Cerebrospinal and Brain Proteins Implicated in Neuropsychiatric and Risk Factor Traits: Evidence from Mendelian Randomization.

Neuropsychiatric disorders present a global health challenge, necessitating an understanding of their molecular mechanisms for therapeutic development. Using Mendelian randomization (MR) analysis, this study explored associations between genetically predicted levels of 173 proteins in cerebrospinal fluid (CSF) and 25 in the brain with 14 neuropsychiatric disorders and risk factors. Follow-up analyses assessed consistency across plasma protein levels and gene expression in various brain regions. Proteins were instrumented using tissue-specific genetic variants, and colocalization analysis confirmed unbiased gene variants. Consistent MR and colocalization evidence revealed that lower cortical expression of low-density lipoprotein receptor-related protein 8, coupled higher abundance in the CSF and plasma, associated with lower fluid intelligence scores and decreased bipolar disorder risk. Additionally, elevated apolipoprotein-E2 and hepatocyte growth factor-like protein in the CSF and brain were related to reduced leisure screen time and lower odds of physical activity, respectively. Furthermore, elevated CSF soluble tyrosine-protein kinase receptor 1 level increased liability to attention deficit hyperactivity disorder and schizophrenia alongside lower fluid intelligence scores. This research provides genetic evidence supporting novel tissue-specific proteomic targets for neuropsychiatric disorders and their risk factors. Further exploration is necessary to understand the underlying biological mechanisms and assess their potential for therapeutic intervention.

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.

BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Developmental origins of psycho-cardiometabolic multimorbidity in adolescence and their underlying pathways through methylation markers: a two-cohort study.

Understanding the biological mechanisms behind multimorbidity patterns in adolescence is important as they may act as intermediary risk factor for long-term health. We aimed to explore relationship between prenatal exposures and adolescent's psycho-cardiometabolic intermediary traits mediated through epigenetic biomarkers, using structural equation modeling (SEM). We used data from mother-child dyads from pregnancy and adolescents at 16-17 years from two prospective cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) and Raine Study from Australia. Factor analysis was applied to generate two different latent factor structures: (a) prenatal exposures and (b) adolescence psycho-cardiometabolic intermediary traits. Furthermore, three types of epigenetic biomarkers were included: (1) DNA methylation score for maternal smoking during pregnancy (DNAmMSS), (2) DNAm age estimate PhenoAge and (3) DNAm estimate for telomere length (DNAmTL). Similar factor structure was observed between both cohorts yielding three prenatal factors, namely BMI (Body Mass Index), SOP (Socio-Obstetric-Profile), and Lifestyle, and four adolescent factors: Anthropometric, Insulin-Triglycerides, Blood Pressure, and Mental health. In the SEM pathways, stronger direct effects of F1prenatal-BMI (NFBC1986 = ß: 0.27; Raine = ß: 0.39) and F2prenatal-SOP (ß: -0.11) factors were observed on adolescent psycho-cardiometabolic multimorbidity. We observed an indirect effect of prenatal latent factors through epigenetic markers on a psycho-cardiometabolic multimorbidity factor in Raine study (P < 0.05). The present study exemplifies an evidence-based approach in two different birth cohorts to demonstrate similar composite structure of prenatal exposures and psycho-cardiometabolic traits (despite cultural, social, and genetic differences) and a common plausible pathway between them through underlying epigenetic markers.

Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Phenome-wide association study on miRNA-related sequence variants: the UK Biobank.

BACKGROUND: Genetic variants in the coding region could directly affect the structure and expression levels of genes and proteins. However, the importance of variants in the non-coding region, such as microRNAs (miRNAs), remain to be elucidated. Genetic variants in miRNA-related sequences could affect their biogenesis or functionality and ultimately affect disease risk. Yet, their implications and pleiotropic effects on many clinical conditions remain unknown. METHODS: Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis. RESULTS: We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10-162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia. CONCLUSIONS: Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.

A bidirectional Mendelian randomisation study to evaluate the relationship between body constitution and hearing loss.

Hearing loss and hearing disorders represent possible mediating pathways in the associations between noise exposures and non-auditory health outcomes. In this context, we assessed whether the noise-obesity associations should consider hearing functions as possible mediators and applied Mendelian randomisation (MR) to investigate causal relationships between body constitution and hearing impairments. We obtained genetic associations from publicly available summary statistics from genome-wide association studies in European ancestry adult populations (N= from 210,088 to 360,564) for (i) body constitution: body mass index (BMI), waist circumference (WC) and body fat percentage (BFP), and (ii) hearing loss: sensorineural hearing loss, noise-induced hearing loss, and age-related hearing impairment (ARHI). We employed colocalisation analysis to investigate the genetic associations for BMI and ARHI liability within an FTO locus. We conducted bi-directional MR for the 'forward' (from body constitution to hearing) and 'reverse' directions. We applied the random effects inverse variance-weighted method as the main MR method, with additional sensitivity analyses. Colocalisation analysis suggested that BMI and ARHI shared a causal variant at the FTO gene. We did not find robust evidence for causal associations from body constitution to hearing loss and suggested that some associations may be driven by FTO variants. In the reverse analyses, ARHI was negatively associated with BMI [effect size - 0.22 (95% CI - 0.44 to - 0.01)] and BFP [effect size - 0.23 (95% CI - 0.45 to 0.00)], supporting the notion that ARHI may diminish body constitution. Finally, our data suggest that there is no strong evidence that hearing explains the association between noise exposure and body constitution.

The Impact of Genetically Proxied AMPK Activation, the Target of Metformin, on Functional Outcome Following Ischemic Stroke.

BACKGROUND AND PURPOSE: We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of genetically proxied AMP-activated protein kinase (AMPK) activation, which is the target of metformin, on functional outcome following ischemic stroke onset. METHODS: A total of 44 AMPK-related variants associated with HbA1c (%) were used as instruments for AMPK activation. The primary outcome was the modified Rankin Scale (mRS) score at 3 months following the onset of ischemic stroke, evaluated as a dichotomous variable (3-6 vs. 0-2) and subsequently as an ordinal variable. Summary-level data for the 3-month mRS were obtained from the Genetics of Ischemic Stroke Functional Outcome network, including 6,165 patients with ischemic stroke. The inverse-variance weighted method was used to obtain causal estimates. The alternative MR methods were used for sensitivity analysis. RESULTS: Genetically predicted AMPK activation was significantly associated with lower odds of poor functional outcome (mRS 3-6 vs. 0-2, odds ratio [OR]: 0.06, 95% confidence interval [CI]: 0.01-0.49, P=0.009). This association was maintained when 3-month mRS was analyzed as an ordinal variable. Similar results were observed in the sensitivity analyses, and there was no evidence of pleiotropy. CONCLUSION: This MR study provided evidence that AMPK activation by metformin may exert beneficial effects on functional outcome following ischemic stroke.

Genetic fine-mapping from summary data using a nonlocal prior improves the detection of multiple causal variants.

MOTIVATION: Genome-wide association studies (GWAS) have been successful in identifying genomic loci associated with complex traits. Genetic fine-mapping aims to detect independent causal variants from the GWAS-identified loci, adjusting for linkage disequilibrium patterns. RESULTS: We present "FiniMOM" (fine-mapping using a product inverse-moment prior), a novel Bayesian fine-mapping method for summarized genetic associations. For causal effects, the method uses a nonlocal inverse-moment prior, which is a natural prior distribution to model non-null effects in finite samples. A beta-binomial prior is set for the number of causal variants, with a parameterization that can be used to control for potential misspecifications in the linkage disequilibrium reference. The results of simulations studies aimed to mimic a typical GWAS on circulating protein levels show improved credible set coverage and power of the proposed method over current state-of-the-art fine-mapping method SuSiE, especially in the case of multiple causal variants within a locus. AVAILABILITY AND IMPLEMENTATION: https://vkarhune.github.io/finimom/.

Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.

Background: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 x 10-8) cis-acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Results: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q-value=0.033, PPH4=84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q-value=0.055, PPH4=73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q-value=0.067, PPH4=81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q-value=0.072, PPH4=76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q-value=0.15), PPH4=85.6%). For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Conclusion: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.

Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study.

BACKGROUND: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. METHODS: Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. RESULTS: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64-0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60-0.92), stroke (0.69, 95% CI 0.50-0.95) and heart failure (0.77, 95% CI 0.58-1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. CONCLUSIONS: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling.

Soluble adhesion molecules and functional outcome after ischemic stroke: A Mendelian randomization study.

OBJECTIVES: We employed Mendelian randomization to determine whether genetically predicted circulating levels of endothelial-derived adhesion molecules (soluble intercellular adhesion molecule-1 [sICAM-1]), soluble vascular-leukocyte adhesion molecule-1 [sVCAM-1], and soluble-endothelial-leukocyte adhesion molecule [sE-selectin]) were associated with functional outcome after ischemic stroke. METHODS: Independent genetic variants robustly associated with soluble adhesion molecules, located at or close to the coding gene (cis), were used as genetic instruments. The functional outcome was evaluated using the 3-month modified Rankin Scale (mRS) score after ischemic stroke. A poor functional outcome was defined as mRS ≥ 3 at 3 months. We extracted summary data for functional outcome after ischemic stroke from the Genetics of Ischaemic Stroke Functional Outcome network (n = 6,021). RESULTS: Genetically elevated sICAM-1 (OR 1.28, 95% CI 1.05-1.56) and sE-selectin (OR 2.69, 95% CI 1.23-5.86) levels were related with poor post-stroke outcome. However, we found no evidence that genetically elevated sVCAM-1 were associated with post-stroke outcome (OR 1.36, 95% CI 0.39-4.66). CONCLUSIONS: We found that genetically elevated higher sICAM-1 and sE-selectin levels are associated with poor post-stroke outcome. Further studies are warranted to evaluate the potential of ICAM-1 and E-selectin to be drug targets for post-stroke recovery.

The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study.

Objective: To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets. Design: Bi-directional Mendelian randomisation study. Setting: Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits. Participants: Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits. Interventions: Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking). Main outcome methods: Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated. Results: Genetic evidence (mendelian randomisation P<0.0011) suggests that higher body mass index, waist circumference, smoking, higher concentrations of lipids, and systolic blood pressure increase circulating concentrations of several inflammatory cytokines and C reactive protein. Evidence for causal relations (mendelian randomisation P<0.0011) were noted between circulating cytokines, including a key role of vascular endothelial growth factor on influencing the concentrations of 10 other cytokines. Both mendelian randomisation (P<0.05) and colocalisation (posterior probability >0.5) suggested that coronary artery disease risk is increased by higher concentrations of circulating tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF). Conclusion: This study offers insight into inflammatory mediators of cardiometabolic risk factors, cytokine signalling cascades, and effects of circulating cytokines on different cardiometabolic outcomes.

Circulating macrophage colony-stimulating factor levels and stroke: A Mendelian randomization study.

OBJECTIVES: Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor, has been shown to be associated with risk of ischemic stroke in conventional epidemiological study. We performed a Mendelian randomization analysis to evaluate the effects of genetically predicted circulating CSF1 levels on stroke and carotid intima-media thickness (cIMT). METHODS: Genetic variants robustly associated with CSF1 levels, located in the vicinity of the CSF1 gene (cis), were used as instruments for CSF1 levels. Genetic association estimates for ischemic stroke and its subtypes, intra-cerebral hemorrhage (ICH), and cIMT were obtained from MEGASTROKE (60,341 cases and 454,450 controls), ISGC (1,545 cases and 1,481 controls), and UK Biobank (22,179 individuals), respectively. RESULTS: Genetically predicted higher CSF1 levels was significantly associated with a higher risk of any ischemic stroke, large artery stroke (LAS) and cardioembolic stroke (CES), but not with small vessel stroke (SVS) and ICH. The odds ratios (ORs) per genetically predicted one standard deviation (SD) increase in circulating CSF1 levels were 1.11 (95% CI 1.04-1.17) for any ischemic stroke, 1.23 (95% CI 1.07-1.42) for LAS, 1.18 (95% CI 1.05-1.33) for CES, 1.07 (95% CI 0.94-1.21) for SVS, and 1.15 (95% CI 0.73-1.83) for ICH. Similarly, we also found that genetically predicted higher CSF1 levels were associated with higher cIMT, as a measure of subclinical atherosclerosis (cIMT, ß 0.016, 95% CI, 0.004-0.029). CONCLUSIONS: This study provides evidence that genetically predicted higher CSF1 levels was associated with higher risk of any ischemic stroke, LAS, and CES. Whether targeting CSF1 or its receptors can reduce the risk of ischemic stroke needs further study.

Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease: An Observational Analysis and Mendelian Randomization.

BACKGROUND AND OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of Alzheimer disease (AD) is controversial. We characterized the relationship between inflammatory diseases and risk of AD and explored the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large-scale genome-wide association study data sets, we performed 2-sample Mendelian randomizations (MRs) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that the overall incidence of AD was higher among patients with inflammatory bowel disease (hazard ratio [HR] 1.17; 95% CI 1.15-1.19; p = 2.1 × 10-4), other inflammatory polyarthropathies and systematic connective tissue disorders (HR 1.13; 95% CI 1.12-1.14; p = 8.6 × 10-5), psoriasis (HR 1.13; 95% CI 1.10-1.16; p = 2.6 × 10-4), rheumatoid arthritis (HR 1.08; 95% CI 1.06-1.11; p = 4.0 × 10-4), and multiple sclerosis (HR 1.06; 95% CI 1.04-1.07; p = 2.8 × 10-4) compared with the age (±5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted [ORIVW] 1.23; 95% CI 1.06-1.42; p IVW = 0.007) and lower risk of Crohn disease (ORIVW 0.73; 95% CI -0.62 to 0.86; p IVW = 1.3 × 10-4). Colocalization supported a common causal single nucleotide polymorphism for MIG and Crohn disease (posterior probability = 0.74), but not AD (posterior probability = 0.03). Using a 2-sample MR approach, genetically predicted risks of inflammatory diseases were not associated with higher AD risk. DISCUSSION: Our data suggest that the association between inflammatory diseases and risk of AD is unlikely to be causal and may be a result of confounding. In support, although inflammatory biomarkers showed evidence for causal associations with inflammatory diseases, evidence was weak that they affected both inflammatory disease and AD.

Genetic Evidence for Protective Effects of Angiotensin-Converting Enzyme Against Alzheimer Disease But Not Other Neurodegenerative Diseases in European Populations.

Background and Objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases. Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm. Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits. Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.

A genome-wide association study of total child psychiatric problems scores.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomisation study.

OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce serum urate, but their efficacy depends on renal function which is often impaired in people with gout. SGLT1 is primarily expressed in the small intestine and its inhibition may be a more suitable therapeutic target. We aimed to investigate the association of genetically proxied SGLT1i with gout risk, serum urate levels and cardiovascular safety using Mendelian randomisation (MR). METHODS: Leveraging data from a genome-wide association study of 344,182 individuals in the UK Biobank, we identified a missense variant in the SLC5A1 gene that associated with glycated haemoglobin (HbA1c) to proxy SGLT1i. Outcome genetic data comprised 13,179 gout cases and 750,634 controls, 457,690 individuals for serum urate levels, and up to 977,323 individuals for cardiovascular safety outcomes. We applied the Wald ratio method and investigated potential genetic confounding using colocalization. RESULTS: The rs17683430 missense variant was selected to instrument SGLT1i. Genetically proxied SGLT1i was associated with 75% reduction in gout risk (OR 0.25; 95%CI 0.06, 0.99; p = 0.048) and 32.0 µmol/L reduction in serum urate (95%CI -56.7, -7.3; p = 0.01), per 6.7 mmol/mol reduction in HbA1c. SGLT1i was associated with increased levels of low-density lipoprotein cholesterol (0.37 mmol/L; 95%CI 0.17, 0.56; p = 0.0002) but not risk of coronary heart disease, stroke, or chronic kidney disease. Colocalization did not suggest that results are attributable to genetic confounding. CONCLUSION: SGLT1 inhibition may represent a novel therapeutic option for preventing gout in people with or without comorbid diabetes. Randomised trials are needed to formally investigate efficacy and safety.

DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases.

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.