ScholarPubMed
Pizzagalli, DA, Jahn, AL and O’Shea, JP (2005) Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. Biological Psychiatry 57(4), 319327.CrossRefGoogle ScholarPubMed
Ramsey, TL and Brennan, MD (2014) Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial. Schizophrenia Research 160, 7379.CrossRefGoogle ScholarPubMed
Ren, H, Fabbri, C, Uher, R, Rietschel, M, Mors, O, Henigsberg, N, Hauser, J, Zobel, A, Maier, W, Dernovsek, MZ and Souery, D (2018) Genes associated with anhedonia: a new analysis in a large clinical trial (GENDEP). Translational Psychiatry 8(1), 111.CrossRefGoogle Scholar
Rinaman, L and Rothe, EE (2002) GLP-1 receptor signaling contributes to anorexigenic effect of centrally administered oxytocin in rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 283, R99R106.CrossRefGoogle ScholarPubMed
Rizvi, SJ, Pizzagalli, DA, Sproule, BA and Kennedy, SH (2016) Assessing anhedonia in depression: potentials and pitfalls. Neuroscience and Biobehavioral Reviews 65, 2135.CrossRefGoogle ScholarPubMed
Sarkar, S, Fekete, C, Legradi, G and Lechan, RM (2003) Glucagon like peptide-1 (7-36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Brain Research 985, 163168.CrossRefGoogle ScholarPubMed
Sathananthan, A, Dalla Man, CD, Micheletto, F, Zinsmeister, AR, Camilleri, M, Giesler, PD, Laugen, JM, Toffolo, G, Rizza, RA, Cobelli, C and Vella, A (2010) Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care 33, 20742076.CrossRefGoogle ScholarPubMed
Schlögl, H, Kabisch, S, Horstmann, A, Lohmann, G, Müller, K, Lepsien, J, Busse-Voigt, F, Kratzsch, J, Pleger, B, Villringer, A and Stumvoll, M (2013) Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. Diabetes Care 36, 19331940.CrossRefGoogle ScholarPubMed
Scott, RA, Freitag, DF, Li, L, Chu, AY, Surendran, P, Young, R, Grarup, N, Stancáková, A, Chen, Y, Varga, TV and Yaghootkar, H (2016) A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Science Translational Medicine 8, 341ra76.CrossRefGoogle ScholarPubMed
Sharma, AN, Ligade, SS, Sharma, JN, Shukla, P, Elased, KM and Lucot, JB (2015) GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats. Metabolic Brain Disease 30, 519527.CrossRefGoogle ScholarPubMed
Sheikh, HI, Dougherty, LR, Hayden, EP, Klein, DN and Singh, SM (2010) Glucagon-like peptide-1 receptor gene polymorphism (Leu260Phe) is associated with morning cortisol in preschoolers. Progress in Neuro-Psychopharmacology and Biological Psychiatry 34, 980983.CrossRefGoogle ScholarPubMed
Skibicka, KP (2013) The central GLP-1: implications for food and drug reward. Frontiers Neuroscience 7, 181.CrossRefGoogle ScholarPubMed
Snaith, RP, Hamilton, M, Morley, S, Humayan, A, Hargreaves, D and Trigwell, P (1995) A scale for the assessment of Hedonic tone – the Snaith-Hamilton pleasure scale. British Journal of Psychiatry 167, 99103.CrossRefGoogle ScholarPubMed
Suchankova, P, Yan, J, Schwandt, ML, Stangl, BL, Caparelli, EC, Momenan, R, Jerlhag, E, Engel, JA, Hodgkinson, CA, Egli, M and Lopez, MF (2015) The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence. Translational Psychiatry 5.CrossRefGoogle Scholar
Tuesta, LM, Chen, Z, Duncan, A, Fowler, CD, Ishikawa, M, Lee, BR, Liu, XA, Lu, Q, Cameron, M, Hayes, MR and Kamenecka, TM (2017) GLP-1 acts on habenular avoidance circuits to control nicotine intake. Nature Neuroscience 20, 708716.CrossRefGoogle ScholarPubMed
Vrieze, E, Pizzagalli, DA, Demyttenaere, K, Hompes, T, Sienaert, P, de Boer, P, Schmidt, M and Claes, S (2013) Reduced reward learning predicts outcome in major depressive disorder. Biological Psychiatry 73, 639645.CrossRefGoogle ScholarPubMed
Ward, J, Lyall, LM, Bethlehem, RA, Ferguson, A, Strawbridge, RJ, Lyall, DM, Cullen, B, Graham, N, Johnston, KJ, Bailey, ME and Murray, GK (2019). Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure. Translational Psychiatry 9(1), 19.CrossRefGoogle ScholarPubMed
Wessel, J, Chu, AY, Willems, SM, Wang, S, Yaghootkar, H, Brody, JA, Dauriz, M, Hivert, MF, Raghavan, S, Lipovich, L and Hidalgo, B (2015) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nature Communications 6, 5897.CrossRefGoogle ScholarPubMed
Whitton, AE, Treadway, MT and Pizzagalli, DA (2015) Reward processing dysfunction in major depression, bipolar disorder and schizophrenia. Current Opinion in Psychiatry 28, 712.CrossRefGoogle Scholar
Williams, DL, Lilly, NA, Edwards, IJ, Yao, P, Richards, JE and Trapp, S (2018) GLP-1 action in the mouse bed nucleus of the stria terminalis. Neuropharmacology 131, 8395.CrossRefGoogle ScholarPubMed
Wimmer, GE, Braun, EK, Daw, ND and Shohamy, D (2014) Episodic memory encoding interferes with reward learning and decreases striatal prediction errors. Journal of Neuroscience 34, 1490114912.CrossRefGoogle ScholarPubMed
Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TM and Bacanu, SA (2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics 50, 668681.CrossRefGoogle ScholarPubMed
Zheng, HY, Reiner, DJ, Hayes, MR and Rinaman, L (2019) Chronic suppression of glucagon-like peptide-1 receptor (GLP1R) mRNA translation in the rat bed nucleus of the stria terminalis reduces anxiety-like behavior and stress-induced hypophagia, but prolongs stress-induced elevation of plasma corticosterone. Journal of Neuroscience 39, 26492663.CrossRefGoogle ScholarPubMed