Boerwinkle, Eric

Abstract Objective To describe and demonstrate use of pediatric data collected by the All of Us Research Program. Materials and Methods All of Us participant physical measurements and electronic health record (EHR) data were analyzed including investigation of trends in childhood obesity and correlation with adult body mass index (BMI). Results We identified 19 729 participants with legacy pediatric EHR data including diagnoses, prescriptions, visits, procedures, and measurements gathered since 1980. We found an increase in pediatric obesity diagnosis over time that correlates with BMI measurements recorded in participants’ adult EHRs and those physical measurements taken at enrollment in the research program. Discussion We highlight the availability of retrospective pediatric EHR data for nearly 20 000 All of Us participants. These data are relevant to current issues such as the rise in pediatric obesity. Conclusion All of Us contains a rich resource of retrospective pediatric EHR data to accelerate pediatric research studies.

Introduction: β-blockers, including atenolol, are among the most widely prescribed antihypertensive drug classes. However, their use has been associated with hyperglycemia and incident diabetes, which poses concern for prescribers and patients. The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study is a multicenter clinical trial with one of its objectives to identify genetic influences on adverse metabolic events in patients treated with atenolol. Here we report a genomics-metabolomics integrative approach to identify biomarkers associated with atenolol-induced glucose change. Methods: PEAR participants were genotyped using the Illumina Omni 1M-Quad Chip. Metabolite profiles were acquired through GC-TOF-MS. Association between baseline levels of metabolites and glucose change was conducted using a multivariate linear regression model adjusted for age, gender and baseline fasting glucose. Genomics-metabolomics integration included selecting SNPs within genes involved in the synthesis and degradation of top metabolites and testing their effect on glucose change in 234 atenolol-treated Caucasians in PEAR, adjusting for age, gender, baseline glucose and principal components 1 and 2. A false discovery rate (FDR) of .05 was used to adjust for multiple comparisons. Replication of significant SNPs was conducted in an additional 228 participants treated with atenolol in PEAR. Results: Metabolomics analysis revealed 3 metabolites associated with glucose change that passed FDR adjustment. The top metabolite signal was beta-alanine. Increasing levels of baseline beta-alanine was significantly correlated with greater glucose increases after atenolol treatment (p=.0003). A total of 79 SNPs in 12 genes in the beta-alanine pathway were explored. SNP rs2669429 in DPYS was significantly associated with glucose change, after FDR adjustment. We found that G allele carriers had significantly greater glucose change compared with non-carriers (p=.0006; β=+2.76 mg/dL). This finding was successfully replicated in the other 228 patients who received atenolol (p=.04; β=+1.86 mg/dL). Conclusions: These results suggest that beta alanine and DPYS rs2669429 SNP might be an important predictor of atenolol-induced dysglycemia.

Abstract Introduction There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results Single‐variant analysis identified associations with apolipoprotein E ( APOE ) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP , PSEN2 , CCK , and ZNF397 . There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD.

Abstract Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

Abstract Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D 5 receptor (D 5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1 −/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT 1 R), NADPH oxidase (NOX) subunits, D 5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1 ‐/‐ mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro‐American males had deficient SNX1 activity, impaired D 5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro‐American males. siRNA‐mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D 5 R agonist‐induced increase in cAMP production and decrease in Na + transport, effects that were normalized by over‐expression of SNX1. Among HT African‐Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

AbstractBackgroundWolff–Parkinson–White (WPW) syndrome is a relatively common arrhythmia affecting ~1–3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.MethodsWe applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW.ResultsA heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF ≤ 0.005) with CADD score ≥ 25 in genes linked to AF in cases compared to controls (P = .0023).ConclusionsOur findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

Abstract Background: The value of the ratio of plasma aldosterone concentration (aldosterone) to plasma renin activity (renin) to identify patients at risk for primary aldosteronism is controversial. We determined the sensitivity, specificity, and predictive value of the ratio to identify combinations of renin and aldosterone compatible with primary aldosteronism. Methods: The ratio was calculated in 505 adults with essential hypertension (143 black women, 82 black men, 122 white women, and 158 white men). We used a conventional cutpoint for an increased ratio (i.e., 20 mL/dL · h). The primary combination of renin and aldosterone considered compatible with primary aldosteronism was increased aldosterone for the concomitant renin, defined as aldosterone in the highest quartile predicted by linear regression on renin. Renin was considered low if it was in the lowest quartile of the sample distribution. Results: The sensitivity of the ratio to identify individuals with increased aldosterone for the concomitant renin was 66% (80% in blacks and 56% in whites; P = 0.009), and the specificity of the ratio was 67% (46% in blacks and 84% in whites; P <0.0001). In 36% of instances of an increased ratio, it was a measure of low renin alone without increased aldosterone for renin (32% in blacks and 45% in whites; P = 0.072). The positive predictive value of the ratio to identify individuals with increased aldosterone for the concomitant renin was 34% (49% in whites and 27% in blacks; P <0.002). Conclusion: The aldosterone/renin ratio lacks sensitivity and specificity and has only a modest predictive value for combinations of renin and aldosterone that are compatible with primary aldosteronism.

Background There exists a wide interindividual variability in blood pressure ( BP ) response to β 1 ‐blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome‐wide meta‐analysis of genetic variants influencing β 1 ‐blocker BP response. Methods and Results Genome‐wide association analysis for systolic BP and diastolic BP response to β 1 ‐blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta‐analysis and single nucleotide polymorphisms (SNPs) with P <10 −4 were tested for replication in 2 independent randomized clinical trials of β 1 ‐blocker–treated patients of European ancestry (n=1552). Regions harboring the replicated SNP s were validated in a β 1 ‐blocker–treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST 1 was associated with systolic BP response to β 1 ‐blockers in the discovery meta‐analysis ( P =9.33×10 −5 , β=−3.21 mm Hg) and replicated at Bonferroni significance ( P =1.85×10 −4 , β=−4.86 mm Hg) in the replication meta‐analysis with combined meta‐analysis approaching genome‐wide significance ( P =2.18×10 −7 ). This SNP in BST 1 is in linkage disequilibrium with several SNP s with putative regulatory functions in nearby genes, including CD 38 , FBXL 5 , and FGFBP 1 , all of which have been implicated in BP regulation. SNP s in this genetic region were also associated with BP response in the black cohort. Conclusions Data from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST 1 containing locus on chromosome 4 is associated with β 1 ‐blocker BP response. Given the previous associations of this region with BP , this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.