Causal modeling in a multi-omic setting: insights from GAW20

Background

Increasingly available multilayered omics data on large populations has opened exciting analytic opportunities and posed unique challenges to robust estimation of causal effects in the setting of complex disease phenotypes. The GAW20 Causal Modeling Working Group has applied complementary approaches (eg, Mendelian randomization, structural equations modeling, Bayesian networks) to discover novel causal effects of genomic and epigenomic variation on lipid phenotypes, as well as to validate prior findings from observational studies.

Results

Two Mendelian randomization studies have applied novel approaches to instrumental variable selection in methylation data, identifying bidirectional causal effects of CPT1A and triglycerides, as well as of RNMT and C6orf42, on high-density lipoprotein cholesterol response to fenofibrate. The CPT1A finding also emerged in a Bayesian network study. The Mendelian randomization studies have implemented both existing and novel steps to account for pleiotropic effects, which were independently detected in the GAW20 data via a structural equation modeling approach. Two studies estimated indirect effects of genomic variation (via DNA methylation and/or correlated phenotypes) on lipid outcomes of interest. Finally, a novel weighted R² measure was proposed to complement other causal inference efforts by controlling for the influence of outlying observations.

Conclusions

The GAW20 contributions illustrate the diversity of possible approaches to causal inference in the multi-omic context, highlighting the promises and assumptions of each method and the benefits of integrating both across methods and across omics layers for the most robust and comprehensive insights into disease processes.

     

Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells.     

Pharmacological experiments demonstrate that toad (Bufo marinus) atrial beta-adrenoceptors are not identical with mammalian beta2- or beta1-adrenoceptors

Chronotropic responses to symphathomimetic amines of isolated atrial preparations from toads ($\text{Bufo marinus}$) were mediated by β-adrenoceptors since isoprenaline was more potent than adrenaline and noradrenaline, and propranolol was a potent antagonist (pA₂, adrenaline as agonist = 9.33). The β-adrenoceptors had some of the characteristics of mammalian β₂-adrenoceptors in that (i) adrenaline was more potent than noradrenaline and (ii) the pA₂ values of two selective β-adrenoceptor antagonists, atenolol (pA₂ = 5.84) and α-methylpropranolol (pA₂ = 8.42), were close to the values reported on β₂-adrenoceptors in mammalian tissues. However, the relative potencies of adrenaline, isoprenaline, noradrenaline, rimiterol, salbutamol and fenoterol (1 : 45.8 : 0.07 : 3.3 : 1.05 : 0.32) did not correspond to the relative potencies reported for these agonist on mammalian tissues which contain predominantly β₂-adrenoceptors. Also the pA₂ value for the β₂-selective antagonist, ICI 118,551 (7.89, adrenaline as agonist) was lower than its reported pA₂ on β₂-adrenoceptors in mammalian tissues. There was no evidence that the response was mediated by both β₁-andβ₂-adrenoceptors since Schild plots for ICI 118,551 using three agonists of differing selectivity (adrenaline, rimiterol and noradrenaline) weer superimposed. It is concluded that, although toad atrial β-adrenoceptors have several characteristics in common with β₂-adrenoceptors in mammalian tissues, these amphibian β-adrenoceptors are not identical with mammalian β₂-adrenoceptors.     

AIDS: A problem of antigen presentation?

Evidence is accumulating that antigen-presenting dendritic cells — both those that activate T cells and those that interact with B cells — may be involved in the development of immunodeficiency during HIV-1 infection.     

Frequent polymorphism in exon 15 of the adenomatous polyposis coli gene

In the course of a study of tumor suppressor gene mutation in hepatoblastoma, a frequent neutral polymorphism was identified at codon 1493 in exon 15 of the gene causing adenomatous polyposis coli (APC). As the polymorphism introduces a new BsaJ1 site, DNA amplified by the polymerase chain reaction (PCR) can be rapidly screened for this polymorphism. This polymorphism can be used in cosegregation studies for presymptomatic diagnosis of APC and family studies.     

The Effect of Tannins on the Morphology and Hydrogenase Activity of Sulphate Reducing Bacteria

Two strains of Desulphovibrio desulphuricans were found to have much reduced hydrogenase activity for sulphate reduction and methylene blue reduction after repeated subculture in medium containing mimosa tannin. The loss of activity was not reversed on transfer back to a medium containing no tannin. Changes in the morphology and motility of these organisms, and of the related organism Desulphovibrio orientis , brought about by culture in media containing tannins are reported.