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Circulatory system diseases and nervous system disorders often co-occur in patients. Here the authors use eMERGE and UK BioBank data to identify genomic regions associated with both phenotypes, providing insight into the relationship between these conditions.

Abstract Background Phenome-wide association studies (PheWAS) are a high-throughput approach to evaluate comprehensive associations between genetic variants and a wide range of phenotypic measures. PheWAS has varying sample sizes for quantitative traits, and variable numbers of cases and controls for binary traits across the many phenotypes of interest, which can affect the statistical power to detect associations. The motivation of this study is to investigate the various parameters which affect the estimation of statistical power in PheWAS, including sample size, case-control ratio, minor allele frequency, and disease penetrance. Results We performed a PheWAS simulation study, where we investigated variations in statistical power based on different parameters, such as overall sample size, number of cases, case-control ratio, minor allele frequency, and disease penetrance. The simulation was performed on both binary and quantitative phenotypic measures. Our simulation on binary traits suggests that the number of cases has more impact on statistical power than the case to control ratio; also, we found that a sample size of 200 cases or more maintains the statistical power to identify associations for common variants. For quantitative traits, a sample size of 1000 or more individuals performed best in the power calculations. We focused on common genetic variants (MAF > 0.01) in this study; however, in future studies, we will be extending this effort to perform similar simulations on rare variants. Conclusions This study provides a series of PheWAS simulation analyses that can be used to estimate statistical power for some potential scenarios. These results can be used to provide guidelines for appropriate study design for future PheWAS analyses.

While genome-wide association studies are an established method of identifying genetic variants associated with disease, environment-wide association studies (EWAS) highlight the contribution of nongenetic components to complex phenotypes. However, the lack of high-throughput quality control (QC) pipelines for EWAS data lends itself to analysis plans where the data are cleaned after a first-pass analysis, which can lead to bias, or are cleaned manually, which is arduous and susceptible to user error. We offer a novel software, CLeaning to Analysis: Reproducibility-based Interface for Traits and Exposures (CLARITE), as a tool to efficiently clean environmental data, perform regression analysis, and visualize results on a single platform through user-guided automation. It exists as both an R package and a Python package. Though CLARITE focuses on EWAS, it is intended to also improve the QC process for phenotypes and clinical lab measures for a variety of downstream analyses, including phenome-wide association studies and gene-environment interaction studies. With the goal of demonstrating the utility of CLARITE, we performed a novel EWAS in the National Health and Nutrition Examination Survey (NHANES) (N overall Discovery=9063, N overall Replication=9874) for body mass index (BMI) and over 300 environment variables post-QC, adjusting for sex, age, race, socioeconomic status, and survey year. The analysis used survey weights along with cluster and strata information in order to account for the complex survey design. Sixteen BMI results replicated at a Bonferroni corrected p < 0.05. The top replicating results were serum levels of g-tocopherol (vitamin E) (Discovery Bonferroni p: 8.67x10-12, Replication Bonferroni p: 2.70x10-9) and iron (Discovery Bonferroni p: 1.09x10-8, Replication Bonferroni p: 1.73x10-10). Results of this EWAS are important to consider for metabolic trait analysis, as BMI is tightly associated with these phenotypes. As such, exposures predictive of BMI may be useful for covariate and/or interaction assessment of metabolic-related traits. CLARITE allows improved data quality for EWAS, gene-environment interactions, and phenome-wide association studies by establishing a high-throughput quality control infrastructure. Thus, CLARITE is recommended for studying the environmental factors underlying complex disease.

Combining samples across multiple cohorts in large-scale scientific research programs is often required to achieve the necessary power for genome-wide association studies. Controlling for genomic ancestry through principal component analysis (PCA) to address the effect of population stratification is a common practice. In addition to local genomic variation, such as copy number variation and inversions, other factors directly related to combining multiple studies, such as platform and site recruitment bias, can drive the correlation patterns in PCA. In this report, we describe combination and analysis of multi-ethnic cohort with biobanks linked to electronic health records for large-scale genomic association discovery analyses. First, we outline the observed site and platform bias, in addition to ancestry differences. Second, we outline a general protocol for selecting variants for input into the subject variance-covariance matrix, the conventional PCA approach. Finally, we introduce an alternative approach to PCA by deriving components from subject loadings calculated from a reference sample. This alternative approach of generating principal components controlled for site and platform bias, in addition to ancestry differences, with the advantage of fewer covariates and degrees of freedom.principal component analysis, ancestry, biobank, loadings, genetic association study

Assumptions are made about the genetic model of single nucleotide polymorphisms (SNPs) when choosing a traditional genetic encoding: additive, dominant, and recessive. Furthermore, SNPs across the genome are unlikely to demonstrate identical genetic models. However, running SNP-SNP interaction analyses with every combination of encodings raises the multiple testing burden. Here, we present a novel and flexible encoding for genetic interactions, the elastic data-driven genetic encoding (EDGE), in which SNPs are assigned a heterozygous value based on the genetic model they demonstrate in a dataset prior to interaction testing. We assessed the power of EDGE to detect genetic interactions using 29 combinations of simulated genetic models and found it outperformed the traditional encoding methods across 10%, 30%, and 50% minor allele frequencies (MAFs). Further, EDGE maintained a low false-positive rate, while additive and dominant encodings demonstrated inflation. We evaluated EDGE and the traditional encodings with genetic data from the Electronic Medical Records and Genomics (eMERGE) Network for five phenotypes: age-related macular degeneration (AMD), age-related cataract, glaucoma, type 2 diabetes (T2D), and resistant hypertension. A multi-encoding genome-wide association study (GWAS) for each phenotype was performed using the traditional encodings, and the top results of the multi-encoding GWAS were considered for SNP-SNP interaction using the traditional encodings and EDGE. EDGE identified a novel SNP-SNP interaction for age-related cataract that no other method identified: rs7787286 (MAF: 0.041; intergenic region of chromosome 7)-rs4695885 (MAF: 0.34; intergenic region of chromosome 4) with a Bonferroni LRT p of 0.018. A SNP-SNP interaction was found in data from the UK Biobank within 25 kb of these SNPs using the recessive encoding: rs60374751 (MAF: 0.030) and rs6843594 (MAF: 0.34) (Bonferroni LRT p: 0.026). We recommend using EDGE to flexibly detect interactions between SNPs exhibiting diverse action.