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Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record.

ABSTRACT: Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases. Twenty-one SNPs previously implicated as common variants predisposing to atrial fibrillation, Crohn disease, multiple sclerosis, rheumatoid arthritis, or type 2 diabetes were successfully genotyped in 9483 samples accrued over 4 mo into BioVU, the Vanderbilt University Medical Center DNA biobank. Previously reported odds ratios (OR(PR)) ranged from 1.14 to 2.36. For each phenotype, natural language processing techniques and billing-code queries were used to identify cases (n = 70-698) and controls (n = 808-3818) from deidentified health records. Each of the 21 tests of association yielded point estimates in the expected direction. Previous genotype-phenotype associations were replicated (p < 0.05) in 8/14 cases when the OR(PR) was > 1.25, and in 0/7 with lower OR(PR). Statistically significant associations were detected in all analyses that were adequately powered. In each of the five diseases studied, at least one previously reported association was replicated. These data demonstrate that phenotypes representing clinical diagnoses can be extracted from EMR systems, and they support the use of DNA resources coupled to EMR systems as tools for rapid generation of large data sets required for replication of associations found in research cohorts and for discovery in genome science.

SUBMITTER: Ritchie MD

PROVIDER: S-EPMC2850440 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record.

Ritchie Marylyn D MD Denny Joshua C JC Crawford Dana C DC Ramirez Andrea H AH Weiner Justin B JB Pulley Jill M JM Basford Melissa A MA Brown-Gentry Kristin K Balser Jeffrey R JR Masys Daniel R DR Haines Jonathan L JL Roden Dan M DM

American journal of human genetics 20100401 4

Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases. Twenty-one SNPs previously implicated as common va ...[more]

PMID: 20362271

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Project description:We aimed to detect cross-sectional phenotype and polygenic risk score (PRS) associations between sleep duration and prevalent diseases using the Partners Biobank, a hospital-based cohort study linking electronic medical records (EMR) with genetic information. Disease prevalence was determined from EMR, and sleep duration was self-reported. A PRS for sleep duration was derived using 78 previously associated SNPs from genome-wide association studies (GWAS) for self-reported sleep duration. We tested for associations between (1) self-reported sleep duration and 22 prevalent diseases (n = 30 251), (2) the PRS and self-reported sleep duration (n = 6903), and (3) the PRS and the 22 prevalent diseases (n = 16 033). For observed PRS-disease associations, we tested causality using two-sample Mendelian randomization (MR). In the age-, sex-, and race-adjusted model, U-shaped associations were observed for sleep duration and asthma, depression, hypertension, insomnia, obesity, obstructive sleep apnea, and type 2 diabetes, where both short and long sleepers had higher odds for these diseases than normal sleepers (p < 2.27 × 10-3). Next, we confirmed associations between the PRS and longer sleep duration (0.65 ± 0.19 SD minutes per effect allele; p = 7.32 × 10-04). The PRS collectively explained 1.4% of the phenotypic variance in sleep duration. After adjusting for age, sex, genotyping array, and principal components of ancestry, we observed that the PRS was also associated with congestive heart failure (CHF; p = 0.015), obesity (p = 0.019), hypertension (p = 0.039), restless legs syndrome (RLS; p = 0.041), and insomnia (p = 0.049). Associations were maintained following additional adjustment for obesity status, except for hypertension and insomnia. For all diseases, except RLS, carrying a higher genetic burden of the 78 sleep duration-increasing alleles (i.e. higher sleep duration PRS) associated with lower odds for prevalent disease. In MR, we estimated causal associations between genetically defined longer sleep duration with decreased risk of CHF (inverse variance weighted [IVW] OR per minute of sleep [95% CI] = 0.978 [0.961-0.996]; p = 0.019) and hypertension (IVW OR [95% CI] = 0.993 [0.986-1.000]; p = 0.049), and increased risk of RLS (IVW OR [95% CI] = 1.018 [1.000-1.036]; p = 0.045). By validating the PRS for sleep duration and identifying cross-phenotype associations, we lay the groundwork for future investigations on the intersection between sleep, genetics, clinical measures, and diseases using large EMR datasets.

Dataset Information

Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record.

Publications

Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record.

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