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Genome-wide survey of parent-of-origin-specific associations across clinical traits derived from electronic health records.

ABSTRACT: Parent-of-origin (PoO) effects refer to the differential phenotypic impacts of genetic variants dependent on their parental inheritance due to imprinting. While PoO effects can influence complex traits, they may be poorly captured by models that do not differentiate the parental origin of the variant. The aim of this study was to conduct a genome-wide screen for PoO effects on a broad range of clinical traits derived from electronic health records (EHR) in the DiscovEHR study enriched with familial relationships. Using pairwise kinship estimates from genetic data and demographic data, we identified 22,051 offspring among 134,049 individuals in the DiscovEHR study. PoO of ~9 million variants was assigned in the offspring by comparing offspring and parental genotypes and haplotypes. We then performed genome-wide PoO association analyses across 154 quantitative and 611 binary traits extracted from EHR. Of the 732 significant PoO associations identified (p < 5 × 10^-8), we attempted to replicate 274 PoO associations in the UK Biobank study with 5,015 offspring and replicated 9 PoO associations (p < 0.05). In summary, our study implements a bioinformatic and statistical approach to examine PoO effects genome-wide in a large population study enriched with familial relationships and systematically characterizes PoO effects on hundreds of clinical traits derived from EHR. Our results suggest that, while the statistical power to detect PoO effects remains modest yet, accurately modeling PoO effects has the potential to find new associations that may have been missed by the standard additive model, further enhancing the mechanistic understanding of genetic influence on complex traits.

SUBMITTER: Kim HI

PROVIDER: S-EPMC8756508 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHypertension is the most prevalent risk factor for mortality globally. Uncontrolled hypertension is associated with excess morbidity and mortality, and nearly one-half of individuals with hypertension do not have the condition under control. Data from electronic health record (EHR) systems may be useful for community hypertension surveillance, filling a gap in local public health departments' community health assessments and supporting the public health data modernization initiatives currently underway. To identify patients with hypertension, computable phenotypes are required. These phenotypes leverage available data elements-such as vitals measurements and medications-to identify patients diagnosed with hypertension. However, there are multiple methodologies for creating a phenotype, and the identification of which method most accurately reflects real-world prevalence rates is needed to support data modernization initiatives.ObjectiveThis study sought to assess the comparability of 6 different EHR-based hypertension prevalence estimates with estimates from a national survey. Each of the prevalence estimates was created using a different computable phenotype. The overarching goal is to identify which phenotypes most closely align with nationally accepted estimations.MethodsUsing the 6 different EHR-based computable phenotypes, we calculated hypertension prevalence estimates for Marion County, Indiana, for the period from 2014 to 2015. We extracted hypertension rates from the Behavioral Risk Factor Surveillance System (BRFSS) for the same period. We used the two 1-sided t test (TOST) to test equivalence between BRFSS- and EHR-based prevalence estimates. The TOST was performed at the overall level as well as stratified by age, gender, and race.ResultsUsing both 80% and 90% CIs, the TOST analysis resulted in 2 computable phenotypes demonstrating rough equivalence to BRFSS estimates. Variation in performance was noted across phenotypes as well as demographics. TOST with 80% CIs demonstrated that the phenotypes had less variance compared to BRFSS estimates within subpopulations, particularly those related to racial categories. Overall, less variance occurred on phenotypes that included vitals measurements.ConclusionsThis study demonstrates that certain EHR-derived prevalence estimates may serve as rough substitutes for population-based survey estimates. These outcomes demonstrate the importance of critically assessing which data elements to include in EHR-based computer phenotypes. Using comprehensive data sources, containing complete clinical data as well as data representative of the population, are crucial to producing robust estimates of chronic disease. As public health departments look toward data modernization activities, the EHR may serve to assist in more timely, locally representative estimates for chronic disease prevalence.

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Genome-wide survey of parent-of-origin-specific associations across clinical traits derived from electronic health records.

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