A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

Shen, Xueyi; Howard, David M.; Adams, Mark J.; Hill, W. David; Clarke, Toni; Deary, Ian J.; Whalley, Heather C.

doi:10.1038/s41467-020-16022-0

Cited by 96 publications

(60 citation statements)

References 71 publications

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“…In over 9,000 participants from UK Biobank, Shen et al . (51) recently found PRS for MDD was associated with white matter integrity of several tracts, such as the SLF, the cingulate gyrus part of cingulum, the inferior fronto-occipital fasciculus and superior thalamic radiation, which were associated with PRS-anhedonia in our study. Previous studies on PRS for MDD have also reported associations with decreased white matter integrity, most notably in the SLF, cingulum and thalamic radiations (52-54), although null findings have also been reported with respect to polygenic risk for MDD or schizophrenia (39, 55).…”

Section: Discussionsupporting

confidence: 72%

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

Cullen

Lyall

Strawbridge

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 72%

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

Cullen

Lyall

Strawbridge

et al. 2020

Preprint

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“…We estimated PRS for N = 29,879 participants with quality controlled genetic and imaging data, using effect sizes for each allele from a large prior GWAS of 7,585,078 SNPs in N = 69,369 schizophrenia cases and N = 236,642 healthy controls [5]. We constructed eight polygenic scores with varying P SNP -value thresholds ( P SNP ≤ 0.0001, ≤ 0.001, ≤ 0.01, ≤ 0.1, ≤ 0.25, ≤0.5, ≤ 0.75, ≤ 1) for each individual [20, 41]. PRS’s were normally distributed at all P SNP -value thresholds ( SI Methods ) and the number of SNPs included in the calculation at each probability threshold is reported in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

“…We constructed eight polygenic scores with varying P SNP -value thresholds (P SNP ≤ 0.0001, ≤ 0.001, ≤ 0.01, ≤ 0.1, ≤ 0.25, ≤ 0.5, ≤ 0.75, ≤ 1) for each individual [20,41]. PRS's were normally distributed at all P SNP -value thresholds (SI Methods) and the number of SNPs included in the calculation at each probability threshold is reported in Table S1.…”

Section: Polygenic Risk Scoresmentioning

confidence: 99%

Grey and white matter micro-structure is associated with polygenic risk for schizophrenia

Stauffer

Bethlehem

Warrier

et al. 2021

Preprint

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Background Recent discovery of hundreds of common gene variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. It is hypothesized that normal variation in genetic risk of schizophrenia should be associated with MRI changes in brain morphometry and tissue composition. Methods We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macro-structural MRI metrics measured at each of 180 cortical areas and seven subcortical structures. Linear mixed effect models were used to investigate associations between schizophrenia PRS and brain structure at global and regional scales, controlled for multiple comparisons. Results Micro-structural phenotypes were more robustly associated with schizophrenia PRS than macro-structural phenotypes. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, and five subcortical structures. Other micro-structural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with schizophrenia PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate and prefrontal cortical areas, insula, and hippocampus. Conclusions We show widespread cortical and subcortical grey matter micro-structure associations with schizophrenia PRS. Across all investigated phenotypes NDI, a measure of the density of myelinated axons and dendrites, showed the most robust associations with schizophrenia PRS. We interpret these results as indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks mediating the genetic risk for schizophrenia.

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“…All analyses were conducted using R (version 3.2.3) in a Linux environment. Linear mixed-effects models (function ‘lme’ in R package ‘nlme’) and general linear models (function ‘glm’ in R package ‘stats’) were used to investigate structural brain metrics 46,47 False Discovery Rate (FDR) multiple comparison correction was applied to all bilateral/unilateral structures, lobes and white matter tracts, referred to as P FDR in this report, using the ‘p.adjust’ function in R and all betas were standardised. FDR correction was also applied over each sub-analysis.…”

Section: Methodsmentioning

confidence: 99%

DNA methylation signatures of C-reactive protein associations with structural neuroimaging measures and major depressive disorder

Green

Shen

Stevenson

et al. 2020

Preprint

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Background: Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear. This study investigates associations between depression, structural neuroimaging measures and two measures of inflammation: serum-based C-reactive protein (CRP) and a methylation-based score for CRP (DNAm CRP) in a large community-based sample. Methods: Serum CRP and DNAm CRP were assessed for participants in Generation Scotland (nMDD cases= 240, nControls= 558) alongside structural brain scans (T1 and diffusion MRI). Linear regression was used to investigate associations between (i) both CRP measures and depressive symptoms, (ii) both CRP measures and structural imaging variables and (iii) inflammation x MDD interaction effects (for both CRP measures) with imaging measures. Results: Increased serum CRP was significantly associated with overall MDD symptom severity and specifically with somatic symptoms- general interest (β= 0.145, pFDR = 6x10-4) and energy levels (β= 0.101, pFDR = 0.027) and also reduced entorhinal cortex thickness (β= -0.095, pFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and reduced integrity of 16 white matter tracts and showed larger effect sizes (βaverage= -0.15) compared to serum CRP across all measures (βaverage = 0.01). Conclusions: Acute measures of CRP were related to current depression symptoms, specifically somatic symptoms, whereas methylation signatures of inflammation demonstrated greater differences in global and regional brain structure. This study highlights the utility of combining serological and methylation markers to study chronic inflammation effects on the brain in psychiatric disorders.

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A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

Cited by 96 publications

References 71 publications

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

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

Grey and white matter micro-structure is associated with polygenic risk for schizophrenia

DNA methylation signatures of C-reactive protein associations with structural neuroimaging measures and major depressive disorder

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