Genetic contributions to cognitive ageing and structural brain magnetic resonance imaging phenotypes

As humans age, specific mental faculties deteriorate even in the absence of dementia. Age related cognitive decline affects quality of life, and has significant implications from a socio-economic perspective; however not everyone declines to equal degrees, at equal rates, or from the same baseline. This PhD examined a large sample of community-dwelling older adults called the Lothian Birth Cohort 1936, most of whom completed an intelligence test at age 11 years, and again around age 73 as part of a detailed assessment that also included detailed brain magnetic resonance imaging (N range = 700-866). I investigated the independent effects of two linked genetic loci which have been associated with greater risk of Alzheimer’s disease – the APOE ε haplotype (commonly ‘genotype’) and a poly-T repeat in the TOMM40 gene. Are 'risk' variants in these loci associated with specific measures of cognitive ageing and brain structure - specifically white matter microstructural integrity, hippocampal volumes, white matter lesions or cerebral microbleeds – in this sample? Firstly, a pilot study aimed to replicate significant associations between the ADRB2 gene and brain imaging/cognitive phenotypes, that had previously been reported in a smaller subsample of the cohort that had by that time undergone MRI (n = 132). Previously reported significant associations were not significant in the larger, full LBC1936 sample (n = 700-866), but novel significant associations were found (P < 0.05). Specifically, integrity of the left arcuate fasciculus white matter tract significantly mediated part of the association between specific genetic variations at ADRB2, and the Digit Symbol Coding task of information processing speed. These findings indicated that this approach – testing three-way genetic/brain imaging/cognitive associations for mediation - was viable for the main APOE/TOMM40 analyses. Results in the main APOE/TOMM40 analyses showed that specific variants in the APOE and TOMM40 gene loci were statistically significantly associated (at raw P value <0.05) with white matter tract microstructural integrity, but not white matter lesions, hippocampal volume or cerebral microbleeds. Inconsistencies with previous, positive reports showing significant associations between APOE ε and these latter phenotypes may reflect a degree of type 1 error or more study-specific discrepancies (which are detailed throughout). APOE ε was significantly associated with average scores on a large proportion of cognitive tests, independent of age 11 intelligence (i.e. ‘cognitive ageing’; Deary et al., 2004). These associations were partly – but not completely – mediated by white matter tract microstructural integrity. TOMM40 poly-T repeat genotype was associated with cognitive ageing to a much lesser extent. A range of brain phenotypes may form the anatomical basis for significant associations between APOE genotype and cognitive ageing, among which includes white matter tract microstructural integrity

Low birth weight and features of neuroticism and mood disorder in 83 545 participants of the UK Biobank cohort

Background: Low birth weight has been inconsistently associated with risk of developing affective disorders, including major depressive disorder (MDD). To date, studies investigating possible associations between birth weight and bipolar disorder (BD), or personality traits known to predispose to affective disorders such as neuroticism, have not been conducted in large cohorts. Aims: To assess whether very low birth weight (7LT;1500 g) and low birth weight (1500–2490 g) were associated with higher neuroticism scores assessed in middle age, and lifetime history of either MDD or BD. We controlled for possible confounding factors. Method: Retrospective cohort study using baseline data on the 83 545 UK Biobank participants with detailed mental health and birth weight data. Main outcomes were prevalent MDD and BD, and neuroticism assessed using the Eysenck Personality Inventory Neuroticism scale - Revised (EPIN-R) Results: Referent to normal birth weight, very low/low birth weight were associated with higher neuroticism scores, increased MDD and BD. The associations between birth weight category and MDD were partially mediated by higher neuroticism. Conclusions: These findings suggest that intrauterine programming may play a role in lifetime vulnerability to affective disorders

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

Anhedonia is a core symptom of multiple psychiatric disorders and has been associated with alterations 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. Here, we investigated how anhedonia and PRS-anhedonia were associated with brain structure within the UK Biobank cohort. Brain measures (including total grey/white matter volumes, subcortical volumes, cortical thickness (CT) and white matter integrity) were analysed using linear mixed models in relation to anhedonia and PRS-anhedonia in 19,592 participants (9225 males; mean age = 62.6 years, SD = 7.44). We found that state anhedonia was significantly associated with reduced total grey matter volume (GMV); increased total white matter volume (WMV); smaller volumes in thalamus and nucleus accumbens; reduced CT within the paracentral cortex, the opercular part of inferior frontal gyrus, precentral cortex, insula and rostral anterior cingulate cortex; and poorer integrity of many white matter tracts. PRS-anhedonia was associated with reduced total GMV; increased total WMV; reduced white matter integrity; and reduced CT within the parahippocampal cortex, superior temporal gyrus and insula. Overall, both state anhedonia and PRS-anhedonia were associated with individual differences in multiple brain structures, including within reward-related circuits. These associations may represent vulnerability markers for psychopathology relevant to a range of psychiatric disorders

Polygenic Risk for Schizophrenia, Brain Structure, and Environmental Risk in UK Biobank

Schizophrenia is a heritable neurodevelopmental disorder characterized by neuroanatomical changes in the brain but exactly how increased genetic burden for schizophrenia influences brain structure is unknown. Similarly, the impact of environmental risk factors for schizophrenia on brain structure is not fully understood. We investigated how genetic burden for schizophrenia (indexed by a polygenic risk score, PRS-SCZ) was associated with cortical thickness (CT), cortical surface area (SA), cortical volume (CV) and multiple subcortical structures within 18,147 White British ancestry participants from UK Biobank. We also explored whether environmental risk factors for schizophrenia (cannabis use, childhood trauma, low birth weight and Townsend social deprivation index) exacerbated the impact of PRS-SCZ on brain structure. We found that PRS-SCZ was significantly associated with lower CT in the frontal lobe, insula lobe, lateral orbitofrontal cortex, medial orbitofrontal cortex, posterior cingulate cortex and inferior frontal cortex, as well as reduced SA and CV in the supramarginal cortex and superior temporal cortex, but not with differences in subcortical volumes. When models included environmental risk factors as covariates, PRS-SCZ was only associated with lower SA/CV within the supramarginal cortex, superior temporal cortex and inferior frontal cortex. Moreover, no interactions were observed between PRS-SCZ and each of the environmental risk factors on brain structure. Overall, we identified brain structural correlates of PRS-SCZ predominantly within frontal and temporal regions. Some of these associations were independent of environmental risk factors, suggesting that they may represent biomarkers of genetic risk for schizophrenia

The associations between self-reported depression, self-reported chronic inflammatory conditions and cognitive abilities in UK Biobank

Background: Depression and chronic inflammatory medical conditions have been linked to impaired cognitive ability. However despite frequent comorbidity, their combined association with cognitive ability has rarely been examined. Methods: This study examined associations between self-reported depression and chronic inflammatory diseases and their interaction with cognitive performance in 456,748 participants of the UK Biobank, adjusting for sociodemographic and lifestyle factors. Numbers with available data ranged from 94,899 to 453,208 depending on the cognitive test. Results: Self-reported depression was associated with poorer performance compared to controls in several cognitive tests (fully adjusted models, reaction time: B = 6.08, 95% CI = 5.09, 7.07; pairs matching: incidence rate ratio = 1.02, 95% CI = 1.02, 1.03; Trail Making Test B: B = 1.37, 95% CI = 0.88, 1.87; Digit Symbol Substitution Test (DSST): B = −0.35, 95% CI = −0.44, −0.27). Self-reported chronic inflammatory conditions were associated with slower reaction time (B = 3.79, 95% CI = 2.81, 4.78) and lower DSST scores (B = −0.21, 95% CI = −0.30, −0.13). No interaction effects were observed. Discussion: In this large, population-based study we provide evidence of lower cognitive performance in both depression and a comprehensive category of chronic inflammatory conditions. Results are consistent with additive effects of both types of disorder on cognitive ability. Clinicians should be aware of such effects, particularly as cognitive impairment is linked to poorer disease outcomes and quality of life

Subjective and objective sleep and circadian parameters as predictors of depression-related outcomes: A machine learning approach in UK Biobank

Background: Sleep and circadian disruption are associated with depression onset and severity, but it is unclear which features (e.g., sleep duration, chronotype) are important and whether they can identify individuals showing poorer outcomes. Methods: Within a subset of the UK Biobank with actigraphy and mental health data (n = 64,353), penalised regression identified the most useful of 51 sleep/rest-activity predictors of depression-related outcomes; including case-control (Major Depression (MD) vs. controls; postnatal depression vs. controls) and within-case comparisons (severe vs. moderate MD; early vs. later onset, atypical vs. typical symptoms; comorbid anxiety; suicidality). Best models (of lasso, ridge, and elastic net) were selected based on Area Under the Curve (AUC). Results: For MD vs. controls (n(MD) = 24,229; n(control) = 40,124), lasso AUC was 0.68, 95 % confidence interval (CI) 0.67–0.69. Discrimination was reasonable for atypical vs. typical symptoms (n(atypical) = 958; n(typical) = 18,722; ridge: AUC 0.74, 95 % CI 0.71–0.77) but poor for remaining models (AUCs 0.59–0.67). Key predictors across most models included: difficulty getting up, insomnia symptoms, snoring, actigraphy-measured daytime inactivity and lower morning activity (~8 am). In a distinct subset (n = 310,718), the number of these factors shown was associated with all depression outcomes. Limitations: Analyses were cross-sectional and in middle-/older aged adults: comparison with longitudinal investigations and younger cohorts is necessary. Discussion: Sleep and circadian measures alone provided poor to moderate discrimination of depression outcomes, but several characteristics were identified that may be clinically useful. Future work should assess these features alongside broader sociodemographic, lifestyle and genetic features

Social engagement after stroke – is it relevant to cognitive function? A cross-sectional analysis of UK Biobank data

Background: Findings from studies in older adult populations suggest that measures of social engagement may be associated with health outcomes, including cognitive function. Plausibly the magnitude and direction of this association may differ in stroke. The disabling nature of stroke increases the likelihood of social isolation and stroke survivors are at high risk of cognitive decline. We assessed the association between social engagement and cognitive function in a sample of stroke survivors. Methods: We included available data from stroke survivors in the UK Biobank (N=8776; age range: 40-72; 57.4% male). In a series of regression models, we assessed cross-sectional associations between proxies of social engagement (frequency of family/friend visits, satisfaction with relationships, loneliness, opportunities to confide in someone, participation in social activities) and performance on domain specific cognitive tasks: reaction time, verbal-numerical reasoning, visual memory and prospective memory. We adjusted for demographics, health-, lifestyle-, and stroke-related factors. Accounting for multiple testing, we set our significance threshold at p&lt;0.003. Results: After adjusting for covariates, we found independent associations between faster reaction times and monthly family visits as compared to no visit (standardised beta=-0.32, 99.7% CI: -0.61 to -0.03, N=4,930); slower reaction times and religious group participation (standardised beta=0.25, 99.7% CI 0.07 to 0.44, N=4,938); and poorer performance on both verbal-numerical reasoning and prospective memory tasks with loneliness (standardised beta=-0.19, 99.7% CI: -0.34 to -0.03, N=2,074; odds ratio=0.66, 99.7% CI: 0.46 to 0.94, N=2,188; respectively). In models where all proxies of social engagement were combined, no associations remained significant. Conclusions: We found limited task-specific associations between cognitive performance and proxies of social engagement, with only loneliness related to two tasks. Further studies are necessary to confirm and improve our understanding of these relationships and investigate the potential to target psychosocial factors to support cognitive function in stroke survivors

Association between active commuting and incident cardiovascular disease, cancer, and mortality: prospective cohort study

Objective: To investigate the association between active commuting and incident cardiovascular disease (CVD), cancer, and all cause mortality. Design: Prospective population based study. Setting: UK Biobank. Participants: 263 450 participants (106 674 (52%) women; mean age 52.6), recruited from 22 sites across the UK. The exposure variable was the mode of transport used (walking, cycling, mixed mode v non-active (car or public transport)) to commute to and from work on a typical day. Main outcome measures: Incident (fatal and non-fatal) CVD and cancer, and deaths from CVD, cancer, or any causes. Results: 2430 participants died (496 were related to CVD and 1126 to cancer) over a median of 5.0 years (interquartile range 4.3-5.5) follow-up. There were 3748 cancer and 1110 CVD events. In maximally adjusted models, commuting by cycle and by mixed mode including cycling were associated with lower risk of all cause mortality (cycling hazard ratio 0.59, 95% confidence interval 0.42 to 0.83, P=0.002; mixed mode cycling 0.76, 0.58 to 1.00, P&lt;0.05), cancer incidence (cycling 0.55, 0.44 to 0.69, P&lt;0.001; mixed mode cycling 0.64, 0.45 to 0.91, P=0.01), and cancer mortality (cycling 0.60, 0.40 to 0.90, P=0.01; mixed mode cycling 0.68, 0.57 to 0.81, P&lt;0.001). Commuting by cycling and walking were associated with a lower risk of CVD incidence (cycling 0.54, 0.33 to 0.88, P=0.01; walking 0.73, 0.54 to 0.99, P=0.04) and CVD mortality (cycling 0.48, 0.25 to 0.92, P=0.03; walking 0.64, 0.45 to 0.91, P=0.01). No statistically significant associations were observed for walking commuting and all cause mortality or cancer outcomes. Mixed mode commuting including walking was not noticeably associated with any of the measured outcomes. Conclusions: Cycle commuting was associated with a lower risk of CVD, cancer, and all cause mortality. Walking commuting was associated with a lower risk of CVD independent of major measured confounding factors. Initiatives to encourage and support active commuting could reduce risk of death and the burden of important chronic conditions