Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene-trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits

Acute Hemorrhagic Leukoencephalitis: A Case and Systematic Review of the Literature

Objectives:; To present a patient with acute hemorrhagic leukoencephalitis (AHLE) and a systematic review of the literature analyzing diagnostic procedures, treatment, and outcomes of AHLE.; Methods:; PubMed and Cochrane databases were screened. Papers published since 01/01/2000 describing adult patients are reported according to the PRISMA-guidelines.; Results:; A 59-year old male with rapidly developing coma and cerebral biopsy changes compatible with AHLE is presented followed by 43 case reports from the literature including males in 67% and a mean age of 38 years. Mortality was 47%. Infectious pathogens were reported in 35%, preexisting autoimmune diseases were identified in 12%. Neuroimaging revealed uni- or bihemispheric lesions in 65% and isolated lesions of the cerebellum, pons, medulla oblongata or the spinal cord without concomitant hemispheric involvement in 16%. Analysis of the cerebrospinal fluid showed an increased protein level in 87%, elevated white blood cells in 65%, and erythrocytes in 39%. Histology (reported in 58%) supported the diagnosis of AHLE in all cases. Glucocorticoids were used most commonly (97%), followed by plasmapheresis (26%), and intravenous immunoglobulins (12%), without a clear temporal relationship between treatment and the patients' clinical course.; Conclusions:; Although mortality was lower than previously reported, AHLE remains a life-threatening neurologic emergency with high mortality. Diagnosis is challenging as the level of evidence regarding the diagnostic yield of clinical, neuroimaging and laboratory characteristics remains low. Hence, clinicians are urged to heighten their awareness and to prompt cerebral biopsies in the context of rapidly progressive neurologic decline of unknown origin with the concurrence of the compiled characteristics. Future studies need to focus on treatment characteristics and their effects on course and outcome

Tree frog attachment: Mechanisms, challenges, and perspectives

Tree frogs have the remarkable ability to attach to smooth, rough, dry, and wet surfaces using their versatile toe pads. Tree frog attachment involves the secretion of mucus into the pad-substrate gap, requiring adaptations towards mucus drainage and pad lubrication. Here, we present an overview of tree frog attachment, with focus on (i) the morphology and material of the toe pad; (ii) the functional demands on the toe pad arising from ecology, lifestyle, and phylogenetics; (iii) experimental data of attachment performance such as adhesion and friction forces; and (iv) potential perspectives on future developments in the field. By revisiting reported data and observations, we discuss the involved mechanisms of attachment and propose new hypotheses for further research. Among others, we address the following questions: Do capillary and hydrodynamic forces explain the strong friction of the toe pads directly, or indirectly by promoting dry attachment mechanisms? If friction primarily relies on van der Waals (vdW) forces instead, how much do these forces contribute to adhesion in the wet environment tree frogs live in and what role does the mucus play? We show that both pad morphology and measured attachment performance suggest the coaction of several attachment mechanisms (e.g. capillary and hydrodynamic adhesion, mechanical interlocking, and vdW forces) with situation-dependent relative importance. Current analytical models of capillary and hydrodynamic adhesion, caused by the secreted mucus and by environmental liquids, do not capture the contributions of these mechanisms in a comprehensive and accurate way. We argue that the soft pad material and a hierarchical surface pattern on the ventral pad surface enhance the effective contact area and facilitate gap-closure by macro- to nanoscopic drainage of interstitial liquids, which may give rise to a significant contribution of vdW interactions to tree frog attachment. Increasing the comprehension of the complex mechanism of tree frog attachment contributes to a better understanding of other biological attachment systems (e.g. in geckos and insects) and is expected to stimulate the development of a wide array of bioinspired adhesive applications.Related blog Julian K.A. Langowski - 'Kermit’s sticky little fingers: What do we know (and what not) about tree frog attachment?': https://blogs.biomedcentral.com/on-biology/2018/09/06/kermits-sticky-little-fingers-know-not-tree-frog-attachment/Medical Instruments & Bio-Inspired Technolog

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Abstract Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits

Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the maj