Adjusted odds ratio (aOR) and 95% confidence interval (95% CI) for opioids use and OUD.

Adjusted odds ratio (aOR) and 95% confidence interval (95% CI) for opioids use and OUD.</p

Sociodemographic characteristics of the <i>All of Us</i> Research Program among participants who completed lifestyle survey and shared their EHR data.

Prevalence (%) and 95% Confidence Interval (95% CI) of opioids use and OUD in the All of Us Research Program among groups of gender, age, race/ethnicity, country of origin, and region of residence.</p

<i>FHOD3</i> locus.

<p>(A) Top wiggle tracks show ATAC-seq signal in multiple cell types, followed by ChromHMM chromatin state tracks. Beneath are <i>FHOD3</i> GWAS loci and the SNPs from this study (reQTL and tSNP). The bottom track shows the FUSION <i>FHOD3</i> RNA-seq signal. (B) ATAC-seq signal highlights potential regulatory regions with the skeletal muscle stretch enhancer. (C) Effects of SNPs overlapping ATAC-seq peaks in the reQTL haplotype on in silico predicted TF binding.</p

<i>FHOD3</i> reQTL, rs17746240 (18:33970347).

<p>The data for each of the three possible reQTL genotypes are presented in separate plots (columns). The top row plots show the relationship between gene expression (y axis) and the clinical variable (x axis). The bottom row plots show the relationship between the allelic imbalance of the tSNP and the clinical variable (x axis). Note the bottom row has fewer samples because it is limited to samples heterozygous for the tSNP. (A) LDLc GxE effect with rs72895597 (18:34232657) as the tSNP. (B) SBP GxE effect with rs2303510 (18:34324091) as the tSNP.</p

Genetic and environmental effects on gene expression.

<p>Blood insulin levels represent a cellular environment for tissues such as skeletal muscle. The left panel depicts a single genome with color-coded genomic elements and various heterozygous sites. The right panel shows the relative transcript abundance for the corresponding locus on the left panel. Some genomic elements contain genetic variants. When the variant is the same color as the element, the element is active. In some cases the variant is black, indicating that the variant renders the regulatory element nonfunctional and only basal transcription occurs. The purple element represents a gene with a transcribed SNP (tSNP), shown in the transcripts. Allele specific expression is calculated across both chromosomes and compared to the high and low environment. (A) When regulated by an insulin-responsive element (green), gene expression changes according to insulin concentrations in the extracellular environment. (B) When regulated by an insulin-independent element (orange) containing genetic variation, gene expression changes according to the presence of a genetic variant (eQTL), but not to insulin levels. The tSNP shows allelic bias due to the eQTL effect, but is not associated with the insulin environment. (C) When regulated by both an insulin-responsive element and an insulin-independent element containing genetic variation, the effects of the insulin environment and the genetic variation on gene expression may be additive, although more complex relationships are possible. The tSNP shows some imbalance due to the eQTL effect and is associated to insulin levels. Such cases may be identified as weak reQTLs. (D) When regulated by an insulin-responsive element containing genetic variation, there may exist an interaction effect between the genetic variant and insulin levels such that changes in gene expression across insulin environments depend on the genetic variant. The tSNP shows allelic imbalance associated with insulin levels due to the reQTL effect. One of several possible interaction effects depicted.</p

GTEx replication.

<p>Replication rate (y axis) as a function of FUSION reQTL p-value cutoff (x axis). Dashed line represents two standard deviations from the null distribution, calculated using the hypergeometric distribution.</p

reQTL results FDR 10%.

<p>reQTL results FDR 10%.</p

GxE signals.

<p>(A) Number of reQTLs per clinical variable (10% FDR). (B) Number of tSNP-environment associations per clinical variable (10% FDR).</p

Genome-wide study of resistant hypertension identified from electronic health records

<div><p>Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among >47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was <i>CLNK</i> rs13144136 at p = 1.00x10^-6 (odds ratio = 0.68; 95% CI = 0.58–0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.</p></div

Characteristics of resistant hypertension cases and controls.

<p>Race/ethnicity is self-reported or administratively-assigned. Here, ethnicity refers to “Hispanic” and race refers to European American, African American, or other.</p