Phenotypic and genetic associations between anhedonia and brain structure in UK Biobank

Abstract

<jats:p>Background: Anhedonia is a core symptom of multiple psychiatric disorders and has been associated with changes in brain structure. Genome-wide association studies suggest that anhedonia is heritable with a polygenic architecture but few studies have explored the association between genetic loading for anhedonia - indexed by polygenic risk scores for anhedonia (PRS-anhedonia) - and structural brain imaging phenotypes. We investigated how anhedonia and polygenic risk for anhedonia were associated with brain structure within the UK Biobank cohort. Methods: Brain measures (including total grey/white matter volumes, subcortical volumes, cortical thickness and white matter integrity) were analysed in relation to the self-reported anhedonia phenotype and PRS-anhedonia for 17,492 participants (8,506 males and 8,986 females; mean age = 62.81 years, SD = 7.43), using linear mixed models and including mediation analyses. Results: State anhedonia was significantly associated with smaller total grey matter volume (GMV), smaller volumes in thalamus and nucleus accumbens; as well as reduced cortical thickness within the paracentral gyrus, the opercular part of inferior frontal gyrus and the rostral anterior cingulate cortex. PRS-anhedonia was associated with reduced total GMV, increased total white matter volume and reduced white matter integrity; in addition to reduced cortical thickness within the parahippocampal cortex, the superior temporal gyrus and the insula cortex. Conclusions: Both the state anhedonia phenotype and PRS-anhedonia were associated with differences in multiple brain structures/areas, including within reward-related circuits. These differences may represent vulnerability markers for psychopathology across a range of psychiatric disorders.</jats:p>

Pathway-based polygenic risk scores for schizophrenia and associations with clinical and neuroimaging phenotypes in UK Biobank

“…The pathways investigated here were previously found to be implicated in schizophrenia in both animal and human studies (4,17,53). In the current study, we were able to identify structural neuroimaging as well as clinical phenotypes associated with biologically informed PRSs, and these were shown to be more strongly associated with neuroimaging phenotypes than whole-genome PRS.…”

“…Here, the axon gene-set was associated with thalamic radiations, white matter microstructural tracts that link the thalamus to the rest of the cerebral cortex (50), and volume of the parahippocampal gyrus, a cortical region that plays a role in memory processes such as encoding and retrieval (51). Both neuroimaging phenotypes have been implicated in schizophrenia (52), and have recently been associated with state anhedonia and PRS for anhedonia, a core negative symptom of schizophrenia (53). The findings here indicate that genes conferring risk for schizophrenia that are aggregated in the axon gene-set are strengthening evidence for brain structural regions that are already implicated in schizophrenia psychopathology.…”

Wellbeing and brain structure: A comprehensive phenotypic and genetic study of image‐derived phenotypes in the UK Biobank

“…The thalamus is involved in emotion regulation via limbic‐thalamo‐cortical projections (Ward, 2013), and previous research has reported positive correlations between optimism and left thalamic (Yang et al, 2013) and left nucleus accumbens volume in young adults (Dolcos et al, 2016). Similarly, anhedonia and lifetime major depressive disorder (MDD; negatively associated with wellbeing) are associated with smaller thalamus and nucleus accumbens volumes (Ancelin et al, 2019; Zhu et al, 2021). In terms of the caudate, a negative association between left caudate volume and subjective wellbeing ( n = 49, aged 12 years; Boyes et al, 2022) is supported by the current study.…”

“…One study found a positive association between subjective wellbeing-PGS and thickness of right superior temporal gyrus and volume of insula (n = 585; Song et al, 2019) while another found no evidence of wellbeing-PGS mediation on hippocampal volume (n = 636 twins/siblings; van't Ent et al, 2017). PGS of anhedonia was also associated with reduced total GMV and thickness of para-hippocampal, superior temporal gyrus and insula (n = 19,592;Zhu et al, 2021). Furthermore, imaging genetic studies have shown that brain structural variations are under polygenic influence (Grasby et al, 2020;Smith et al, 2021), but whether genetic variants that influence brain structure overlap with those that influence wellbeing is yet to be investigated.…”

Associations between self-reported rheumatoid arthritis, rheumatoid factor positivity and structural brain phenotypes in the UK Biobank

“…There is very limited research into potential effects of rheumatoid arthritis (RA) on the brain. It is essential to investigate and monitor the role of cognition and brain phenotype differences that come with age as these can be a potentially early substrate of cognitive and psychological health Zhu et al, 2021).…”