Progress in Polygenic Composite Scores in Alzheimer's and Other Complex Diseases.

Advances in high-throughput genotyping and next-generation sequencing (NGS) coupled with larger sample sizes brings the realization of precision medicine closer than ever. Polygenic approaches incorporating the aggregate influence of multiple genetic variants can contribute to a better understanding of the genetic architecture of many complex diseases and facilitate patient stratification. This review addresses polygenic concepts, methodological developments, hypotheses, and key issues in study design. Polygenic risk scores (PRSs) have been applied to many complex diseases and here we focus on Alzheimer's disease (AD) as a primary exemplar. This review was designed to serve as a starting point for investigators wishing to use PRSs in their research and those interested in enhancing clinical study designs through enrichment strategies.

Integrative analysis of eQTL and GWAS summary statistics reveals transcriptomic alteration in Alzheimer brains.

BACKGROUND: Large-scale genome-wide association studies have successfully identified many genetic variants significantly associated with Alzheimer's disease (AD), such as rs429358, rs11038106, rs723804, rs13591776, and more. The next key step is to understand the function of these SNPs and the downstream biology through which they exert the effect on the development of AD. However, this remains a challenging task due to the tissue-specific nature of transcriptomic and proteomic data and the limited availability of brain tissue.In this paper, instead of using coupled transcriptomic data, we performed an integrative analysis of existing GWAS findings and expression quantitative trait loci (eQTL) results from AD-related brain regions to estimate the transcriptomic alterations in AD brain. RESULTS: We used summary-based mendelian randomization method along with heterogeneity in dependent instruments method and were able to identify 32 genes with potential altered levels in temporal cortex region. Among these, 10 of them were further validated using real gene expression data collected from temporal cortex region, and 19 SNPs from NECTIN and TOMM40 genes were found associated with multiple temporal cortex imaging phenotype. CONCLUSION: Significant pathways from enriched gene networks included neutrophil degranulation, Cell surface interactions at the vascular wall, and Regulation of TP53 activity which are still relatively under explored in Alzheimer's Disease while also encouraging a necessity to bind further trans-eQTL effects into this integrative analysis.

Mining Directional Drug Interaction Effects on Myopathy Using the FAERS Database.

Mining high-order drug-drug interaction (DDI) induced adverse drug effects from electronic health record databases is an emerging area, and very few studies have explored the relationships between high-order drug combinations. We investigate a novel pharmacovigilance problem for mining directional DDI effects on myopathy using the FDA Adverse Event Reporting System (FAERS) database. Our paper provides information on the risk of myopathy associated with adding new drugs on the already prescribed medication, and visualizes the identified directional DDI patterns as user-friendly graphical representation. We utilize the Apriori algorithm to extract frequent drug combinations from the FAERS database. We use odds ratio to estimate the risk of myopathy associated with directional DDI. We create a tree-structured graph to visualize the findings for easy interpretation. Our method confirmed myopathy association with previously reported HMG-CoA reductase inhibitors like rosuvastatin, fluvastatin, simvastatin, and atorvastatin. New, previously unidentified but mechanistically plausible associations with myopathy were also observed, such as the DDI between pamidronate and levofloxacin. Additional top findings are gadolinium-based imaging agents, which however are often used in myopathy diagnosis. Other DDIs with no obvious mechanism are also reported, such as that of sulfamethoxazole with trimethoprim and potassium chloride. This study shows the feasibility to estimate high-order directional DDIs in a fast and accurate manner. The results of the analysis could become a useful tool in the specialists' hands through an easy-to-understand graphic visualization.

Transcriptome-Guided Imaging Genetic Analysis via a Novel Sparse CCA Algorithm.

Imaging genetics is an emerging field that studies the influence of genetic variation on brain structure and function. The major task is to examine the association between genetic markers such as single nucleotide polymorphisms (SNPs) and quantitative traits (QTs) extracted from neuroimaging data. Sparse canonical correlation analysis (SCCA) is a bi-multivariate technique used in imaging genetics to identify complex multi-SNP-multi-QT associations. In imaging genetics, genes associated with a phenotype should at least expressed in the phenotypical region. We study the association between the genotype and amyloid imaging data and propose a transcriptome-guided SCCA framework that incorporates the gene expression information into the SCCA criterion. An alternating optimization method is used to solve the formulated problem. Although the problem is not biconcave, a closed-form solution has been found for each subproblem. The results on real data show that using the gene expression data to guide the feature selection facilities the detection of genetic markers that are not only associated with the identified QTs, but also highly expressed there.