Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study

Exposures to copper have become a health concern.We aim to explore the broad clinical effects of blood copper concentrations.A total of 376,346 Caucasian subjects were enrolled.We performed a Mendelian randomization and phenome-wide association study(MR-PheWAS)to evaluate the causal association between copper and a wide range of outcomes in UK Biobank,and we constructed a protein-protein interaction network.We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male.MR analysis implicated a causal role of blood copper in five diseases(overall population),including prostate cancer(OR=0.87,95%CI 0.77-0.98),malignant and unknown neoplasms of the brain and nervous system(OR=0.58,95%CI 0.38-0.89),and hypertension(OR=0.94,95%CI 0.90-0.98),essential hypertension(OR=0.94,95%CI 0.90-0.98)and cancer of brain and nervous system(OR=0.63,95%CI 0.41-0.98).For male,except for dysphagia being newly associated with blood copper(OR=1.39,95%CI 1.18-1.63),other MR results were consistent with the overall population.In addition,the PPI network showed possible relationship between blood copper and four outcomes,namely brain cancer,prostate cancer,hypertension,and dysphagia.Blood copper may have causal association with prostate cancer,malignant and unknown neoplasms of the brain and nervous system,hypertension,and dysphagia.Considering that copper is modifiable,exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance.

Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice

Attention-deficit hyperactivity disorder(ADHD) is a neurodevelopmental disorder prevalent in schoolage children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid(AMPA) receptor regulatory protein γ-8(TARP γ-8,also known as calcium voltage-gated channel auxiliary subunit gamma 8(CACNG8)) is an auxiliary AMPA receptor(AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD,whereby adolescent TARP γ-8 knockout(KO) mice exhibitedADHD-likebehaviors,including hyperactivity, impulsivity, anxiety, impaired cognition,and memory deficits. Human single-nucleotide polymorphism(SNP) analysis also revealed strong associations between intronic alleles in CACNG8genes and ADHD susceptibility. In addition,synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice.Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice.Methylphenidate(MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans.This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8deficiency, which has great potential for the development of new therapies.

Health consequences of early-onset compared with late-onset type 2 diabetes mellitus

Background:Although cumulating evidence has suggested that early-onset type 2 diabetes mellitus(T2DM)conferred on patients a broader tendency for complications beyond vascular ones,a comprehensive analysis of patterns of complications across all relevant systems is currently lacking.Method:We prospectively studied 1777 early-onset(age at diagnosis≤45 years)and 35889 late-onset(>45 years)T2DM patients with matched unexposed individuals from the UK Biobank.Diabetes-specific and-related complications were examined using phenomewide association analysis,with patterns identified by comorbidity network analysis.We also evaluated the effect of lifestyle modifications and glycemic control on complication development.Results:The median follow-up times for early-onset and late-onset T2DM patients were 17.83 and 9.39 years,respectively.Compared to late-onset T2DM patients,patients with early-onset T2DM faced a significantly higher relative risk of developing subsequent complications that primarily affected sense organs[hazard ratio(HR)3.46 vs.1.72],the endocrine/metabolic system(HR 3.08 vs.2.01),and the neurological system(HR 2.70 vs.1.81).Despite large similarities in comorbidity patterns,a more complex and well-connected network was observed for early-onset T2DM.Furthermore,while patients with early-onset T2DM got fewer benefits(12.67%reduction in pooled HR for all studied complications)through fair glycemic control(median HbA1c≤53 mmol/mol)compared to late-onset T2DM patients(18.01%reduction),they seemed to benefit more from favorable lifestyles,including weight control,healthy diet,and adequate physical activity.Conclusions:Our analyses reveal that early-onset T2DM is an aggressive disease resulting in more complex complication networks than late-onset T2DM.Aggressive glucose-lowering intervention,complemented by lifestyle modifications,are feasible strategies for controlling early-onset T2DM-related complications.