Schizophrenia is a highly heritable disorder for which anatomical brain alterations have been repeatedly reported in clinical samples. Unaffected at-risk groups have also been studied in an attempt ...to identify brain changes that do not reflect reverse causation or treatment effects. However, no robust associations have been observed between neuroanatomical phenotypes and known genetic risk factors for schizophrenia. We tested subcortical brain volume differences between 49 unaffected participants carrying at least one of the 12 copy number variants associated with schizophrenia in UK Biobank and 9063 individuals who did not carry any of the 93 copy number variants reported to be pathogenic. Our results show that CNV carriers have reduced volume in some of the subcortical structures previously shown to be reduced in schizophrenia. Moreover, these associations partially accounted for the association between pathogenic copy number variants and cognitive impairment, which is one of the features of schizophrenia.
Abstract Background Recent genome-wide association studies have identified genetic loci that jointly make a considerable contribution to risk of developing Alzheimer’s disease (AD). Because ...neuropathological features of AD can be present several decades before disease onset, we investigated whether effects of polygenic risk are detectable by neuroimaging in young adults. We hypothesised that higher polygenic risk scores (PRS) for AD would be associated with reduced volume of the hippocampus, and other limbic and paralimbic areas. We further hypothesised that AD PRS would affect the microstructure of fibre tracts connecting the hippocampus with other brain areas. Methods We analysed the association between AD PRS and brain imaging parameters using T1-weighted structural (n=272) and diffusion-weighted scans (n=197). Results We found a significant association between AD PRS and left hippocampal volume, with higher risk associated with lower left hippocampal volume (p=0.001). This effect remained when the APOE gene was excluded (p=0.031), suggesting that the relationship between hippocampal volume and AD is the result of multiple genetic factors, not exclusively variability in the APOE gene. The diffusion tensor imaging analysis revealed that fractional anisotropy of the right cingulum was inversely correlated with AD PRS (p=0.009). We thus show that polygenic effects of AD risk variants on brain structure can already be detected in young adults. Conclusions This finding paves the way for further investigation of the effects of AD risk variants and may become useful for efforts to combine genotypic and phenotypic data for risk prediction and to enrich future prevention trials of AD.
Preclinical models of Alzheimer's disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD ...risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD.
Interest in the cerebellum is expanding given evidence of its contributions to cognition and emotion, and dysfunction in various psychopathologies. However, research into its genetic architecture and ...shared influences with liability for mental disorders is lacking. We conducted a genome-wide association study (GWAS) of total cerebellar volume and underlying cerebellar lobe volumes in 33,265 UK-Biobank participants. Total cerebellar volume was heritable (h
= 50.6%), showing moderate genetic homogeneity across lobes (h
from 35.4% to 57.1%; mean genetic correlation between lobes r
≈ 0.44). We identified 33 GWAS signals associated with total cerebellar volume, of which 6 are known to alter protein-coding gene structure, while a further five mapped to genomic regions known to alter cerebellar tissue gene expression. Use of summary data-based Mendelian randomisation further prioritised genes whose change in expression appears to mediate the SNP-trait association. In total, we highlight 21 unique genes of greatest interest for follow-up analyses. Using LD-regression, we report significant genetic correlations between total cerebellar volume and brainstem, pallidum and thalamus volumes. While the same approach did not result in significant correlations with psychiatric phenotypes, we report enrichment of schizophrenia, bipolar disorder and autism spectrum disorder associated signals within total cerebellar GWAS results via conditional and conjunctional-FDR analysis. Via these methods and GWAS catalogue, we identify which of our cerebellar genomic regions also associate with psychiatric traits. Our results provide important insights into the common allele architecture of cerebellar volume and its overlap with other brain volumes and psychiatric phenotypes.
Gray In H. J. Eysenck,
A model for personality (pp. 246–276). New York: Springer; 1981;
The neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system. Oxford: Oxford ...University Press; 1982 has described two motivational systems, the Behavioural Inhibition System (BIS) and the Behavioural Activation System (BAS), that control aversive and appetitive behaviour, respectively. Research on Gray's model of personality has been hindered by the lack of specific self-report measures of the reactivity and responsivity of these systems. We describe a set of studies that illustrate the main psychometrical characteristics of the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ). The two scales of the questionnaire were developed by writing items to assess BIS and BAS functioning, respectively. Results showed that both scales were independent, and presented satisfactory internal consistency and test-retest reliability. Studies 2–5 reported data related to convergent and discriminant validity of the scales. The Sensitivity to Punishment scale was: (1) positively related to Eysenck's neuroticism dimension; (2) negatively related to extraversion; (3) not related to psychoticism; (4) significantly related to the STAI-Trait scale of Spielberger; and (5) related to the somatic, behavioral, and cognitive anxiety scales of Lehrer and Woolfolk
Behavioral Assessment,
4, (1982) 167–177.. The Sensitivity to Reward scale was: (1) positively related to Eysenck's extraversion and neuroticism; (2) moderately related to psychoticism; (3) positively related to the Eysenck's Impulsiveness scale
Psychological Reports,
43, (1978) 1247–1255 and the Zuckerman's Sensation Seeking Scales
Journal of Consulting and Clinical Psychology,
46, (1978) 139–149. Although future construct validity studies are needed, discussion is focused on the importance of using specific designed measures to evaluate and develop Gray's model.
Objectives
Emotion regulation deficits are a core feature of bipolar disorder. However, their potential neurobiological underpinnings and existence beyond bipolar I disorder remain unexplored. Our ...main goal was to investigate whether both individuals with bipolar I and bipolar II disorder show deficits in emotion regulation during an attention control task, and to explore the neurophysiological underpinnings of this potential deficit.
Methods
Twenty healthy controls, 16 euthymic participants with bipolar I disorder, and 19 euthymic participants with bipolar II disorder completed psychometric and clinical assessments, a neuroimaging emotion regulation paradigm, and an anatomical diffusion‐weighted scan. Groups were matched for age, gender, and verbal IQ.
Results
During the presence of emotional distracters, subjects with bipolar I disorder showed slowed reaction times to targets, and increased blood oxygenation level‐dependent (BOLD) responses in the amygdala, accumbens, and dorsolateral prefrontal cortex, but not increased inverse functional connectivity between these prefrontal and subcortical areas, and altered white matter microstructure organization in the right uncinate fasciculus. Subjects with bipolar II disorder showed no altered reaction times, increased BOLD responses in the same brain areas, increased inverse functional connectivity between the prefrontal cortex and amygdala, and no abnormalities in white matter organization.
Conclusions
Participants with bipolar I disorder showed abnormalities in functional and anatomical connectivity between prefrontal cortices and subcortical structures in emotion regulation circuitry. However, these deficits did not extend to subjects with bipolar II disorder, suggesting fundamental differences in the pathophysiology of bipolar disorder subtypes.
Recent research has highlighted the role of complement genes in shaping the microstructure of the brain during early development, and in contributing to common allele risk for Schizophrenia. We ...hypothesised that common risk variants for schizophrenia within complement genes will associate with structural changes in white matter microstructure within tracts innervating the frontal lobe. Results showed that risk alleles within the complement gene set, but also intergenic alleles, significantly predict axonal density in white matter tracts connecting frontal cortex with parietal, temporal and occipital cortices. Specifically, risk alleles within the Major Histocompatibility Complex region in chromosome 6 appeared to drive these associations. No significant associations were found for the orientation dispersion index. These results suggest that changes in axonal packing - but not in axonal coherence - determined by common risk alleles within the MHC genomic region - including variants related to the Complement system - appear as a potential neurobiological mechanism for schizophrenia.
Research has shown differences in subcortical brain volumes between participants with schizophrenia and healthy controls. However, none of these differences have been found to associate with ...schizophrenia polygenic risk. Here, in a large sample (n = 14,701) of unaffected participants from the UK Biobank, we test whether schizophrenia polygenic risk scores (PRS) limited to specific gene-sets predict subcortical brain volumes. We compare associations with schizophrenia PRS at the whole genome level ('genomic', including all SNPs associated with the disorder at a p-value threshold < 0.05) with 'genic' PRS (based on SNPs in the vicinity of known genes), 'intergenic' PRS (based on the remaining SNPs), and genic PRS limited to SNPs within 7 gene-sets previously found to be enriched for genetic association with schizophrenia ('abnormal behaviour,' 'abnormal long-term potentiation,' 'abnormal nervous system electrophysiology,' 'FMRP targets,' '5HT2C channels,' 'CaV2 channels' and 'loss-of-function intolerant genes'). We observe a negative association between the 'abnormal behaviour' gene-set PRS and volume of the right thalamus that survived correction for multiple testing (ß = -0.031, p
= 0.005) and was robust to different schizophrenia PRS p-value thresholds. In contrast, the only association with genomic PRS surviving correction for multiple testing was for right pallidum, which was observed using a schizophrenia PRS p-value threshold < 0.01 (ß = -0.032, p = 0.0003, p
= 0.02), but not when using other PRS P-value thresholds. We conclude that schizophrenia PRS limited to functional gene sets may provide a better means of capturing differences in subcortical brain volume than whole genome PRS approaches.
We investigated the structural brain networks of 562 young adults in relation to polygenic risk for Alzheimer's disease, using magnetic resonance imaging (MRI) and genotype data from the Avon ...Longitudinal Study of Parents and Children.
Diffusion MRI data were used to perform whole-brain tractography and generate structural brain networks for the whole-brain connectome, and for the default mode, limbic and visual subnetworks. The mean clustering coefficient, mean betweenness centrality, characteristic path length, global efficiency and mean nodal strength were calculated for these networks, for each participant. The connectivity of the rich-club, feeder and local connections was also calculated. Polygenic risk scores (PRS), estimating each participant's genetic risk, were calculated at genome-wide level and for nine specific disease pathways. Correlations were calculated between the PRS and (a) the graph theoretical metrics of the structural networks and (b) the rich-club, feeder and local connectivity of the whole-brain networks.
In the visual subnetwork, the mean nodal strength was negatively correlated with the genome-wide PRS (
= -0.19,
= 1.4 × 10
), the mean betweenness centrality was positively correlated with the plasma lipoprotein particle assembly PRS (
= 0.16,
= 5.5 × 10
), and the mean clustering coefficient was negatively correlated with the tau-protein binding PRS (
= -0.16,
= 0.016). In the default mode network, the mean nodal strength was negatively correlated with the genome-wide PRS (
= -0.14,
= 0.044). The rich-club and feeder connectivities were negatively correlated with the genome-wide PRS (
= -0.16,
= 0.035;
= -0.15,
= 0.036).
We identified small reductions in brain connectivity in young adults at risk of developing Alzheimer's disease in later life.
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