Genomic Meta-Analysis Combining Microarray Studies with Confounding Clinical Variables: Application to Depression Analysis

Major depressive disorder (MDD) is a heterogeneous psychiatric illness with mostly un-characterized pathology and is the fourth most common cause of disability according to the World Health Organization (WHO) and has a significant impact on public health in the United States. To understand the genetics of MDD, we aim to develop effective meta-analysis approaches to provide high-quality characterization of MDD related biomarkers and pathways with proper clinical variable adjustment. First, genomic meta-analysis in MDD faces multiple unique difficulties, such as weak expression signal of MDD, substantial clinical heterogeneity and small sample size. Given these obstacles, it is hard to identify consistent and robust biomarkers in an individual study. To achieve a more accurate and robust detection of differentially expressed (DE) genes and pathways associated with MDD, we proposed a statistical framework of meta-analysis for adjusting confounding variables (MetaACV). The result showed that more MDD related biomarkers and pathways were detected that greatly enhanced understanding of MDD neurobiology. Secondly, Meta-analysis has become popular in the biomedical research because it generally can increase statistical power and provide validated conclusions. However, its result is often biased due to the heterogeneity. Meta-regression has been a useful tool for exploring the source of heterogeneity among studies in a meta-analysis. In this dissertation, we will explore the use of meta-regression in microarray meta-analysis. To account for heterogeneities introduced by study-specific features such as sex, brain region and array platform in the meta-analysis of major depressive disorder (MDD) microarray studies, we extended the random effects model (REM) for genomic meta-regression, combining eight MDD microarray studies. The result shows increased statistical power to detect gender-dependent and brain-region-dependent biomarkers that traditional meta-analysis methods cannot detect. The identified gender-dependent markers have provided new biological insights as to why females are more susceptible to MDD and the result may lead to novel therapeutic targets. Finally, we present an open-source R package called Meta-analysis for Differential Expression analysis (MetaDE) which provides 12 commonly used methods of meta-analysis. It is a friendly used software such that biologists implement meta-analysis in their research

Neural Innervation of the Immune Response Could Lead to Treatments for Severe Asthma: The Screening of Neurotransmitters on T Helper 17 Cell Differentiation

T Helper 17 (Th17) cell-driven neutrophilic asthma is a rare, yet severe phenotype that accounts for over 75% of all asthma related medical costs. Neural innervation has been known play a role in the immune response and we investigated whether the addition of neurotransmitters to would affect Th17 cell differentiation. Results indicated that neural innervation upregulated Th17 cell differentiation and expression of its cytokine IL-17 that is responsible for the severe symptoms seen in neutrophilic asthma

Detecting disease-associated genes with confounding variable adjustment and the impact on genomic meta-analysis: With application to major depressive disorder

<p>Abstract</p> <p>Background</p> <p>Detecting candidate markers in transcriptomic studies often encounters difficulties in complex diseases, particularly when overall signals are weak and sample size is small. Covariates including demographic, clinical and technical variables are often confounded with the underlying disease effects, which further hampers accurate biomarker detection. Our motivating example came from an analysis of five microarray studies in major depressive disorder (MDD), a heterogeneous psychiatric illness with mostly uncharacterized genetic mechanisms.</p> <p>Results</p> <p>We applied a random intercept model to account for confounding variables and case-control paired design. A variable selection scheme was developed to determine the effective confounders in each gene. Meta-analysis methods were used to integrate information from five studies and post hoc analyses enhanced biological interpretations. Simulations and application results showed that the adjustment for confounding variables and meta-analysis improved detection of biomarkers and associated pathways.</p> <p>Conclusions</p> <p>The proposed framework simultaneously considers correction for confounding variables, selection of effective confounders, random effects from paired design and integration by meta-analysis. The approach improved disease-related biomarker and pathway detection, which greatly enhanced understanding of MDD neurobiology. The statistical framework can be applied to similar experimental design encountered in other complex and heterogeneous diseases.</p

Ethylene synthesis, ripening capacity, and superficial scald inhibition in 1-MCP treated ‘d’Anjou’ pears are affected by storage temperature

A continuing challenge for commercializing 1-methylcyclopropene (1-MCP) to extend the storage life and control superficial scald of ‘d’Anjou’ pear (Pyrus communis L.) is how to initiate ripening in 1-MCP treated fruit. ‘D’Anjou’ pears harvested at commercial and late maturity were treated with 1-MCP at 0.15 μL L⁻¹ and stored either at the commercial storage temperature -1.1 °C ([email protected]°C), or at 1.1 °C ([email protected]°C) or 2.2 °C ([email protected]°C) for 8 months. Control fruit stored at -1.1 °C ripened and developed significant scald within 7 d at 20 °C following 3-5 months of storage. While [email protected]°C fruit did not develop ripening capacity due to extremely low internal ethylene concentration (IEC) and ethylene production rate for 8 months, [email protected]°C fruit produced significant amounts of IEC during storage and developed ripening capacity with relatively low levels of scald within 7 d at 20 °C following 6-8 months of storage. [email protected]°C fruit lost quality quickly during storage. Compared to the control, the expression of ethylene synthesis (PcACS1, PcACO1) and signal (PcETR1, PcETR2) genes was stable at extremely low levels in [email protected]°C fruit. In contrast, they increased expression after 4 or 5 months of storage in [email protected] °C fruit. Other genes (PcCTR1, PcACS2, PcACS4 and PcACS5) remained at very low expression regardless of fruit capacity to ripen. A storage temperature of 1.1 °C can facilitate initiation of ripening capacity in 1-MCP treated ‘d’Anjou’ pears with relatively low scald incidence following 6-8 months storage through recovering the expression of certain ethylene synthesis and signal genes.Keywords: Ethylene, Pyrus communis, Ripening capacity, 1-MCP, Gene expressio

Assessment of absorption of four lignan constituents of JingNing particles in rat gut using in situ single-pass intestinal perfusion

Purpose: To study small intestinal absorption of schisadrol A, schisandrol B, schizandrin A and schisandrin B in JingNing particles using in situ single-pass intestinal perfusion (SPIP).Methods: Absorption rate constant (Ka) and apparent permeability (Papp) of the drugs at different concentrations in various parts of rat small intestine (duodenum, jejunum and ileum) were determined using SPIP. JingNing particles were also perfused in situ at different pH in the entire rat intestine. Ethanol extract of Schisandra chinensis (standard) at low concentration was perfused in the duodenum for comparison with extract of JingNing particles.Results: The order of apparent permeability of the four lignans was schisandrol A &lt; schisandrol B &lt; schizandrin A &lt; schisandrin B. Ka and Papp values of the four lignans in JingNing particles were concentration-dependent. Absorption increased in the rank order: ileum &gt; duodenum &gt; jejunum. Optimum absorption pH was 6.50. Polygala tenuifolia extract and volatile oil of Rhizoma acori tatarinowii significantly (p &lt; 0.05) enhanced the absorption of the four lignans.Conclusion: The four lignans were well absorbed in the intestinal tract, particularly the ileum, probably through carrier-mediated transport. The alcohol extract of Polygala tenuifolia and volatile oil of Rhizoma acori graminei enhanced the absorption of the four lignans.Keywords: JingNing, Intestinal absorption, Polygala tenuifolia, Rhizoma acori graminei, Lignans, Schisandrol, Schisandrin, Single-pass intestinal perfusio

Predicting risk for radiographic damage in rheumatoid arthritis:comparative analysis of the multi-biomarker disease activity score and conventional measures of disease activity in multiple studies

Pathophysiology and treatment of rheumatic disease

Foxo1 Promotes Th9 Cell Differentiation and Airway Allergy

T helper 9 (Th9) cells are effector CD4+ T cells that are characterized by the production of interleukin-9 (IL-9) and have been associated with allergic responses. Here, we found that the expression of the transcription factor forkhead box O1 (Foxo1) was induced in Th9 and Foxo1 plays a crucial role in the differentiation of Th9 cells. Pharmacological inhibition of Foxo1 or genetic disruption of Foxo1 in CD4+ T cells caused a reduction in IL-9 expression while upregulating IL-17A and IFNγ production. Furthermore, chromatin immunoprecipitation (ChIP) followed by luciferase assays revealed direct binding of Foxo1 to both the Il9 and Irf4 promoters and induces their transactivation. Lastly, adoptive transfer of Th9 cells into lungs induced asthma-like symptoms that were ameliorated by Foxo1 inhibitor, AS1842856. Together, our findings demonstrate a novel regulator of Th9 cells with a direct implication in allergic inflammation

Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25-35% of the amyloid variance in different datasets, of which 14-17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition

Connecting the dots: Potential of data integration to identify regulatory snps in late-onset alzheimer's disease GWAS findings

Late-onset Alzheimer's disease (LOAD) is a multifactorial disorder with over twenty loci associated with disease risk. Given the number of genome-wide significant variants that fall outside of coding regions, it is possible that some of these variants alter some function of gene expression rather than tagging coding variants that alter protein structure and/or function. RegulomeDB is a database that annotates regulatory functions of genetic variants. In this study, we utilized RegulomeDB to investigate potential regulatory functions of lead single nucleotide polymorphisms (SNPs) identified in five genome-wide association studies (GWAS) of risk and age-at onset (AAO) of LOAD, as well as SNPs in LD (r2≥0.80) with the lead GWAS SNPs. Of a total 614 SNPs examined, 394 returned RegulomeDB scores of 1-6. Of those 394 variants, 34 showed strong evidence of regulatory function (RegulomeDB score ,3), and only 3 of them were genome-wide significant SNPs (ZCWPW1/ rs1476679, CLU/rs1532278 and ABCA7/rs3764650). This study further supports the assumption that some of the non-coding GWAS SNPs are true associations rather than tagged associations and demonstrates the application of RegulomeDB to GWAS data.©2014 Rosenthal et al