Nanofibrous polycaprolactone/gelatin scaffold containing gold nanoparticles: Physicochemical and biological characterization for wound healing.

In this study, gold nanoparticles were loaded into poly (ε-caprolactone) (PCL)/gelatin nanofibrous matrices to fabricate a potential wound dressing. The mats were produced by electrospinning of PCL/gelatin solution supplemented with synthesized gold nanoparticles (200, 400 and 800 ppm). Prepared scaffolds were investigated regarding their chemical properties, morphology, mechanical properties, surface wettability, water-uptake capacity, water vapor permeability, porosity, blood compatibility, microbial penetration test and cellular response. In addition to in vivo study, a full-thickness excisional wound in a rat model was used to evaluate the healing effect of prepared scaffolds. Results showed appropriate mechanical properties and porosity of prepared scaffolds. With L929 cells, the PCL/gelatin scaffold containing 400 ppm gold nanoparticles demonstrated the greatest cell growth. In vivo results validated the favorable wound-healing benefits of the scaffold incorporating gold nanoparticles, which triggered wound healing compared to sterile gauze. Our results showed the capability of nanofibrous matrices containing gold nanoparticles for successful wound treatment.

Neuro-nanotechnology: diagnostic and therapeutic nano-based strategies in applied neuroscience.

Artificial, de-novo manufactured materials (with controlled nano-sized characteristics) have been progressively used by neuroscientists during the last several decades. The introduction of novel implantable bioelectronics interfaces that are better suited to their biological targets is one example of an innovation that has emerged as a result of advanced nanostructures and implantable bioelectronics interfaces, which has increased the potential of prostheses and neural interfaces. The unique physical-chemical properties of nanoparticles have also facilitated the development of novel imaging instruments for advanced laboratory systems, as well as intelligently manufactured scaffolds and microelectrodes and other technologies designed to increase our understanding of neural tissue processes. The incorporation of nanotechnology into physiology and cell biology enables the tailoring of molecular interactions. This involves unique interactions with neurons and glial cells in neuroscience. Technology solutions intended to effectively interact with neuronal cells, improved molecular-based diagnostic techniques, biomaterials and hybridized compounds utilized for neural regeneration, neuroprotection, and targeted delivery of medicines as well as small chemicals across the blood-brain barrier are all purposes of the present article.

Moving beyond nanotechnology to uncover a glimmer of hope in diabetes medicine: Effective nanoparticle-based therapeutic strategies for the management and treatment of diabetic foot ulcers.

Hyperglycemia, a distinguishing feature of diabetes mellitus that might cause a diabetic foot ulcer (DFU), is an endocrine disorder that affects an extremely high percentage of people. Having a comprehensive understanding of the molecular mechanisms underlying the pathophysiology of diabetic wound healing can help researchers and developers design effective therapeutic strategies to treat the wound healing process in diabetes patients. Using nanoscaffolds and nanotherapeutics with dimensions ranging from 1 to 100 nm represents a state-of-the-art and viable therapeutic strategy for accelerating the wound healing process in diabetic patients, particularly those with DFU. Nanoparticles can interact with biological constituents and infiltrate wound sites owing to their reduced diameter and enhanced surface area. Furthermore, it is noteworthy that they promote the processes of vascularization, cellular proliferation, cell signaling, cell-to-cell interactions, and the formation of biomolecules that are essential for effective wound healing. Nanomaterials possess the ability to effectively transport and deliver various pharmacological agents, such as nucleic acids, growth factors, antioxidants, and antibiotics, to specific tissues, where they can be continuously released and affect the wound healing process in DFU. The present article elucidates the ongoing endeavors in the field of nanoparticle-mediated therapies for the management of DFU.

Re-investigation of functional gastrointestinal disorders utilizing a machine learning approach.

BACKGROUND: Functional gastrointestinal disorders (FGIDs), as a group of syndromes with no identified structural or pathophysiological biomarkers, are currently classified by Rome criteria based on gastrointestinal symptoms (GI). However, the high overlap among FGIDs in patients makes treatment and identifying underlying mechanisms challenging. Furthermore, disregarding psychological factors in the current classification, despite their approved relationship with GI symptoms, underlines the necessity of more investigation into grouping FGID patients. We aimed to provide more homogenous and well-separated clusters based on both GI and psychological characteristics for patients with FGIDs using an unsupervised machine learning algorithm. METHODS: Based on a cross-sectional study, 3765 (79%) patients with at least one FGID were included in the current study. In the first step, the clustering utilizing a machine learning algorithm was merely executed based on GI symptoms. In the second step, considering the previous step's results and focusing on the clusters with a diverse combination of GI symptoms, the clustering was re-conducted based on both GI symptoms and psychological factors. RESULTS: The first phase clustering of all participants based on GI symptoms resulted in the formation of pure and non-pure clusters. Pure clusters exactly illustrated the properties of most pure Rome syndromes. Re-clustering the members of the non-pure clusters based on GI and psychological factors (i.e., the second clustering step) resulted in eight new clusters, indicating the dominance of multiple factors but well-discriminated from other clusters. The results of the second step especially highlight the impact of psychological factors in grouping FGIDs. CONCLUSIONS: In the current study, the existence of Rome disorders, which were previously defined by expert opinion-based consensus, was approved, and, eight new clusters with multiple dominant symptoms based on GI and psychological factors were also introduced. The more homogeneous clusters of patients could lead to the design of more precise clinical experiments and further targeted patient care.

GWASinspector: comprehensive quality control of genome-wide association study results.

SUMMARY: Quality control (QC) of genome wide association study (GWAS) result files has become increasingly difficult due to advances in genomic technology. The main challenges include continuous increases in the number of polymorphic genetic variants contained in recent GWASs and reference panels, the rising number of cohorts participating in a GWAS consortium, and inclusion of new variant types. Here, we present GWASinspector, a flexible R package for comprehensive QC of GWAS results. This package is compatible with recent imputation reference panels, handles insertion/deletion and multi-allelic variants, provides extensive QC reports and efficiently processes big data files. Reference panels covering three human genome builds (NCBI36, GRCh37 and GRCh38) are available. GWASinspector has a user friendly design and allows easy set-up of the QC pipeline through a configuration file. In addition to checking and reporting on individual files, it can be used in preparation of a meta-analysis by testing for systemic differences between studies and generating cleaned, harmonized GWAS files. Comparison with existing GWAS QC tools shows that the main advantages of GWASinspector are its ability to more effectively deal with insertion/deletion and multi-allelic variants and its relatively low memory use. AVAILABILITY AND IMPLEMENTATION: Our package is available at The Comprehensive R Archive Network (CRAN): https://CRAN.R-project.org/package=GWASinspector. Reference datasets and a detailed tutorial can be found at the package website at http://gwasinspector.com/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Large-Scale Multi-Omics Studies Provide New Insights into Blood Pressure Regulation.

Recent genome-wide association studies uncovered part of blood pressure's heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressure-associated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort (n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice.

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

Janus nanoparticles: an efficient intelligent modern nanostructure for eradicating cancer.

In the modern age, the struggle to generate appropriate bio-based materials and nano-scaled colloidal particulates for developed application domains, has already resulted in remarkable attempts in the advancement of regulated size and shape, anisotropy, and characteristics of nanostructures. The bottom-up development strategies of components are among the most important science areas throughout nanotechnology, in which the designed building blocks are often utilized to generate novel structures by random self-assembly. In biomedical applications, Janus nanoparticles (JNPs) are necessary. This is due to their effective stimulus-responsive properties, tunable structure, biocompatibility, containing two surfaces with various hydrophobic characteristics and distinct functional groups. Featuring two parts with differing hydrophobicity has been the most critical aspect of the Janus amphiphilic particles. Development of JNPs has been afforded, using imaging agents (e.g. gold (AU) for photoacoustic imaging processing (PAI), silver for surface-enhanced Raman scattering (SERS), and Fe3O4 and MnO2 to magnetic resonance imaging (MRI)). It is also to be mentioned that a number of other properties become salient - properties such as integration imaging factors into JNPs (like quantum dots, fluorescent dyes), multiple imaging methods for screening and diagnosis application can indeed be accomplished. Janus nanostructures have been promising platforms for bioengineering as therapeutic carriers, drug delivery vehicles, and biosensor equipment; they may also be employed for the transport of bioactive hydrophilic and hydrophobic materials. The main production approaches and major advancement of JNPs in the biomedical sector and cancer therapy will be described in this paper.

The promising shadow of microbubble over medical sciences: from fighting wide scope of prevalence disease to cancer eradication.

Microbubbles are typically 0.5-10 µm in size. Their size tends to make it easier for medication delivery mechanisms to navigate the body by allowing them to be swallowed more easily. The gas included in the microbubble is surrounded by a membrane that may consist of biocompatible biopolymers, polymers, surfactants, proteins, lipids, or a combination thereof. One of the most effective implementation techniques for tiny bubbles is to apply them as a drug carrier that has the potential to activate ultrasound (US); this allows the drug to be released by US. Microbubbles are often designed to preserve and secure medicines or substances before they have reached a certain area of concern and, finally, US is used to disintegrate microbubbles, triggering site-specific leakage/release of biologically active drugs. They have excellent therapeutic potential in a wide range of common diseases. In this article, we discussed microbubbles and their advantageous medicinal uses in the treatment of certain prevalent disorders, including Parkinson's disease, Alzheimer's disease, cardiovascular disease, diabetic condition, renal defects, and finally, their use in the treatment of various forms of cancer as well as their incorporation with nanoparticles. Using microbubble technology as a novel carrier, the ability to prevent and eradicate prevalent diseases has strengthened the promise of effective care to improve patient well-being and life expectancy.

Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression.

Although a genetic basis of depression has been well established in twin studies, identification of genome-wide significant loci has been difficult. We hypothesized that bivariate analyses of findings from a meta-analysis of genome-wide association studies (meta-GWASs) of the broad depression phenotype with those from meta-GWASs of self-reported and recurrent major depressive disorder (MDD), bipolar disorder and schizophrenia would enhance statistical power to identify novel genetic loci for depression. LD score regression analyses were first used to estimate the genetic correlations of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia. Then, we performed four bivariate GWAS analyses. The genetic correlations (rg ± SE) of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia were 0.79 ± 0.07, 0.24 ± 0.08, 0.53 ± 0.09 and 0.57 ± 0.05, respectively. From a total of 20 independent genome-wide significant loci, 13 loci replicated of which 8 were novel for depression. These were MUC21 for the broad depression phenotype with self-reported MDD and ZNF804A, MIR3143, PSORS1C2, STK19, SPATA31D1, RTN1 and TCF4 for the broad depression phenotype with schizophrenia. Post-GWAS functional analyses of these loci revealed their potential biological involvement in psychiatric disorders. Our results emphasize the genetic similarities among different psychiatric disorders and indicate that cross-disorder analyses may be the best way forward to accelerate gene finding for depression, or psychiatric disorders in general.

Extracellular micro/nanovesicles rescue kidney from ischemia-reperfusion injury.

Acute renal failure (ARF) is a clinical challenge that is highly resistant to treatment, and its high rate of mortality is alarming. Ischemia-reperfusion injury (IRI) is the most common cause of ARF. Especially IRI is implicated in kidney transplantation and can determine graft survival. Although the exact pathophysiology of renal IRI is unknown, the role of inflammatory responses has been elucidated. Because mesenchymal stromal cells (MSCs) have strong immunomodulatory properties, they are under extensive investigation as a therapeutic modality for renal IRI. Extracellular vesicles (EVs) play an integral role in cell-to-cell communication. Because the regenerative potential of the MSCs can be recapitulated by their EVs, the therapeutic appeal of MSC-derived EVs has dramatically increased in the past decade. Higher safety profile and ease of preservation without losing function are other advantages of EVs compared with their producing cells. In the current review, the preliminary results and potential of MSC-derived EVs to alleviate kidney IRI are summarized. We might be heading toward a cell-free approach to treat renal IRI.

DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci.

BACKGROUND: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. METHODS: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. RESULTS: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. CONCLUSIONS: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.

Sciatic nerve regeneration by using collagen type I hydrogel containing naringin.

In the present study, collagen hydrogel containing naringin was fabricated, characterized and used as the scaffold for peripheral nerve damage treatment. The collagen was dissolved in acetic acid, naringin added to the collagen solution, and cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide powder (EDC; 0.10 mM) to form the hydrogel. The microstructure, swelling behavior, biodegradation, and cyto/hemocompatibility of the fabricated hydrogels were assessed. Finally, the healing efficacy of the prepared collagen hydrogel loaded with naringin on the sciatic nerve crush injury was assessed in the animal model. The characterization results showed that the fabricated hydrogels have a porous structure containing interconnected pores with the average pore size of 90 µm. The degradation results demonstrated that about 70% of the primary weight of the naringin loaded hydrogel had been lost after 4 weeks of storage in PBS. The in vitro study showed that the proliferation of Schwann cells on the collagen/naringin hydrogel was higher than the control group (tissue culture plate) at both 48 and 72 h after cell seeding and even significantly higher than pure collagen 72 h after cell seeding (*p < 0.005, **p < 0.001). The animal study implied that the sciatic functional index reached to -22.13 ± 3.00 at the end of 60th days post-implantation which was statistically significant (p < 0.05) compared with the negative control (injury without the treatment) (-82.60 ± 1.06), and the pure collagen hydrogel (-59.80 ± 3.20) groups. The hot plate latency test, the compound muscle action potential, and wet weight-loss of the gastrocnemius muscle evaluation confirmed the positive effect of the prepared hydrogels on the healing process of the induced nerve injury. In the final, the histopathologic examinations depicted that the collagen/naringin hydrogel group reduced all the histological changes induced from the nerve injury and showed more resemblance to the normal sciatic nerve, with well-arranged fibers and intact myelin sheath. The overall results implied that the prepared collagen/naringin hydrogel can be utilized as a sophisticated alternative to healing peripheral nerve damages.

lodGWAS: a software package for genome-wide association analysis of biomarkers with a limit of detection.

UNLABELLED: Genome-wide association study (GWAS) of a biomarker is complicated when the assay procedure of the biomarker is restricted by a Limit of Detection (LOD). Those observations falling outside the LOD cannot be simply discarded, but should be included into the analysis by applying an appropriate statistical method. However, the problem of LOD in GWAS analysis of such biomarkers is usually overlooked. 'lodGWAS' is a flexible, easy-to-use R package that provides a simple and elegant way for GWAS analysis of such biomarkers while simultaneously accommodating the problem of LOD by applying a parametric survival analysis method. AVAILABILITY AND IMPLEMENTATION: http://cran.r-project.org/web/packages/lodGWAS CONTACTS: a.vaez@umcg.nl or i.m.nolte@umcg.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Sciatic nerve regeneration by transplantation of menstrual blood-derived stem cells.

This is the first study demonstrating the efficacy of menstrual blood-derived stem cell (MenSC) transplantation via a neural guidance conduit, for peripheral nerve regeneration. The synthesized poly (ɛ-caprolactone)/Gelatin conduit, filled with collagen type I and seeded with 3 × 104 MenSCs, was implanted into a rat's 10 mm sciatic nerve defect. The results of hot plate latency, sciatic functional index and weight-loss percentage of wet gastrocnemius muscle demonstrated that the MenSC transplantation had comparable nerve regeneration outcome to autograft, as the gold standard of nerve bridging. The transplantation of MenSCs via a synthetic conduit could ameliorate the functional recovery of sciatic nerve-injured rats which make them a potential candidate for cell therapy of peripheral nervous system disorders.

Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation.

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple genetic loci for C-reactive protein (CRP) and lipids, of which some overlap. We aimed to identify genetic pleiotropy among CRP and lipids in order to better understand the shared biology of chronic inflammation and lipid metabolism. RESULTS: In a bivariate GWAS, we combined summary statistics of published GWAS on CRP (n = 66,185) and lipids, including LDL-cholesterol, HDL-cholesterol, triglycerides, and total cholesterol (n = 100,184), using an empirical weighted linear-combined test statistic. We sought replication for novel CRP associations in an independent sample of 17,743 genotyped individuals, and performed in silico replication of novel lipid variants in 93,982 individuals. Fifty potentially pleiotropic SNPs were identified among CRP and lipids: 21 for LDL-cholesterol and CRP, 20 for HDL-cholesterol and CRP, 21 for triglycerides, and CRP and 20 for total cholesterol and CRP. We identified and significantly replicated three novel SNPs for CRP in or near CTSB/FDFT1 (rs10435719, Preplication: 2.6 × 10(-5)), STAG1/PCCB (rs7621025, Preplication: 1.4 × 10(-3)) and FTO (rs1558902, Preplication: 2.7 × 10(-5)). Seven pleiotropic lipid loci were replicated in the independent set of MetaboChip samples of the Global Lipids Genetics Consortium. Annotating the effect of replicated CRP SNPs to the expression of nearby genes, we observed an effect of rs10435719 on gene expression of FDFT1, and an effect of rs7621025 on PCCB. CONCLUSIONS: Our large scale combined GWAS analysis identified numerous pleiotropic loci for CRP and lipids providing further insight in the genetic interrelation between lipids and inflammation. In addition, we provide evidence for FDFT1, PCCB and FTO to be associated with CRP levels.

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

QCGWAS: A flexible R package for automated quality control of genome-wide association results.

QCGWAS is an R package that automates the quality control of genome-wide association result files. Its main purpose is to facilitate the quality control of a large number of such files before meta-analysis. Alternatively, it can be used by individual cohorts to check their own result files. QCGWAS is flexible and has a wide range of options, allowing rapid generation of high-quality input files for meta-analysis of genome-wide association studies. AVAILABILITY: http://cran.r-project.org/web/packages/QCGWAS CONTACT: i.m.nolte@umcg.nl Supplementary information: Supplementary data are available at Bioinformatics online.