Understanding bias in DNA repair

QDM elements used to build an AMI DCDO. An Excel spreadsheet file containing a list of QDM elements related to AMI diagnostic criteria, This is an example for illustrating the DCDO building. (XLSX 11 kb

Additional file 1: of Developing a modular architecture for creation of rule-based clinical diagnostic criteria

QDM elements used to build an AMI DCDO. An Excel spreadsheet file containing a list of QDM elements related to AMI diagnostic criteria, This is an example for illustrating the DCDO building. (XLSX 11 kb

Comparison of associations in eMERGE European Americans to previously published genetic associations with serum thyroid stimulating hormone (TSH) levels.

<p>SNP rs number, chromosomal location, nearest gene/gene region, coded allele (CA), coded allele frequency (CAF), and association summary statistics (betas, standard errors, and p-values) are given for each previously reported association with TSH levels in European Americans. CAF for rs4704397 is the mean CAF for the combined cohorts described in Taylor et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111301#pone.0111301-Panicker3" target="_blank">[16]</a>. For SNPs not directly genotyped in this study, the proxy in highest linkage disequilibrium in 1000 Genomes CEU reference panel was identified. Results of adjusted (age, sex, body mass index, and principal component 1) tests of association are given for each previously reported SNP or its proxy in this European American dataset (n = 4,501).</p><p>Comparison of associations in eMERGE European Americans to previously published genetic associations with serum thyroid stimulating hormone (TSH) levels.</p

Population characteristics in euthyroid individuals for serum thyroid stimulating hormone (TSH) levels and demographics in the eMERGE Network.

<p>Means (standard deviation) are presented unless otherwise noted.</p><p>Population characteristics in euthyroid individuals for serum thyroid stimulating hormone (TSH) levels and demographics in the eMERGE Network.</p

Genome-wide significant SNP associations for serum thyroid stimulating hormone (TSH) levels in eMERGE euthyroid European Americans (n = 4,501).

<p>Significance defined as p<5×10⁻⁸. Tests of association using linear regression for 474,366 SNPs assuming an additive genetic model and adjusted for age, sex, principal component (PC1), and body mass index were performed.</p><p>Genome-wide significant SNP associations for serum thyroid stimulating hormone (TSH) levels in eMERGE euthyroid European Americans (n = 4,501).</p

Comparison of most significant associations identified in European Americans with African Americans from the eMERGE Network.

<p>We plotted p-values, coded allele frequencies, and betas for euthyroid European Americans (n = 4,501) and African Americans (n = 351) in the eMERGE Network for serum TSH level tests of association using SynthesisView. Data shown are comparisons between European Americans (blue markers) and African Americans (red markers) for p-values (data shown are –log10 (pvalue)), genetic effect magnitudes (beta), and minor (coded) allele frequencies (MAF) for the 31 most significant SNPs in European Americans. Red horizontal line on p-value track indicates p = 0.05. SNPs are oriented across the top of the figure, arranged by chromosomal location. Large triangles represent p-values at or smaller than 5×10⁻⁰⁸. Direction of the marker for p-values indicates direction of effect for each SNP.</p

Body mass index as a modifier of serum thyroid stimulating hormone (TSH) levels genetic associations in eMERGE European Americans.

<p>Interaction analyses were performed using the SNPs with p<1×10⁻⁰⁴ significance levels in the model adjusted for age, sex, PC1, and body mass index in European Americans (n = 4,501). For each significant (p<0.05) interaction term, the model was then stratified by normal/overweight BMI (normal BMI  = 18–24.9; overweight BMI ≥25). We considered a SNPxBMI interaction significant at a threshold of p<0.05. Shown are p-values from Wilcoxon rank-sum test comparing median TSH values between BMI categories at each genotype.</p

Manhattan plot of tests of association with serum thyroid stimulating hormone (TSH) levels in euthyroid European Americans in eMERGE.

<p>Data shown are p-values from single SNP tests of association with serum TSH levels in a model adjusted for age, sex, principal component (PC1), and body mass index in euthyroid European Americans in eMERGE Network (n = 4,501). The y-axis represents the –log10 (p-value); horizontal lines represent Bonferroni corrected significance level (p<5×10⁻⁰⁸) (top) and suggestive significance level (1×10⁻⁰⁴) (bottom). Chromosomes are arranged on the x axis.</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

Q-Q plot of genome-wide association analysis of individuals with resistant hypertension versus controlled hypertensives.

<p>The Q-Q plots were re-generated after removal of <i>ESR1</i> rs9479122.</p