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

Abstract

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 (h 2 SNP) 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 anhedoniaassociated 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.

Dissecting clinical heterogeneity of bipolar disorder using multiple polygenic risk scores

“…PRSs were included in the analysis if: (1) there was evidence of significant genetic correlation of the trait with BD and (2) we had at least 80% power to detect PRS association in a general case-only analysis of our data assuming 50% prevalence of the sub-phenotype. We began by considering PRSs for major psychiatric disorders (BD 33 , SCZ 34 , MDD 35 , ADHD 36 , anxiety 37 , PTSD 19 , OCD 38 , anorexia nervosa 39 , alcohol use disorder 40 , and insomnia 41 ) and personality and lifestyle traits related to BD (alcohol consumption 40 , educational attainment (EA) 42 , risk-taking 43 , subjective well-being 44 , neuroticism 45 , anhedonia 46 , and body mass index (BMI) 47 ). The GWAS summary statistics were restricted to well-imputed variants (INFO > 0.9) when information on imputation quality was available.…”

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): I. Psychosis superspectrum

“…Schizophrenia polygenic risk score was found to predict negative symptoms both in patients and in the general population 140‐143 . Also, anhedonia and low sociability demonstrated moderate genetic correlations with schizophrenia 144,145 .…”

The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

“…The authors also reported high genetic correlations between anhedonia and depression, as well as a moderate genetic correlation with schizophrenia [73]. Moreover, a higher anhedonia polygenic score predicted reduced brain volumes, including in the NAcc and mPFC, as well as altered white matter integrity in multiple pathways [73].…”

“…Strikingly, a UK Biobank meta-GWAS (n = 375,275) identified an association between anhedonia and a locus in DCC, which was the most statistically significant finding [73]. The authors also reported high genetic correlations between anhedonia and depression, as well as a moderate genetic correlation with schizophrenia [73].…”

“…Strikingly, a UK Biobank meta-GWAS (n = 375,275) identified an association between anhedonia and a locus in DCC, which was the most statistically significant finding [73]. The authors also reported high genetic correlations between anhedonia and depression, as well as a moderate genetic correlation with schizophrenia [73]. Moreover, a higher anhedonia polygenic score predicted reduced brain volumes, including in the NAcc and mPFC, as well as altered white matter integrity in multiple pathways [73].…”