Urban-living individuals are exposed to many environmental factors that may combine and interact to influence mental health. While individual factors of an urban environment have been investigated in isolation, no attempt has been made to model how complex, real-life exposure to living in the city relates to brain and mental health, and how this is moderated by genetic factors. Using the data of 156,075 participants from the UK Biobank, we carried out sparse canonical correlation analyses to investigate the relationships between urban environments and psychiatric symptoms. We found an environmental profile of social deprivation, air pollution, street network and urban land-use density that was positively correlated with an affective symptom group (r = 0.22, P_perm < 0.001), mediated by brain volume differences consistent with reward processing, and moderated by genes enriched for stress response, including CRHR1, explaining 2.01% of the variance in brain volume differences. Protective factors such as greenness and generous destination accessibility were negatively correlated with an anxiety symptom group (r = 0.10, P_perm < 0.001), mediated by brain regions necessary for emotion regulation and moderated by EXD3, explaining 1.65% of the variance. The third urban environmental profile was correlated with an emotional instability symptom group (r = 0.03, P_perm < 0.001). Our findings suggest that different environmental profiles of urban living may influence specific psychiatric symptom groups through distinct neurobiological pathways.

Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer’s disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level.

Schizophrenia is highly heritable, and polygenic risk score for schizophrenia (PRS_SCZ) has been associated with brain and behavior in healthy populations. However, the full associations of PRS_SCZ with brain white matter microstructure and cognitive and mental health outcomes, the potential effects of sex and areal deprivation on these associations, and the mediation of white matter microstructure for the associations between PRS_SCZ and behavioral outcomes remain largely unknown. In up to 300,000 participants from the UK Biobank, we investigated the associations of PRS_SCZ with eight white matter microstructure metrics of 48 tracts and 14 cognitive and mental health phenotypes, and we further tested the moderation of sex and index of multiple deprivation (IMD) on these associations and the mediation of brain white matter phenotypes for the associations between PRS_SCZ and behavioral outcomes. We found that higher PRS_SCZ was associated with decreased white matter integrity in 26 tracts, such as cingulum, corona radiata, and fornix. We also found that higher PRS_SCZ was associated with poorer mental health and worse cognitive performance. These associations were not significantly moderated by sex and IMD. Causal mediation analyses revealed that these adverse effects of PRS_SCZ on cognitive and mental health outcomes were partially mediated by brain white matter phenotypes. These results indicate that genetic risk for schizophrenia affects the integrity of white matter tracts, which may account for its adverse effects on cognitive and mental health outcomes.

Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process. Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms. Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (β = -0.09; p = 5.13 × 10^-5), amygdala (β = -0.07; p = 8.44 × 10^-4), and hippocampus (β = -0.07; p = 0.001), as well as with low serum vitamin D level (β = -0.02; p = 6.84 × 10^-6). Specifically, decreased serum vitamin D level mediated 3.99 % (95 % CI: -0.006 to -5.82 × 10^-5) and 3.97 % (95 % CI: -0.007 to -2.94 × 10^-4) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampal and NAc atrophy, a significant reduction of β-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet. These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.

Socioeconomic status (SES) correlates with both mental symptoms and systemic health traits, suggesting systemic health conditions as potential complementary pathways for SES-mental health associations alongside neural mechanisms. Here, we distinguished independent associations of areal and personal SES with 95 whole-body health traits, including anxiety and depression, tested whether these associations differ by age and sex, and assessed the extent to which associations between areal SES and mental health are statistically attributable to personal SES and whole-body health traits in 489,543 participants from the UK Biobank. We identified 144 independent associations of areal and personal SES with whole-body health traits, including 14 with significant age differences and 65 with significant sex differences. The associations between areal SES and mental symptoms were primarily mediated by personal SES and whole-body health traits. The pathways from areal SES to depression and anxiety symptoms may inform multiple-level interventions for mental health improvement.