Genetic Associations of Anhedonia: Insights into Overlap of Mental and Somatic Disorders

Abstract

BACKGROUND: Anhedonia is characterized by a reduced ability to anticipate, experience, and/or learn about pleasure. This phenomenon has a transdiagnostic nature and is one of the key symptoms of mood disorders, schizophrenia, addictions, and somatic conditions.

AIM: To evaluate the genetic architecture of anhedonia and its overlap with other mental disorders and somatic conditions.

METHODS: We performed a genome-wide association study of anhedonia on a sample of 4,520 individuals from a Russian non-clinical population. Using the available summary statistics, we calculated polygenic risk scores (PRS) to investigate the genetic relationship between anhedonia and other psychiatric or somatic phenotypes.

RESULTS: No variants with a genome-wide significant association were identified. PRS for major depression, bipolar disorder, and schizophrenia were significantly associated with anhedonia. Conversely, no significant associations were found between PRS for anxiety and anhedonia, which aligns well with existing clinical evidence. None of the PRS for somatic phenotypes attained a significance level after correction for multiple comparisons. A nominal significance for the anhedonia association was determined for omega-3 fatty acids, type 2 diabetes mellitus, and Crohn’s disease.

CONCLUSION: Anhedonia has a complex polygenic architecture, and its presence in somatic diseases or normal conditions may be due to a genetic predisposition to mood disorders or schizophrenia.

Keywords

anhedonia / depression / bipolar disorder / schizophrenia / polygenic risk scores

References

[1] Craske MG, Meuret AE, Ritz T, et al. Treatment for Anhedonia: A neuroscience driven approach. Depress Anxiety. 2016;33(10):927–38. doi: 10.1002/da.22490

[2] Der-Avakian A, Markou A. The neurobiology of Anhedonia and other reward-related deficits. Trends Neurosci. 2012;35(1):68–77. doi: 10.1016/j.tins.2011.11.005

[3] Husain M, Roiser JP. Neuroscience of apathy and Anhedonia: a transdiagnostic approach. Nat Rev Neurosci. 2018;19(8):470–84. doi: 10.1038/s41583-018-0029-9

[4] Kibitov AO, Mazo GE. [Anhedonia in depression: neurobiological and genetic aspects]. Zh Nevrol Psikhiatr Im SS Korsakova. 2021;121(3):146–54. doi: 10.17116/jnevro2021121031146. Russian.

[5] Ducasse D, Loas G, Dassa D, et al. Anhedonia is associated with suicidal ideation independently of depression: A meta-analysis. Depress Anxiety. 2018;35(5):382–92. doi: 10.1002/da.22709

[6] Cuthbert BN, Insel TR. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 2013;11:126. doi: 10.1186/1741-7015-11-126

[7] Liu WH, Roiser JP, Wang LZ, et al. Anhedonia is associated with blunted reward sensitivity in first-degree relatives of patients with major depression. J Affect Disord. 2016;190:640–8. doi: 10.1016/j.jad.2015.10.050

[8] Guffanti G, Kumar P, Admon R, et al. Depression genetic risk score is associated with Anhedonia-related markers across units of analysis. Transl Psychiatry. 2019;9(1):236. doi: 10.1038/s41398-019-0566-7

[9] Xu C, Chen J, Cui Z, et al. Abnormal Anhedonia as a potential endophenotype in obsessive-compulsive disorder. Neuropsychiatr Dis Treat. 2020;16:3001–10. doi: 10.2147/NDT.S268148

[10] Hatzigiakoumis DS, Martinotti G, Giannantonio MD, Janiri L. Anhedonia and substance dependence: clinical correlates and treatment options. Front Psychiatry. 2011;2:10. doi: 10.3389/fpsyt.2011.00010

[11] Gorwood P. Neurobiological mechanisms of Anhedonia. Dialogues Clin Neurosci. 2008;10(3):291–9. doi: 10.31887/DCNS.2008.10.3/pgorwood

[12] Zhang B, Lin P, Shi H, et al. Mapping Anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis. Brain Imaging Behav. 2016;10(3):920–39. doi: 10.1007/s11682-015-9457-6

[13] Pizzagalli DA, Holmes AJ, Dillon DG, et al. Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry. 2009;166(6):702–10. doi: 10.1176/appi.ajp.2008.08081201

[14] Carter J, Swardfager W. Mood and metabolism: Anhedonia as a clinical target in Type 2 diabetes. Psychoneuroendocrinology. 2016;69:123–32. doi: 10.1016/j.psyneuen.2016.04.002

[15] Hamer JA, Testani D, Mansur RB, et al. Brain insulin resistance: A treatment target for cognitive impairment and Anhedonia in depression. Exp Neurol. 2019;315:1–8. doi: 10.1016/j.expneurol.2019.01.016

[16] Trøstheim M, Eikemo M, Meir R, et al. Assessment of Anhedonia in adults with and without mental illness: A systematic review and meta-analysis. JAMA Netw Open. 2020;3(8):e2013233. doi: 10.1001/jamanetworkopen.2020.13233

[17] Pelle AJ, Pedersen SS, Erdman RAM, et al. Anhedonia is associated with poor health status and more somatic and cognitive symptoms in patients with coronary artery disease. Qual Life Res. 2011;20(5):643–51. doi: 10.1007/s11136-010-9792-4

[18] Ren H, Fabbri C, Uher R, et al. Genes associated with Anhedonia: a new analysis in a large clinical trial (GENDEP). Transl Psychiatry. 2018;8(1):150. doi: 10.1038/s41398-018-0198-3

[19] Pain O, Dudbridge F, Cardno AG, et al. Genome-wide analysis of adolescent psychotic-like experiences shows genetic overlap with psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet. 2018;177(4):416–25. doi: 10.1002/ajmg.b.32630

[20] Ortega-Alonso A, Ekelund J, Sarin AP, et al. Genome-wide association study of psychosis proneness in the finnish population. Schizophr Bull. 2017;43(6):1304–14. doi: 10.1093/schbul/sbx006

[21] Ward J, Lyall LM, Bethlehem RAI, et al. Novel genome-wide associations for Anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure. Transl Psychiatry. 2019;9(1):327. doi: 10.1038/s41398-019-0635-y

[22] Kibitov AO, Mazo GE, Rakitko AS, et al. [GWAS-based polygenic risk scores for depression with clinical validation: methods and study design in the Russian population]. Zh Nevrol Psikhiatr Im SS Korsakova. 2020;120(11):131–40. doi: 10.17116/jnevro2020120111131. Russian.

[23] Kasyanov ED, Verbitskaya EV, Rakitko AS, et al. [Validation of a DSM-5-based screening test using digital phenotyping in the Russian population]. Zh Nevrol Psikhiatr Im SS Korsakova. 2022; 122(6. Vyp. 2):64–70. doi: 10.17116/jnevro202212206264. Russian.

[24] Browning SR, Browning BL. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet. 2007;81(5):1084–97. doi: 10.1086/521987

[25] 1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68–74. doi: 10.1038/nature15393

[26] McCarthy S, Das S, Kretzschmar W, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016;48(10):1279–83. doi: 10.1038/ng.3643

[27] Marees AT, de Kluiver H, Stringer S, et al. A tutorial on conducting genome-wide association studies: Quality control and statistical analysis. Int J Methods Psychiatr Res. 2018;27(2):e1608. doi: 10.1002/mpr.1608

[28] Chang CC, Chow CC, Tellier LC, et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience. 2015;4:7. doi: 10.1186/s13742-015-0047-8

[29] Cingolani P, Platts A, Wang le L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012;6(2):80–92. doi: 10.4161/fly.19695

[30] Kasyanov ED, Pinakhina DV, Rakitko AS, et al. [Anhedonia in mood disorders and somatic diseases: results of exploratory Mendelian randomization analysis]. Zh Nevrol Psikhiatr Im SS Korsakova. 2023;123(4. Vyp. 2):65–73. doi: 10.17116/jnevro202312304265. Russian.

[31] Grote S, Prüfer K, Kelso J, Dannemann M. ABAEnrichment: an R package to test for gene set expression enrichment in the adult and developing human brain. Bioinformatics. 2016;32(20):3201–3. doi: 10.1093/bioinformatics/btw392

[32] Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489(7416):391–9. doi: 10.1038/nature11405

[33] Kessler RC, Petukhova M, Sampson NA, et al. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169–84. doi: 10.1002/mpr.1359

[34] Choi SW, Mak TSH, O’Reilly PF. Tutorial: a guide to performing polygenic risk score analyses. Nat Protoc. 2020;15(9):2759–72. doi: 10.1038/s41596-020-0353-1

[35] Clark LA, Watson D. Tripartite model of anxiety and depression: Psychometric evidence and taxonomic implications. J Abnorm Psychol. 1991;100(3):316–36. doi: 10.1037//0021-843x.100.3.316

[36] Liao A, Walker R, Carmody TJ, et al. Anxiety and Anhedonia in depression: Associations with neuroticism and cognitive control. J Affect Disord. 2019;245:1070–8. doi: 10.1016/j.jad.2018.11.072

[37] Appleton KM, Voyias PD, Sallis HM, et al. Omega-3 fatty acids for depression in adults. Cochrane Database Syst Rev. 2015(11):CD004692. doi: 10.1002/14651858.CD004692.pub4

[38] Roy T, Lloyd CE. Epidemiology of depression and diabetes: a systematic review. J Affect Disord. 2012;142 Suppl:S8–21. doi: 10.1016/S0165-0327(12)70004-6

[39] Barberio B, Zamani M, Black CJ, et al. Prevalence of symptoms of anxiety and depression in patients with inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(5):359–70. doi: 10.1016/S2468-1253(21)00014-5

[40] Pan A, Sun Q, Okereke OI, et al. Depression and risk of stroke morbidity and mortality: a meta-analysis and systematic review. JAMA. 2011;306(11):1241–9. doi: 10.1001/jama.2011.1282. Erratum in: JAMA. 2011;306(23):2565.

[41] Mullins N, Forstner AJ, O’Connell KS, et al. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nat Genet. 2021;53(6):817–29. doi: 10.1038/s41588-021-00857-4

[42] Fabbri C, Kasper S, Kautzky A, et al. Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples. Br J Psychiatry. 2019;214(1):36–41. doi: 10.1192/bjp.2018.256

[43] Fjukstad KK, Athanasiu L, Bahrami S, et al. Genetic variants associated with cardiometabolic abnormalities during treatment with selective serotonin reuptake inhibitors: a genome-wide association study. Pharmacogenomics J. 2021;21(5):574–85. doi: 10.1038/s41397-021-00234-8

[44] Ortega-Azorín C, Coltell O, Asensio EM, et al. Candidate Gene and genome-wide association studies for circulating leptin levels reveal population and sex-specific associations in high cardiovascular risk Mediterranean subjects. Nutrients. 2019;11(11):2751. doi: 10.3390/nu11112751

[45] Wood AR, Esko T, Yang J, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014;46(11):1173–86. doi: 10.1038/ng.3097

[46] Wojcik GL, Graff M, Nishimura KK, et al. Genetic analyses of diverse populations improves discovery for complex traits. Nature. 2019;570:514–8. doi: 10.1038/s41586-019-1310-4

[47] Wootton RE, Richmond RC, Stuijfzand BG, et al. Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study. Psychol Med. 2020;50(14):2435–43. doi: 10.1017/S0033291719002678

[48] Mills MC, Tropf FC, Brazel DM, et al. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour. Nat Hum Behav. 2021;5(12):1717–30. doi: 10.1038/s41562-021-01135-3

[49] Kulminski AM, Loiko E, Loika Y, Culminskaya I. Pleiotropic predisposition to Alzheimer’s disease and educational attainment: insights from the summary statistics analysis. Geroscience. 2022;44(1):265–80. doi: 10.1007/s11357-021-00484-1

[50] Bogdan R, Pizzagalli DA. The heritability of hedonic capacity and perceived stress: a twin study evaluation of candidate depressive phenotypes. Psychol Med. 2009;39(2):211–8. doi: 10.1017/S0033291708003619

[51] Bolzetta F, Veronese N, Stubbs B, et al. The relationship between dietary vitamin K and depressive symptoms in late adulthood: A cross-sectional analysis from a large cohort study. Nutrients. 2019;11(4):787. doi: 10.3390/nu11040787

[52] Duric V, Banasr M, Licznerski P, et al. A negative regulator of MAP kinase causes depressive behavior. Nat Med. 2010;16(11):1328–32. doi: 10.1038/nm.2219

[53] Liu YX, Wang J, Guo J, et al. DUSP1 is controlled by p53 during the cellular response to oxidative stress. Mol Cancer Res. 2008;6(4):624–33. doi: 10.1158/1541-7786.MCR-07-2019

[54] Catani M. The anatomy of the human frontal lobe. Handb Clin Neurol. 2019;163:95–122. doi: 10.1016/B978-0-12-804281-6.00006-9

[55] Luby JL, Agrawal A, Belden A, et al. Developmental trajectories of the orbitofrontal cortex and Anhedonia in middle childhood and risk for substance use in adolescence in a longitudinal sample of depressed and healthy preschoolers. Am J Psychiatry. 2018;175(10):1010–21. doi: 10.1176/appi.ajp.2018.17070777

[56] Samara Z, Evers EAT, Peeters F, et al. Orbital and medial prefrontal cortex functional connectivity of major depression vulnerability and disease. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3(4):348–357. doi: 10.1016/j.bpsc.2018.01.004

[57] Zhang Y-J, Cai X-L, Hu H-X, et al. Social brain network predicts real-world social network in individuals with social Anhedonia. Psychiatry Res Neuroimaging. 2021;317:111390. doi: 10.1016/j.pscychresns.2021.111390

Funding

Russian Science FoundationРоссийский научный фонд(20-15-00132-П)

RIGHTS & PERMISSIONS

Kasyanov E., Pinakhina D., Rakitko A., Vergasova E., Yermakovich D., Rukavishnikov G., Malyshko L., Popov Y., Kovalenko E., Ilinskaya A., Kim A., Plotnikov N., Neznanov N., Ilinsky V., Kibitov A., Mazo G.