Nicholas Graham

Background: The link between cardiometabolic and psychiatric illness has long been attributed to human behaviour, however recent research highlights shared biological mechanisms. The ASTN2 locus has been previously implicated in psychiatric and cardiometabolic traits, therefore this study aimed to systematically investigate the genetic architecture of ASTN2 in relation to a wide range of relevant traits. Methods: Baseline questionnaire, assessment and genetic data of 402111 unrelated white British ancestry individuals from the UK Biobank was analysed. Genetic association analyses were conducted using PLINK 1.07, assuming an additive genetic model and adjusting for age, sex, genotyping chip, and population structure. Conditional analyses and linkage disequilibrium assessment were used to determine whether cardiometabolic and psychiatric signals were independent. Results: Associations between genetic variants in the ASTN2 locus and blood pressure, total and central obesity, neuroticism, anhedonia and mood instability were identified. All analyses support the independence of the cardiometabolic traits from the psychiatric traits. In silico analyses provide support for the central obesity signal acting through ASTN2, however most of the other signals are likely acting through other genes in the locus. Conclusions: Our systematic analysis demonstrates that ASTN2 has pleiotropic effects on cardiometabolic and psychiatric traits, rather than contributing to shared pathology.

Recent assessments of future risk to atoll habitability have focused on island erosion and submergence, and have overlooked the effects of other climate‐related drivers, as well as differences between ocean basins and island types. Here we investigate the cumulative risk arising from multiple drivers (sea‐level rise; changes in rainfall, ocean–atmosphere oscillations and tropical cyclone intensity; ocean warming and acidification) to five Habitability Pillars: Land, Freshwater supply, Food supply, Settlements and infrastructure, and Economic activities. Risk is assessed for urban and rural islands of the Pacific and Indian Oceans, under RCP2.6 and RCP8.5, in 2050 and 2090, and considering a moderate adaptation scenario. Risks will be highest in the Western Pacific which will experience increased island destabilization together with a high threat to freshwater, and decreased land‐based and marine food supply from reef‐dependent fish and tuna and tuna‐like resources. Risk accumulation will occur at a lower rate in the Central Pacific (lower pressure on land, with more limited cascading effects on other Habitability Pillars; increase in pelagic fish stocks) and the Central Indian Ocean (mostly experiencing increased land destabilization and reef degradation). Risk levels will vary significantly between urban islands, depending on geomorphology and local shoreline disturbances. Rural islands will experience less contrasting risk levels, but higher risks than urban islands in the second half of the century.This article is categorized under: Trans‐Disciplinary Perspectives > Regional Reviews

Individuals with severe mental illness have an increased risk of cardiometabolic diseases compared to the general population. Shared risk factors and medication effects explain part of this excess risk; however, there is growing evidence to suggest that shared biology (including genetic variation) is likely to contribute to comorbidity between mental and physical illness. Contactins are a family of genes involved in development of the nervous system and implicated, though genome-wide association studies, in a wide range of psychological, psychiatric and cardiometabolic conditions. Contactins are plausible candidates for shared pathology between mental and physical health. We used data from UK Biobank to systematically assess how genetic variation in contactin genes was associated with a wide range of psychological, psychiatric and cardiometabolic conditions. We also investigated whether associations for cardiometabolic and psychological traits represented the same or distinct signals and how the genetic variation might influence the measured traits. We identified: A novel genetic association between variation in CNTN1 and current smoking; two independent signals in CNTN4 for BMI; and demonstrated that associations between CNTN5 and neuroticism were distinct from those between CNTN5 and blood pressure/HbA1c. There was no evidence that the contactin genes contributed to shared aetiology between physical and mental illness

Objectives To assess whether a history of major depressive disorder (MDD) in middle-aged individuals with hypertension influences first-onset cardiovascular disease outcomes. Design Prospective cohort survival analysis using Cox proportional hazards regression with a median follow-up of 63 months (702 902 person-years). Four mutually exclusive groups were compared: hypertension only (n=56 035), MDD only (n=15 098), comorbid hypertension plus MDD (n=12 929) and an unaffected (no hypertension, no MDD) comparison group (n=50 798). Setting UK Biobank. Participants UK Biobank participants without cardiovascular disease aged 39–70 who completed psychiatric questions relating International Classification of Diseases-10 Revision (ICD-10) diagnostic criteria on a touchscreen questionnaire at baseline interview in 2006–2010 (n=134 860). Primary and secondary outcome measures First-onset adverse cardiovascular outcomes leading to hospital admission or death (ICD-10 codes I20–I259, I60–69 and G45–G46), adjusted in a stepwise manner for sociodemographic, health and lifestyle features. Secondary analyses were performed looking specifically at stroke outcomes (ICD-10 codes I60–69 and G45–G46) and in gender-separated models. Results Relative to controls, adjusted HRs for adverse cardiovascular outcomes were increased for the hypertension only group (HR 1.36, 95% CI 1.22 to 1.52) and were higher still for the comorbid hypertension plus MDD group (HR 1.66, 95% CI 1.45 to 1.9). HRs for the comorbid hypertension plus MDD group were significantly raised compared with hypertension alone (HR 1.22, 95% CI 1.1 to 1.35). Interaction measured using relative excess risk due to interaction (RERI) and likelihood ratios (LRs) were identified at baseline (RERI 0.563, 95% CI 0.189 to 0.938; LR p=0.0116) but not maintained during the follow-up. Limitations Possible selection bias in UK Biobank and inability to assess for levels of medication adherence. Conclusions Comorbid hypertension and MDD conferred greater hazard than hypertension alone for adverse cardiovascular outcomes, although evidence of interaction between hypertension and MDD was inconsistent over time. Future cardiovascular risk prediction tools may benefit from the inclusion of questions about prior history of depressive disorders.

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here we report the results of a GWAS of mood instability (MI) as a trait in a large population cohort (UK Biobank, n=363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with MI were identified with a heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia (SZ), anxiety and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified total 244 significant genes and 6 enriched gene sets. Tissue expression analysis from the SNP level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. Additionally, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues, and gene sets contributing to MI as a normal trait and will inform future work on the biology of mood and psychotic disorders, and to point the way towards potential for new stratified medicine approaches and the identification of novel trans-diagnostic drug targets.

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 783). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10-5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.