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Patients with pulmonary arterial hypertension (PAH) often present with anxiety, depression and cognitive deterioration. Structural changes in the cerebral cortex in PAH patients have also been reported in observational studies. PAH genome-wide association (GWAS) including 162,962 European individuals was used to assess genetically determined PAH. GWAS summary statistics were obtained for cognitive performance, depression, anxiety and alterations in cortical thickness (TH) or surface area (SA) of the brain cortex, respectively. Two-sample Mendelian randomization (MR) was performed. Finally, sensitivity analyses including Cochran's Q test, MR-Egger intercept test, leave-one-out analyses, and funnel plot was performed. PAH had no causal relationship with depression, anxiety, and cognitive performance. At the global level, PAH was not associated with SA or TH of the brain cortex; at the functional regional level, PAH increased TH of insula (P = 0.015), pars triangularis (P = 0.037) and pars opercularis (P = 0.010) without global weighted. After global weighted, PAH increased TH of insula (P = 0.004), pars triangularis (P = 0.032), pars opercularis (P = 0.007) and rostral middle frontal gyrus (P = 0.022) while reducing TH of inferior parietal (P = 0.004), superior parietal (P = 0.031) and lateral occipital gyrus (P = 0.033). No heterogeneity and pleiotropy were detected. The enrolled patients were all European and the causal relationship between PAH and the structure of the cerebral cortex in other populations remains unknown. Causal relationship between PAH and the brain cortical structure was implied, thus providing novel insights into the PAH associated neuropsychiatric symptoms. Using a Mendelian randomization study, a causal effect of PAH on the brain cortical structure was revealed, which suggested the presence of lung-brain axis. We acknowledge BioRender.com for the generation of cartoon figures. [Display omitted] • Using a Mendelian randomization study, we reveal the causal effect of PAH on the brain cortical structure, namely magnetic resonance imaging (MRI)-measure surficial areas and cortical thickness, which suggested the presence of lung-brain axis. • Using a Mendelian randomization study, it was revealed that PAH had no causal relationship with two kinds Neuropsychological disorders of depression and anxiety. • Using a Mendelian randomization study, it was revealed that PAH had no causal relationship with cognitive performance, in what is referred to general cognitive performance. fluid intelligence score and memory performance. [ABSTRACT FROM AUTHOR]

BackgroundPrevious observational studies have suggested associations between high-level educational attainment (EA) and a lower risk of sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. The protective effect of EA on sarcopenia may be mediated via changes in brain cortical structure. The aim of this study was to use a two-step Mendelian randomization (MR) analysis to illustrate the causal relationship between EA, brain cortical structure, and sarcopenia.MethodsInstrumental variables at the genome-wide significance level were obtained from publicly available datasets, and inverse variance weighted as the primary method was used for MR analysis. We perform several sensitivity analyses, including Cochran Q test, MR-Egger intercept test, leave-one-out analyses, and MR Pleiotropy Residual Sum and Outlier to evaluate the reliability of the results.ResultsEA was causally associated with increased appendicular lean mass (β = 0.25, 95% confidence interval (CI): 0.19 to 0.31, p = 2.25 × 10−15), hand grip strength (left: β = 0.042, 95% CI: 0.013 to 0.071, p = 4.77 × 10−3 and right: β = 0.050, 95% CI: 0.022 to 0.079, p = 5.17 × 10−4), and usual walking pace (β = 0.20, 95% CI: 0.18 to 0.22, p = 6.16 × 10−83). In addition, EA was associated with increased brain cortical surface area (β = 4082.36, 95% CI: 2513.35 to 5681.38, p = 3.40 × 10−7) and cortical thickness (TH) (β = 0.014, 95% CI: 0.0045 to 0.023, p = 3.45 × 10−3). Regarding the causal effect of EA on usual walking pace, the mediatory effect of TH was 0.0069 and the proportion of mediation by TH was 3.43%.ConclusionThe study will have revealed the protective causal effect of EA on sarcopenia, which provides a reference for the prevention of sarcopenia at the public health level. We also will have found EA could affect the brain cortical structure, and the brain cortical structure could mediate the protective effect of EA against sarcopenia risk.

Introduction: The bidirectional relationship between the brain cortex and cardiovascular diseases (CVDs) remains inadequately explored. Methods: This study used bidirectional Mendelian randomization (MR) analysis to explore the interactions between nine phenotypes associated with hypertension, heart failure, atrial fibrillation (AF), and coronary heart disease (CHD), and brain cortex measurements. These measurements included total surface area (SA), average thickness (TH), and the SA and TH of 34 regions defined by the Desikan-Killiany atlas. The nine traits were obtained from sources such as the UK Biobank and FinnGen, etc., while MRI-derived traits of cortical structure were sourced from the ENIGMA Consortium. The primary estimate was obtained using the inverse-variance weighted approach. A false discovery rate adjustment was applied to the p-values (resulting in q-values) in the analyses of regional cortical structures. Results: A total of 1,260 two-sample MR analyses were conducted. Existing CHD demonstrated an influence on the SA of the banks of the superior temporal sulcus (bankssts) (q=0.018) and the superior frontal lobe (q=0.018), while hypertension was associated with changes in the TH of the lateral occipital region (q=0.02). Regarding the effects of the brain cortex on CVD incidence, total SA was significantly associated with the risk of CHD. Additionally, 16 and 3 regions exhibited significant effects on blood pressure and AF risk, respectively (q

Background: Reduced brain volume, impaired cognition, and possibly a range of psychoneurological disorders have been reported in patients with nonalcoholic fatty liver disease (NAFLD); however, no underlying cause has been specified. Here, Mendelian randomization (MR) was employed to determine the causative NAFLD effects on cortical structure. Methods: We used pooled-level data from FinnGen's published genome-wide association study (GWAS) of NAFLD (1908 cases and 340,591 healthy controls), as well as published GWAS with NAFLD activity score (NAS) and fibrosis stageassociated SNPs as genetic tools, in addition to the Enigma Consortium data from 51,665 patients, were used to assess genetic susceptibility in relation to changes with cortical thickness (TH) and surface area (SA). A main estimate was made by means of inverse variance weighted (IVW), while heterogeneity and pleiotropy were detected using MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier to perform a two-sample MR analysis. Results: At the global level, NAFLD reduced SA (beta = -586.72 mm², se = 217.73, p = 0.007) and several changes in the cortical structure of the cerebral gyrus were found, with no detectable pleiotropy. Conclusion: NAFLD causally affects cortical structures, which supports the presence of an intricate liver-brain axis. [ABSTRACT FROM AUTHOR]

IntroductionObservational studies have reported associations between gut microbiota composition and central nervous system diseases. However, the potential causal relationships and underlying mechanisms remain unclear. Here, we applied Mendelian randomization (MR) to investigate the causal effects of gut microbiota on cortical surface area (SA) and thickness (TH) in the brain.MethodsWe used genome-wide association study summary statistics of gut microbiota abundance in 18,340 individuals from the MiBioGen Consortium to identify genetic instruments for 196 gut microbial taxa. We then analyzed data from 56,761 individuals from the ENIGMA Consortium to examine associations of genetically predicted gut microbiota with alterations in cortical SA and TH globally and across 34 functional brain regions. Inverse-variance weighted analysis was used as the primary MR method, with MR Egger regression, MR-PRESSO, Cochran’s Q test, and leave-one-out analysis to assess heterogeneity and pleiotropy.ResultsAt the functional region level, genetically predicted higher abundance of class Mollicutes was associated with greater SA of the medial orbitofrontal cortex (β = 8.39 mm2, 95% CI: 3.08–13.70 mm2, p = 0.002), as was higher abundance of phylum Tenericutes (β = 8.39 mm2, 95% CI: 3.08–13.70 mm2, p = 0.002). Additionally, higher abundance of phylum Tenericutes was associated with greater SA of the lateral orbitofrontal cortex (β = 10.51 mm2, 95% CI: 3.24–17.79 mm2, p = 0.0046). No evidence of heterogeneity or pleiotropy was detected.ConclusionSpecific gut microbiota may causally influence cortical structure in brain regions involved in neuropsychiatric disorders. The findings provide evidence for a gut-brain axis influencing cortical development, particularly in the orbitofrontal cortex during adolescence.

Background: Structural abnormalities in the brain of patients with atopic dermatitis (AD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of AD on brain structure. Methods: This study utilized summary statistics from genome‐wide association studies (GWASs) to investigate a collection of cerebral structural measures, encompassing cortical thickness (CT), cortical surface area (CA), and subcortical volumes in T1 images. A comprehensive GWAS meta‐analysis identified a total of 20 independent single nucleotide polymorphisms linked to AD, surpassing the genome‐wide significance threshold (p < 5 × 10⁻⁸). MR estimates were aggregated through the application of the inverse variance weighted method. Additional complementary analyses (i.e., MR‐Egger and weighted median approaches) were conducted to further assess the robustness of the obtained results. Sensitivity analysis and multivariate MR (MVMR) while adjusting for brain structural changes risk factors (i.e., depression and anxiety) were performed to assess the reliability and stability of observed causality. Results: Genetically determined AD exhibited a causal link with reduced caudate volumes (IVW‐MR: β = ‐0.186, p = 0.001, p‐corrected = 0.009). Furthermore, we identified potential causal associations between AD and reduced CT in the cingulate region (posterior cingulate, IVW‐MR: β = ‐0.065, p = 0.018, p‐corrected = 0.551; isthmus cingulate, IVW‐MR: β = ‐0.086, p = 0.003, p‐corrected = 0.188), as well as abnormal cortical surface area (CA) in the supramarginal (IVW‐MR: β = ‐0.047, p = 0.044, p‐corrected = 0.714) and isthmus cingulate (IVW‐MR: β = 0.053, p = 0.018, p‐corrected = 0.714). Additional supplementary analyses yielded consistent outcomes. There was no evidence of horizontal pleiotropy. MVMR analysis showed that the causal effects of AD on abnormal brain structure remained significant while adjusting for depression and anxiety. Conclusion: This MR study provided suggestive evidence that decreased caudate nucleus, posterior cingulate cortex, isthmus cingulate cortex and supramarginal gyrus are suggestively associated with higher AD risk. Future investigation into the brain regions is recommended, which helps to clarify the underlying mechanisms and point to new therapies against AD. [ABSTRACT FROM AUTHOR]

Background: Brain imaging results in sleep deprived patients showed structural changes in the cerebral cortex; however, the reasons for this phenomenon need to be further explored. Methods: This MR study evaluated causal associations between morningness, ease of getting up, insomnia, long sleep, short sleep, and the cortex structure. Results: At the functional level, morningness increased the surface area (SA) of cuneus with global weighted (beta(b) (95% CI): 32.63 (10.35, 54.90), p = 0.004). Short sleep increased SA of the lateral occipital with global weighted (b (95% CI): 394.37(107.89, 680.85), p = 0.007. Short sleep reduced cortical thickness (TH) of paracentral with global weighted (OR (95% CI): −0.11 (−0.19, −0.03), p = 0.006). Short sleep reduced TH of parahippocampal with global weighted (b (95% CI): −0.25 (−0.42, −0.07), p = 0.006). No pleiotropy was detected. However, none of the Bonferroni-corrected p values of the causal relationship between cortical structure and the five types of sleep traits met the threshold. Conclusions: Our results potentially show evidence of a higher risk association between neuropsychiatric disorders and not only paracentral and parahippocampal brain areas atrophy, but also an increase in the middle temporal zone. Our findings shed light on the associations of cortical structure with the occurrence of five types of sleep traits. [ABSTRACT FROM AUTHOR]

Background: Neurological involvement and psychiatric manifestations have been documented in clinical cases of inflammatory bowel disease (IBD); however, the presence of a causal relationship remains elusive. The objective of this study is to investigate the modifications occurring in the cerebral cortex as a result of IBD. Methods: A compendium of data extracted from a genome-wide association study (GWAS) involving a maximum of 133,380 European subjects. A series of Mendelian random analyses were applied to exclude heterogeneity and pleiotropy, ensuring the stability of the results. Results: Neither IBDs nor inflammatory cytokines (IL-6/IL-6Ra) were found to have a significant causality with surface area (SA) and thickness (TH) at the global level. At the regional functional brain level, Crohn's disease (CD) significantly decreased the TH of pars orbitalis (b=-0.003mm, Se=0.001mm, pivw =4.85×10-4). IL-6 was observed to reduce the SA of middle temporal (b=-28.575mm2, Se=6.482mm2, pivw=1.04×10-5) and increase the TH of fusiform (b=0.008mm, Se=0.002mm, pivw=8.86×10-5) and pars opercularis (b=0.009mm, Se=0.002mm, pivw=2.34×10-4). Furthermore, a causal relationship between IL-6Ra and an increase in the SA of superior frontal (b=21.132mm2, Se=5.806mm2, pivw=2.73×10-4) and the TH of supramarginal (b=0.003mm, Se=0.0002mm, pivw=7.86×10-37). All results passed sensitivity analysis and no heterogeneity and pleiotropy were detected. Conclusion: The correlation between IBD and changes in cerebral cortical structures implies the existence of a gut-brain axis at the organismal level. It is recommended that clinical patients with IBD prioritize long-term management of inflammation, as changes at the organismal level can lead to functional pathologies. Magnetic resonance imaging (MRI) may be considered as an additional screening option for IBD. [ABSTRACT FROM AUTHOR]

The bidirectional relationship between the brain cortex and cardiovascular diseases (CVDs) remains inadequately explored. This study used bidirectional Mendelian randomization (MR) analysis to explore the interactions between nine phenotypes associated with hypertension, heart failure, atrial fibrillation (AF), and coronary heart disease (CHD), and brain cortex measurements. These measurements included total surface area (SA), average thickness (TH), and the SA and TH of 34 regions defined by the Desikan-Killiany atlas. The nine traits were obtained from sources such as the UK Biobank and FinnGen, etc., while MRI-derived traits of cortical structure were sourced from the ENIGMA Consortium. The primary estimate was obtained using the inverse-variance weighted approach. A false discovery rate adjustment was applied to the p-values (resulting in q-values) in the analyses of regional cortical structures. A total of 1,260 two-sample MR analyses were conducted. Existing CHD demonstrated an influence on the SA of the banks of the superior temporal sulcus (bankssts) (q=0.018) and the superior frontal lobe (q=0.018), while hypertension was associated with changes in the TH of the lateral occipital region (q=0.02). Regarding the effects of the brain cortex on CVD incidence, total SA was significantly associated with the risk of CHD. Additionally, 16 and 3 regions exhibited significant effects on blood pressure and AF risk, respectively (q<0.05). These regions were primarily located in the frontal, temporal, and cingulate areas, which are associated with cognitive function and mood regulation. The detection of cortical changes through MRI could aid in screening for potential neuropsychiatric disorders in individuals with established CVD. Moreover, abnormalities in cortical structure may predict future CVD risk, offering new insights for prevention and treatment strategies. [Display omitted] • This study delved into the mutual effects between cardiovascular disease (CVD) and brain MRI-derived cortical structures. • Remarkable interactions were observed between CVD and the surface area and thickness of cortical structures at global and regional levels. • The heart-brain axis and brain-heart axis could help in managing CVD and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies have suggested associations between high-level educational attainment (EA) and a lower risk of sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. The protective effect of EA on sarcopenia may be mediated via changes in brain cortical structure. The aim of this study was to use a two-step Mendelian randomization (MR) analysis to illustrate the causal relationship between EA, brain cortical structure, and sarcopenia., Methods: Instrumental variables at the genome-wide significance level were obtained from publicly available datasets, and inverse variance weighted as the primary method was used for MR analysis. We perform several sensitivity analyses, including Cochran Q test, MR-Egger intercept test, leave-one-out analyses, and MR Pleiotropy Residual Sum and Outlier to evaluate the reliability of the results., Results: EA was causally associated with increased appendicular lean mass ( β  = 0.25, 95% confidence interval (CI): 0.19 to 0.31, p  = 2.25 × 10 -15 ), hand grip strength (left: β  = 0.042, 95% CI: 0.013 to 0.071, p  = 4.77 × 10 -3 and right: β  = 0.050, 95% CI: 0.022 to 0.079, p  = 5.17 × 10 -4 ), and usual walking pace (β = 0.20, 95% CI: 0.18 to 0.22, p  = 6.16 × 10 -83 ). In addition, EA was associated with increased brain cortical surface area ( β  = 4082.36, 95% CI: 2513.35 to 5681.38, p  = 3.40 × 10 -7 ) and cortical thickness (TH) ( β  = 0.014, 95% CI: 0.0045 to 0.023, p  = 3.45 × 10 -3 ). Regarding the causal effect of EA on usual walking pace, the mediatory effect of TH was 0.0069 and the proportion of mediation by TH was 3.43%., Conclusion: The study will have revealed the protective causal effect of EA on sarcopenia, which provides a reference for the prevention of sarcopenia at the public health level. We also will have found EA could affect the brain cortical structure, and the brain cortical structure could mediate the protective effect of EA against sarcopenia risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wang, Chen, Zhou and Su.)

Background: Brain imaging results in sleep deprived patients showed structural changes in the cerebral cortex; however, the reasons for this phenomenon need to be further explored. Methods: This MR study evaluated causal associations between morningness, ease of getting up, insomnia, long sleep, short sleep, and the cortex structure. Results: At the functional level, morningness increased the surface area (SA) of cuneus with global weighted (beta(b) (95% CI): 32.63 (10.35, 54.90), p = 0.004). Short sleep increased SA of the lateral occipital with global weighted (b (95% CI): 394.37(107.89, 680.85), p = 0.007. Short sleep reduced cortical thickness (TH) of paracentral with global weighted (OR (95% CI): −0.11 (−0.19, −0.03), p = 0.006). Short sleep reduced TH of parahippocampal with global weighted (b (95% CI): −0.25 (−0.42, −0.07), p = 0.006). No pleiotropy was detected. However, none of the Bonferroni-corrected p values of the causal relationship between cortical structure and the five types of sleep traits met the threshold. Conclusions: Our results potentially show evidence of a higher risk association between neuropsychiatric disorders and not only paracentral and parahippocampal brain areas atrophy, but also an increase in the middle temporal zone. Our findings shed light on the associations of cortical structure with the occurrence of five types of sleep traits.

Background: Alterations in the brain cortical structures of patients with chronic kidney disease (CKD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of kidney damage on brain cortical structure. Methods: Genome-wide association studies summary data of estimated glomerular filtration rate (eGFR) in 480,698 participants from the CKDGen Consortium were used to identify genetically predicted eGFR. Data from 567,460 individuals from the CKDGen Consortium were used to assess genetically determined CKD; 302,687 participants from the UK Biobank were used to evaluate genetically predicted albuminuria. Further, data from 51,665 patients from the ENIGMA Consortium were used to assess the relationship between genetic predisposition and reduced eGFR, CKD, and progressive albuminuria with alterations in cortical thickness (TH) or surficial area (SA) of the brain. Magnetic resonance imaging was used to measure the SA and TH globally and in 34 functional regions. Inverse-variance weighted was used as the primary estimate whereas MR Pleiotropy RESidual Sum and Outlier, MR-Egger and weighted median were used to detect heterogeneity and pleiotropy. Findings: At the global level, albuminuria decreased TH (β = −0.07 mm, 95% CI: −0.12 mm to −0.02 mm, P = 0.004); at the functional level, albuminuria reduced TH of pars opercularis gyrus without global weighted (β = −0.11 mm, 95% CI: −0.16 mm to −0.07 mm, P = 3.74×10−6). No pleiotropy was detected. Interpretation: Kidney damage causally influences the cortex structure which suggests the existence of a kidney-brain axis. Funding: This study was supported by the Science and Technology Planning Project of Guangdong Province (Grant No. 2020A1515111119 and 2017B020227007), the National Key Research and Development Program of China (Grant No. 2018YFA0902803), the National Natural Science Foundation of China (Grant No. 81825016, 81961128027, 81772719, 81772728), the Key Areas Research and Development Program of Guangdong (Grant No. 2018B010109006), Guangdong Special Support Program (2017TX04R246), Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, and Grants from the Guangdong Science and Technology Department (2020B1212060018).

• We leveraged genetic variants associated specifically with sarcopenia-associated traits to evaluate their effects on brain cortex surficial area and cortex thickness globally and in 34 functional regions. • Our findings revealed genetically predicted sarcopenia-associated traits including appendicular lean mass, hand grip strength (right) could affect brain cortical structure thus highlighting the existence of muscle-brain axis. • To our knowledge, this was the first Mendelian randomization study that investigated the causal relationship between sarcopenia and brain cortical structure. Previous observational studies have reported sarcopenia can affect the structure and function of brain cortical structure. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. Herein, we use a two-sample Mendelian randomization (MR) analysis to illustrate the causal effect of sarcopenia-associated traits on brain cortical structure. We selected appendicular lean mass (ALM), hand grip strength (left and right) (HGSL and HGSR), and usual walking pace (UWP) to symbolize sarcopenia. The definition of brain cortical structure is human brain cortical surface area (SA) and cortical thickness (TH) globally and in 34 functional regions measured by magnetic resonance imaging. Instrumental variables at the genome‐wide significance level were obtained from publicly available datasets, and inverse variance weighted as the primary method was used for MR analysis. At the global level, we found ALM (β=2604.68, 95 % confidence interval (CI): 1886.17 to 3323.19, P = 1.20 × 10−12) and HGSR (β=4733.05, 95 % CI: 2245.08 to 7221.01, P = 1.93 × 10−4) were associated with increased SA. At the region level, the SA of 25 functional gyrus without global weighted was influenced by ALM. The HGSR significantly increased SA of medial orbitofrontal and precentral gyrus without global weighted and ALM was associated with decrease of TH of lateral occipital gyrus with global weighted. No pleiotropy was detected. This was the first MR study investigated the causal effect of sarcopenia-associated traits on brain cortical structure. In our study, we revealed genetically predicted sarcopenia-associated traits including ALM and HGSR could affect brain cortical structure. [Display omitted] [ABSTRACT FROM AUTHOR]

Physical activity and sedentary behavior, both distinct lifestyle behaviors associated with brain health, have an unclear potential relationship with brain cortical structure. This study aimed to determine the causal link between physical activity, sedentary behavior, and brain cortical structure (cortical surface area and thickness) through Mendelian randomization analysis. The inverse-variance weighted method was primarily utilized, accompanied by sensitivity analyses, to confirm the results' robustness and accuracy. Analysis revealed nominally significant findings, indicating a potential positive influence of physical activity on cortical thickness in the bankssts (β = 0.002 mm, P = 0.043) and the fusiform (β = 0.002 mm, P = 0.018), and a potential negative association of sedentary behavior with cortical surface area in the caudal middle frontal (β = -34.181 mm2, P = 0.038) and the pars opercularis (β = -33.069 mm2, P = 0.002), alongside a nominally positive correlation with the cortical surface area of the inferior parietal (β = 58.332 mm2, P = 0.035). Additionally, a nominally significant negative correlation was observed between sedentary behavior and cortical thickness in the paracentral (β = -0.014 mm, P = 0.042). These findings offer insights into how lifestyle behaviors may influence brain cortical structures, advancing our understanding of their interaction with brain health., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Reduced brain volume, impaired cognition, and possibly a range of psychoneurological disorders have been reported in patients with non-alcoholic fatty liver disease (NAFLD); however, no underlying cause has been specified. Here, Mendelian randomization (MR) was employed to determine the causative NAFLD effects on cortical structure., Methods: We used pooled-level data from FinnGen's published genome-wide association study (GWAS) of NAFLD (1908 cases and 340,591 healthy controls), as well as published GWAS with NAFLD activity score (NAS) and fibrosis stage-associated SNPs as genetic tools, in addition to the Enigma Consortium data from 51,665 patients, were used to assess genetic susceptibility in relation to changes with cortical thickness (TH) and surface area (SA). A main estimate was made by means of inverse variance weighted (IVW), while heterogeneity and pleiotropy were detected using MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier to perform a two-sample MR analysis., Results: At the global level, NAFLD reduced SA (beta = -586.72 mm 2 , se = 217.73, p  = 0.007) and several changes in the cortical structure of the cerebral gyrus were found, with no detectable pleiotropy., Conclusion: NAFLD causally affects cortical structures, which supports the presence of an intricate liver-brain axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Cai, Chen, Hong, Tu, Chen and Du.)

Introduction: Observational studies have reported associations between gut microbiota composition and central nervous system diseases. However, the potential causal relationships and underlying mechanisms remain unclear. Here, we applied Mendelian randomization (MR) to investigate the causal effects of gut microbiota on cortical surface area (SA) and thickness (TH) in the brain., Methods: We used genome-wide association study summary statistics of gut microbiota abundance in 18,340 individuals from the MiBioGen Consortium to identify genetic instruments for 196 gut microbial taxa. We then analyzed data from 56,761 individuals from the ENIGMA Consortium to examine associations of genetically predicted gut microbiota with alterations in cortical SA and TH globally and across 34 functional brain regions. Inverse-variance weighted analysis was used as the primary MR method, with MR Egger regression, MR-PRESSO, Cochran's Q test, and leave-one-out analysis to assess heterogeneity and pleiotropy., Results: At the functional region level, genetically predicted higher abundance of class Mollicutes was associated with greater SA of the medial orbitofrontal cortex ( β = 8.39 mm 2 , 95% CI: 3.08-13.70 mm 2 , p = 0.002), as was higher abundance of phylum Tenericutes ( β = 8.39 mm 2 , 95% CI: 3.08-13.70 mm 2 , p = 0.002). Additionally, higher abundance of phylum Tenericutes was associated with greater SA of the lateral orbitofrontal cortex ( β = 10.51 mm 2 , 95% CI: 3.24-17.79 mm 2 , p = 0.0046). No evidence of heterogeneity or pleiotropy was detected., Conclusion: Specific gut microbiota may causally influence cortical structure in brain regions involved in neuropsychiatric disorders. The findings provide evidence for a gut-brain axis influencing cortical development, particularly in the orbitofrontal cortex during adolescence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Chen, Chen, Wang and Chen.)

Obesity may lead to cognitive impairment and psychiatric disorders, which are associated with alterations in the brain cortical structure. However, the exact causality remains inconclusive. We aimed to conduct two-sample Mendelian randomization (MR) analysis to identify the causal associations of obesity [body mass index (BMI), waist-hip ratio (WHR), and waist-hip ratio adjusted for BMI ((WHRadjBMI)) and brain cortical structure (cortical thickness and cortical surface area). Inverse-variance weighted (IVW) method was used as the main analysis, whereas a series of sensitivity analyses were employed to assess heterogeneity and pleiotropy. The main MR results showed that higher BMI significantly increased the cortical surface area of the transverse temporal (β = 5.13 mm2, 95% confidence interval [CI]: 2.55-7.71, P = 9.9 × 10-5); higher WHR significantly decreased cortical surface area of the inferior temporal (β = -38.60, 95% CI: -56.67- -20.54, P = 1.2 × 10-5), but significantly increased cortical surface area of the isthmus cingulate (β = 14.25, 95% CI: 6.97-21.54, P = 1.2 × 10-4). No significant evidence of pleiotropy was found in the MR analyses. This study supports that obesity has a causal effect on the brain cortical structure. Further studies are warranted to understand the clinical outcomes caused by these effects., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Neurological involvement and psychiatric manifestations have been documented in clinical cases of inflammatory bowel disease (IBD); however, the presence of a causal relationship remains elusive. The objective of this study is to investigate the modifications occurring in the cerebral cortex as a result of IBD., Methods: A compendium of data extracted from a genome-wide association study (GWAS) involving a maximum of 133,380 European subjects. A series of Mendelian random analyses were applied to exclude heterogeneity and pleiotropy, ensuring the stability of the results., Results: Neither IBDs nor inflammatory cytokines (IL-6/IL-6Rα) were found to have a significant causality with surface area (SA) and thickness (TH) at the global level. At the regional functional brain level, Crohn's disease (CD) significantly decreased the TH of pars orbitalis (β=-0.003mm, Se=0.001mm, p ivw =4.85×10 -4 ). IL-6 was observed to reduce the SA of middle temporal (β=-28.575mm 2 , Se=6.482mm 2 , p ivw =1.04×10 -5 ) and increase the TH of fusiform (β=0.008mm, Se=0.002mm, p ivw =8.86×10 -5 ) and pars opercularis (β=0.009mm, Se=0.002mm, p ivw =2.34×10 -4 ). Furthermore, a causal relationship between IL-6Rα and an increase in the SA of superior frontal (β=21.132mm 2 , Se=5.806mm 2 , p ivw =2.73×10 -4 ) and the TH of supramarginal (β=0.003mm, Se=0.0002mm, p ivw =7.86×10 -37 ). All results passed sensitivity analysis and no heterogeneity and pleiotropy were detected., Conclusion: The correlation between IBD and changes in cerebral cortical structures implies the existence of a gut-brain axis at the organismal level. It is recommended that clinical patients with IBD prioritize long-term management of inflammation, as changes at the organismal level can lead to functional pathologies. Magnetic resonance imaging (MRI) may be considered as an additional screening option for IBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Zhu, Zhang, Ren, Li and Yu.)

Background: Alterations in the brain cortical structures of patients with chronic kidney disease (CKD) have been reported; however, the cause has not been determined yet. Herein, we used Mendelian randomization (MR) to reveal the causal effect of kidney damage on brain cortical structure., Methods: Genome-wide association studies summary data of estimated glomerular filtration rate (eGFR) in 480,698 participants from the CKDGen Consortium were used to identify genetically predicted eGFR. Data from 567,460 individuals from the CKDGen Consortium were used to assess genetically determined CKD; 302,687 participants from the UK Biobank were used to evaluate genetically predicted albuminuria. Further, data from 51,665 patients from the ENIGMA Consortium were used to assess the relationship between genetic predisposition and reduced eGFR, CKD, and progressive albuminuria with alterations in cortical thickness (TH) or surficial area (SA) of the brain. Magnetic resonance imaging was used to measure the SA and TH globally and in 34 functional regions. Inverse-variance weighted was used as the primary estimate whereas MR Pleiotropy RESidual Sum and Outlier, MR-Egger and weighted median were used to detect heterogeneity and pleiotropy., Findings: At the global level, albuminuria decreased TH (β = -0.07 mm, 95% CI: -0.12 mm to -0.02 mm, P = 0.004); at the functional level, albuminuria reduced TH of pars opercularis gyrus without global weighted (β = -0.11 mm, 95% CI: -0.16 mm to -0.07 mm, P = 3.74×10 -6 ). No pleiotropy was detected., Interpretation: Kidney damage causally influences the cortex structure which suggests the existence of a kidney-brain axis., Funding: This study was supported by the Science and Technology Planning Project of Guangdong Province (Grant No. 2020A1515111119 and 2017B020227007), the National Key Research and Development Program of China (Grant No. 2018YFA0902803), the National Natural Science Foundation of China (Grant No. 81825016, 81961128027, 81772719, 81772728), the Key Areas Research and Development Program of Guangdong (Grant No. 2018B010109006), Guangdong Special Support Program (2017TX04R246), Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, and Grants from the Guangdong Science and Technology Department (2020B1212060018)., Competing Interests: Declaration of Competing Interest All authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)