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Background: Alzheimer’s disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterising their genetic overlap may provide aetiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects. Methods: We applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD ( n = 79,145) and depression ( n = 450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (UKB) (mean age 57.21, 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data. Results: MiXer estimated 98 causal genetic variants overlapping between the 2 disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD ( B = −0.002, p = 9.1 × 10 –4 ) and depression ( B = 0.007, p = 3.2 × 10 –9 ) in the UKB. This SNP was also associated with several regions of the corpus callosum volume anterior ( B > 0.024, p < 8.6 × 10 –4 ), third ventricle volume ventricle ( B = −0.025, p = 5.0 × 10 –6 ), and inferior temporal gyrus surface area ( B = 0.017, p = 5.3 × 10 –4 ). Discussion: Our results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.
Objective We aimed to investigate the incidence of juvenile idiopathic arthritis (JIA) in the three geographic regions of Norway and whether potential regional incidence differences are explained by environmental or genetic factors across regions. Methods We conducted a register‐based cohort study including all Norwegian children born from 2004 to 2019, with follow‐up throughout 2020. The JIA diagnosis, defined by at least two International Classification of Diseases, Tenth Revision codes for JIA, was validated against medical records. The incidence rate (IR) and hazard ratio (HR) for JIA were estimated for all Norway and for the North, Mid, and South regions. In a subsample from the Norwegian Mother, Father, and Child Cohort Study (MoBa), the genetic risk for JIA was assessed in the three regions. Results After median 9.1 (range 0.3–16.0) years of follow‐up, we identified 1,184 patients with JIA and 910,058 controls. The IR for JIA/100,000 person‐years was 14.4 in all of Norway, 25.9 in the North region, 17.9 in the Mid region, and 12.5 in the South region. The HR (95% confidence interval [CI]) of JIA in the North region was 2.07 (1.77–2.43) and in the Mid region HR 1.43 (95% CI 1.23–1.67) compared with the South region. Adjustments for perinatal factors, socioeconomic status, and early antibiotic exposure did not change our estimates substantially. In MoBa (238 patients with JIA, 57,392 controls), the association between JIA and region of birth was no longer significant when adjusting for genetic factors. Conclusion We found a higher incidence of JIA with increasing latitude without evidence for available environmental factors explaining the observed gradient. In contrast, genetic factors modified the association, but further studies are warranted.
Research has demonstrated associations between pubertal development and brain maturation. However, existing studies have been limited by small samples, cross-sectional designs, and inconclusive findings regarding directionality of effects and sex differences. We examined the longitudinal temporal coupling of puberty status assessed using the Pubertal Development Scale (PDS) and magnetic resonance imaging (MRI)-based grey and white matter brain structure. Our sample consisted of 8896 children and adolescents at baseline (mean age = 9.9) and 6099 at follow-up (mean age = 11.9) from the Adolescent Brain and Cognitive Development (ABCD) Study cohort. Applying multigroup Bivariate Latent Change Score (BLCS) models, we found that baseline PDS predicted the rate of change in cortical thickness among females and rate of change in cortical surface area for both males and females. We also found a correlation between baseline PDS and surface area and co-occurring changes over time in males. Diffusion tensor imaging (DTI) analyses revealed correlated change between PDS and fractional anisotropy (FA) for both males and females, but no significant associations for mean diffusivity (MD). Our results suggest that pubertal status predicts cortical maturation, and that the strength of the associations differ between sex. Further research spanning the entire duration of puberty is needed to understand the extent and contribution of pubertal development on the youth brain.
Epilepsy is clinically heterogeneous, and neurological or psychiatric comorbidities are frequently observed in patients. It has not been tested whether common risk variants for generalized or focal epilepsy are enriched in people with other disorders or traits related to brain or cognitive function. Here, we perform two brain-focused phenome association studies of polygenic risk scores (PRS) for generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) with all binary brain or cognitive function-related traits available for 334,310 European-ancestry individuals of the UK Biobank. Higher GE-PRS were associated with not having a college or university degree (P = 3.00x10-4), five neuroticism-related personality traits (P<2.51x10-4), and having ever smoked (P = 1.27x10-6). Higher FE-PRS were associated with several measures of low educational attainment (P<4.87x10-5), one neuroticism-related personality trait (P = 2.33x10-4), having ever smoked (P = 1.71x10-4), and having experienced events of anxiety or depression (P = 2.83x10-4). GE- and FE-PRS had the same direction of effect for each of the associated traits. Genetic factors associated with GE or FE showed similar patterns of correlation with genetic factors associated with cortical morphology in a subset of the UKB with 16,612 individuals and T1 magnetic resonance imaging data. In summary, our results suggest that genetic factors associated with epilepsies may confer risk for other neurological and psychiatric disorders in a population sample not enriched for epilepsy.
Background Lower vitamin D levels are found in people with schizophrenia and depressive disorders, and also associated with neuroimaging abnormalities such as reduced brain volume in both animals and humans. Reduced whole brain and increased ventricular volume are also systematically reported in schizophrenia. Even though vitamin D deficiency has been proposed as a risk mechanism for schizophrenia there exist no studies to date of the association between vitamin D levels and brain volume in this population. Therefore, we investigated the relationship between vitamin D levels and brain phenotypes in psychotic disorders, and assessed possible interactions with genetic variants in vitamin D receptor (VDR) and other genetic variants that play a role in vitamin D levels in the body. Methods Our sample consisted of 83 psychosis patients and 101 healthy controls. We measured vitamin D levels as serum 25-hydroxyvitamin D. All participants were genotyped and neuroimaging conducted by structural magnetic resonance imaging. Results Vitamin D levels were significantly positively associated with peripheral grey matter volume in patients (β 860.6; 95% confidence interval (CI) 333.4–1466, p < .003). A significant interaction effect of BSML marker (rs1544410) was observed to mediate the association between patient status and both white matter volume (β 23603.3; 95% CI 2732.8–48708.6, p < .05) and whole brain volume (β 46670.6, 95% CI 8817.8–93888.3, p < .04). Vitamin D did not predict ventricular volume, which rather was associated with patient status (β 4423.3, 95% CI 1583.2–7267.8p < .002) and CYP24A1 marker (rs6013897) (β 2491.5, 95% CI 269.7–4978.5, p < .04). Conclusions This is the first study of the association between vitamin D levels and brain volume in patients with psychotic disorders that takes into account possible interaction with genetic polymorphisms. The present findings warrant replication in independent samples.
Optical methods that rely on fluorescence for mapping changes in neuronal membrane potential in the brains of awake animals provide a powerful way to interrogate the activity of neurons that underlie neural computations ranging from sensation and perception to learning and memory. To achieve this goal, fluorescent indicators should be bright, highly sensitive to small changes in membrane potential, nontoxic, and excitable with infrared light. We report a new class of fluorescent, voltage-sensitive dyes: sulfonated rhodamine voltage reporters (sRhoVR), synthetic fluorophores with high voltage sensitivity, excellent two-photon performance, and compatibility in intact mouse brains. sRhoVR dyes are based on a tetramethyl rhodamine fluorophore coupled to a phenylenevinylene molecular wire/diethyl aniline voltage-sensitive domain. When applied to cells, sRhoVR dyes localize to the plasma membrane and respond to membrane depolarization with a fluorescence increase. The best of the new dyes, sRhoVR 1, displays a 44% ΔF/F increase in fluorescence per 100 mV change, emits at 570 nm, and possesses excellent two-photon absorption of approximately 200 GM at 840 nm. sRhoVR 1 can detect action potentials in cultured rat hippocampal neurons under both single- and two-photon illumination with sufficient speed and sensitivity to report on action potentials in single trials, without perturbing underlying physiology or membrane properties. The combination of speed, sensitivity, and brightness under two-photon illumination makes sRhoVR 1 a promising candidate for in vivo imaging in intact brains. We show sRhoVR powerfully complements electrode-based modes of neuronal activity recording in the mouse brain by recording neuronal transmembrane potentials from the neuropil of layer 2/3 of the mouse barrel cortex in concert with extracellularly recorded local field potentials (LFPs). sRhoVR imaging reveals robust depolarization in response to whisker stimulation; concurrent electrode recordings reveal negative deflections in the LFP recording, consistent with the canonical thalamocortical response. Importantly, sRhoVR 1 can be applied in mice with chronic optical windows, presaging its utility in dissecting and resolving voltage dynamics using two-photon functional imaging in awake, behaving animals.
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