Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure

Ward, J. et al. (2019) Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure. Translational Psychiatry, 9, 327. (doi: 10.1038/s41398-019-0635-y) (PMID:31797917) (PMCID:PMC6892870)

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Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson’s Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h2SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson’s Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Smith, Professor Daniel and Cullen, Dr Breda and Graham, Dr Nicholas and Ferguson, Ms Amy and Lyall, Dr Laura and Bailey, Dr Mark and Ward, Dr Joey and Johnston, Ms Keira and Lyall, Dr Donald and Strawbridge, Dr Rona
Authors: Ward, J., Lyall, L. M., Bethlehem, R. A.I., Ferguson, A., Strawbridge, R., Lyall, D. M., Cullen, B., Graham, N., Johnston, K. J.A., Bailey, M. E.S., Murray, G. K., and Smith, D. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Translational Psychiatry
Publisher:Springer Nature
ISSN (Online):2158-3188
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Translational Psychiatry 9:327
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
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190660MRC Doctoral Training Grant 2013/14 and 2014/15George BaillieMedical Research Council (MRC)MR/K501335/1MVLS - Graduate School
302131Understanding the excess risk of cardiometabolic disease in individuals with serious mental illnessJill PellMedical Research Council (MRC)MR/S003061/1HW - Public Health
173096Investigating comorbidity between hypertension and bipolar disorder to identify new and repurposed medications for bipolar disorderDaniel SmithLister Institute of Preventive Medicine (LISTININ)Research Prize 2016HW - Mental Health and Wellbeing
302957Mental Health Data PathfinderDaniel SmithMedical Research Council (MRC)MC_PC_17217HW - Mental Health and Wellbeing