Ulrich Broeckel

Medical College of Wisconsin, Milwaukee, Wisconsin, United States

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Publications (113)812.94 Total impact

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    ABSTRACT: Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
    Nature 07/2015; DOI:10.1038/nature14618 · 42.35 Impact Factor
  • Peter K. Joshi · Tonu Esko · Hannele Mattsson · Niina Eklund · Ilaria Gandin · Teresa Nutile · Anne U. Jackson · Claudia Schurmann · Albert V. Smith · Weihua Zhang · [...] · Vilmundur Gudnason · Atsushi Takahashi · John C. Chambers · Jaspal S. Kooner · David P. Strachan · Harry Campbell · Joel N. Hirschhorn · Markus Perola · Ozren Polašek · James F. Wilson
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    ABSTRACT: Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
    Nature 07/2015; · 42.35 Impact Factor
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    ABSTRACT: Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, P = 0.05 and rs9730100: β = 1.0, P = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (P = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies.
    Frontiers in Genetics 04/2015; 6:136. DOI:10.3389/fgene.2015.00136
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    ABSTRACT: We report on a father and his two daughters diagnosed with Klippel–Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2015; 167(1). DOI:10.1002/ajmg.a.36799 · 2.05 Impact Factor
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    ABSTRACT: Introduction Pharmacogenetic testing is increasingly being offered by clinical laboratories; however, only a limited number of quality control and other reference materials (RM) are currently available. Previously, we published the characterization of 107 publicly available genomic DNA samples for five commonly tested pharmacogenetic genes using single gene tests. In this study we have expanded the number of genes and alleles characterized and included additional assays that interrogate multiplex panels of pharmacogenetic variants. The Centers for Disease Control and Prevention (CDC) based Genetic Testing Reference Material Coordination Program (GeT-RM), in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, have characterized a panel of 137 additional genomic DNA samples for 27 genes commonly interrogated by pharmacogenetic testing assays and proficiency testing surveys (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, , CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, DPYD, GSTM1, GSTP1, GSTT1, NAT1, SLC15A2, SLC22A2, SLCO1B1, SLCO2B1, UGT1A1, UGT2B7, UGT2B15, UGT2B17, VKORC1, TPMT). Materials and Methods In an effort to identify low frequency pharmacogenetic variants in addition to the common alleles, 137 Coriell cell lines were selected based on partial genotype characterization. Blinded DNA samples from these cell lines were sent to volunteer testing laboratories for targeted (*) allele genotyping. Participants utilized a variety of commercially available and laboratory developed tests which included almost all of the currently available commercial platforms. The genotype data on approximately 2,000 pharmacogenetic variants was also determined and will be reported separately. Results Each sample was tested by two to five star (*) allele assay platforms. The results were consistent among laboratories, with differences in allele assignments related to manufacture assay design and variability in reported allele nomenclature, particularly for CYP2D6. The alleles included in the different assay varied, but most were identified in the set of 137 DNA samples. Genotypic information on 28 additional less frequently tested pharmacogenetic genes was also generated. Conclusions We have characterized a set of 137 genomic DNA RMs for 27 important pharmacogenetic genes using a variety of assay platforms in multiple pharmacogenetic testing laboratories. These samples will be very useful for assay development and validation, quality control and proficiency testing, and should help to improve the accuracy of pharmacogenetic testing in clinical laboratories. These and other RMs developed by GeT-RM, are available from the Coriell Cell Repositories, and are listed on the GeT-RM website: http://wwwn.cdc.gov/dls/genetics/qcmaterials/default.aspx.
    Association of Molecular Pathology; 11/2014
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    ABSTRACT: Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 55 is January 06, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual Review of Pharmacology 10/2014; 55(1). DOI:10.1146/annurev-pharmtox-010814-124835 · 18.52 Impact Factor
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    ABSTRACT: Cardiac hypertrophy is an independent risk factor for cardiovascular disease and heart failure. There is increasing evidence that microRNAs (miRNAs) play an important role in the regulation of messenger RNA (mRNA) and the pathogenesis of various cardiovascular diseases. However, the ability to comprehensively study cardiac hypertrophy on a gene regulatory level is impacted by the limited availability of human cardiomyocytes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer the opportunity for disease modeling. Here we utilize a previously established in vitro model of cardiac hypertrophy to interrogate the regulatory mechanism associated with the cardiac disease process. We perform miRNA sequencing and mRNA expression analysis on endothelin 1 (ET-1) stimulated hiPSC-CMs to describe associated RNA expression profiles. MicroRNA sequencing revealed over 250 known and 34 predicted novel miRNAs to be differentially expressed between ET-1 stimulated and unstimulated control hiPSC-CMs. Messenger RNA expression analysis identified 731 probe sets with significant differential expression. Computational target prediction on significant differentially expressed miRNAs and mRNAs identified nearly 2000 target pairs. A principal component analysis approach comparing the in vitro data with human myocardial biopsies detected overlapping expression changes between the in vitro samples and myocardial biopsies with Left Ventricular Hypertrophy. These results provide further insights into the complex RNA regulatory mechanism associated with cardiac hypertrophy.
    PLoS ONE 09/2014; 9(9):e108051. DOI:10.1371/journal.pone.0108051 · 3.23 Impact Factor
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    ABSTRACT: Purpose We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer. Patients and methods Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95 % for age or as body fat >30 %. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters. Results A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m2/h ± 14 % and 68.1 L/m2 ± 24 %, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m2/h ± 5.6 % and 232 L/m2 ± 10 %, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction. Conclusions We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.
    Cancer Chemotherapy and Pharmacology 08/2014; 74(4). DOI:10.1007/s00280-014-2535-4 · 2.57 Impact Factor
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    ABSTRACT: Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele.
    Pharmacogenomics 06/2014; 15(8):1065-78. DOI:10.2217/pgs.14.53 · 3.43 Impact Factor
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    ABSTRACT: Background The GIANT consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio adjusted for BMI (WHR). These loci are wide and narrowing the signals remains necessary.ResultsTwelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/AA analysis (log-Bayes factor>6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity.Conclusion By leveraging varying linkage disequilibrium structures across different populations, SNPs with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role.Methods Meta-analysis results for WHR were obtained from 77,167 EA participants from GIANT and 23,564 African Ancestry (AA) participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ±250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.
    Human Molecular Genetics 04/2014; DOI:10.1093/hmg/ddu183 · 6.68 Impact Factor
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    ABSTRACT: We aim to quantify HMG-CoA reductase inhibitor (statin) prescriber-intended exposure-time using a generalizable algorithm that interrogates data stored in the electronic health record (EHR). This study was conducted using the Marshfield Clinic (MC) Personalized Medicine Research Project (PMRP) a central Wisconsin-based population and biobank with, on average, 30 years of electronic health data available in the independently-developed MC Cattails MD EHR. Individuals with evidence of statin exposure were identified from the electronic records, and manual chart abstraction of all mentions of prescribed statins was completed. We then performed electronic chart abstraction of prescriber-intended exposure time for statins, using previously identified logic to capture pill-splitting events, normalizing dosages to atorvastatin-equivalent dose. Four models using iterative training sets were tested to capture statin end-dates. Calculated cumulative provider-intended exposures were compared to manually abstracted gold-standard measures of ordered statin prescriptions, and aggregate model results (totals) for training and validation populations were compared. The most successful model was the one with the smallest discordance between modeled and manually abstracted Atorvastatin 10mg/year Equivalents (AEs). Of the approximately 20,000 patients enrolled in the PMRP, 6,243 were identified with statin exposure during the study period (1997-2011), 59.8% of whom had been prescribed multiple statins over an average of approximately 11 years. When the best-fit algorithm was implemented and validated by manual chart review for the statin-ordered population, it was found to capture 95.9% of the correlation between calculated and expected statin provider-intended exposure time for a random validation set, and the best-fit model was able to predict intended statin exposure to within a standard deviation of 2.6 AEs, with a standard error of +0.23 AEs. We demonstrate that normalized provider-intended statin exposure time can be estimated using a combination of structured clinical data sources, including a medications ordering system and a clinical appointment coordination system, supplemented with text data from clinical notes.
    Journal of Biomedical Informatics 03/2014; 49. DOI:10.1016/j.jbi.2014.02.014 · 2.48 Impact Factor
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    ABSTRACT: Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children's Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1,559 patients have been enrolled, and four gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1,016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 03/2014; 166(1). DOI:10.1002/ajmg.c.31391 · 3.54 Impact Factor
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    ABSTRACT: BACKGROUND: Increased susceptibility to Crohn's disease (CD) is associated with mutations in several genes that have roles in the functioning of Paneth cells (PCs). PCs produce and secrete antimicrobial peptides and proteins, which are critical for host defense against pathogens and regulation of intestinal homeostasis, notably in regulating the composition of the small intestinal biota. We hypothesize that a significant subset of patients with CD carry susceptibility genes that cause PC dysfunction, resulting in decreased expression of PC antimicrobials, leading to intestinal dysbiosis. We tested this by evaluating a cohort of pediatric patients with CD and non-IBD controls, for genotype, PC gene expression, and microbiota composition.METHODS: We recruited patients <19 years age from Children's hospital of Wisconsin. We obtained clinical data for disease phenotyping. We genotyped subjects for known CD susceptibility gene mutations by Immunochip. Total RNA was isolated from biopsy tissue and analyzed by RTqPCR for levels of PC product gene expression, including defensins HD5 and HD6, lysozyme, sPLA2, and RegIIIgamma. We evaluated differences in PC gene expression among patients with CD and non-inflamed controls. We also characterized the ileal microbiota for bacterial composition and diversity using 16S rRNA gene sequence analysis to determine associations between PC antimicrobial expression and biome composition.RESULTS: We recruited a total of 70 CD patients and 192 non-IBD controls. Control patients skewed younger than disease cohorts. There was male preponderance in CD cohort. Immunochip analysis, subsequently validated by qPCR SNP typing, demonstrated statistically significant correlations between SNP mutations and CD, most notably with the NOD2 insertion mutant (SNP13) (P = 0.0001272). Microbiota analysis showed no significant differences in alpha diversity between control and CD, however there were notable differences in composition. Various sub species of Firmicutes, Actinobacteria and Bacterioidetesare all reduced in CD samples compared to Control. Veillonellaceae (Firmicutes), Alcaligenaceae, Enterobacteriaceae, and Pasteurellaceae (Proteobacteria) are all increased in CD samples. PCA analysis suggested that Lachnospira and Enterobacteria are the main determinants of variance, with a smaller contribution by Prevotella. The relative abundance of bacterial families was significantly different in CD patients compared to controls (Adonis analysis, P < 0.001). The abundance of Lachnospiraceae is consistently higher in controls than CD, while the abundance of Enterobacteriaceae is consistently lower in controls than in CD samples. Ileal samples from CD patients show significantly altered expression of HD6, PSP/REG, and Lysozyme, when compared to controls (Kruskal-Wallis Test).CONCLUSIONS: There are statistically significant correlations between SNP mutations and CD, most notably with the NOD2 insertion mutant (SNP13). The ileal microbiota composition of CD samples differs significantly from control samples. Expression of PC antimicrobial peptides is dysregulated in CD ileal samples compared to controls, with significantly altered expression of human defensin 6, PSP/REG and lysozyme, which may contribute to dysbiosis at the ileal surface. PC morphology and location are abnormal in CD ileal samples compared to controls, which may contribute to abnormalities in mRNA expression.(C) Crohn's & Colitis Foundation of America, Inc.
    Inflammatory Bowel Diseases 12/2013; 19:S119. DOI:10.1097/01.MIB.0000439034.18466.ae · 5.48 Impact Factor
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    ABSTRACT: Metabolic Syndrome (MetS)is a phenotype cluster predisposing to type 2 diabetes and cardiovascular diseases. In extended families of Northern European ancestry, we previously identified two significant QTLs 3q27 and 17p12 that werelinked with multiple representative traits of MetS. Todetermine the genetic basis of these linkage signals, QTL-specific genomic and transcriptomic analyses were performed in 1,137 individuals from 85 extended families that contributed to the original linkage.We tested in SOLAR association of MetS phenotypes with QTL-specific haplotype-tagging SNPs as well as transcriptional profiles of peripheral blood mononuclear cells (PBMCs). SNPs significantly associated with phenotypes under the prior hypothesis of linkage mapped to seven genes at 3q27 and seven at 17p12. Prioritization based on biologic relevance, SNP association, and expression analyses identified two genes: insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) at 3q27 and tumor necrosis factor receptor 13B (TNFRSF13B) at 17p12.Prioritized genescould influence cell-cell adhesion and adipocyte differentiation, insulin/glucose responsiveness, cytokine effectiveness and plasma lipids and lipoprotein densities. In summary, our results combine genomic, transcriptomic, and bioinformaticdata to identify novel candidate loci for MetS.
    Obesity 10/2013; 21(10). DOI:10.1002/oby.20324 · 4.39 Impact Factor
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    ABSTRACT: High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 x 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.
    The American Journal of Human Genetics 09/2013; 93(3-3):545-54. DOI:10.1016/j.ajhg.2013.07.010 · 10.99 Impact Factor
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    ABSTRACT: Active clinical decision support (CDS) delivered through an electronic health record (EHR) facilitates gene-based drug prescribing and other applications of genomics to patient care. We describe the development, implementation, and evaluation of active CDS for multiple pharmacogenetic test results reported preemptively. Clinical pharmacogenetic test results accompanied by clinical interpretations are placed into the patient's EHR, typically before a relevant drug is prescribed. Problem list entries created for high-risk phenotypes provide an unambiguous trigger for delivery of post-test alerts to clinicians when high-risk drugs are prescribed. In addition, pre-test alerts are issued if a very-high risk medication is prescribed (eg, a thiopurine), prior to the appropriate pharmacogenetic test result being entered into the EHR. Our CDS can be readily modified to incorporate new genes or high-risk drugs as they emerge. Through November 2012, 35 customized pharmacogenetic rules have been implemented, including rules for TPMT with azathioprine, thioguanine, and mercaptopurine, and for CYP2D6 with codeine, tramadol, amitriptyline, fluoxetine, and paroxetine. Between May 2011 and November 2012, the pre-test alerts were electronically issued 1106 times (76 for thiopurines and 1030 for drugs metabolized by CYP2D6), and the post-test alerts were issued 1552 times (1521 for TPMT and 31 for CYP2D6). Analysis of alert outcomes revealed that the interruptive CDS appropriately guided prescribing in 95% of patients for whom they were issued. Our experience illustrates the feasibility of developing computational systems that provide clinicians with actionable alerts for gene-based drug prescribing at the point of care.
    Journal of the American Medical Informatics Association 08/2013; 21(E1). DOI:10.1136/amiajnl-2013-001993 · 3.93 Impact Factor
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    ABSTRACT: Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10(-8); RREB1: p = 5.7×10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
    PLoS Genetics 08/2013; 9(8):e1003681. DOI:10.1371/journal.pgen.1003681 · 8.17 Impact Factor
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    ABSTRACT: Many lines of evidence demonstrate that genetic variability contributes to chronic kidney disease susceptibility in humans as well as rodent models. Little progress has been made in discovering causal kidney disease genes in humans mainly due to genetic complexity. Here, we use a minimal congenic mapping strategy in the FHH (Fawn Hooded Hypertensive) rat to identify Sorcs1 as a novel renal disease candidate gene. We investigated the hypothesis that genetic variation in Sorcs1 influences renal disease susceptibility in both rat and human. Sorcs1 is expressed in the kidney, and knocking out this gene in a rat strain with a sensitized genome background produced increased proteinuria. In vitro knockdown of Sorcs1 in proximal tubule cells impaired protein trafficking, suggesting a mechanism for the observed proteinuria in the FHH rat. Since Sorcs1 influences renal function in the rat, we went on to test this gene in humans. We identified associations between single nucleotide polymorphisms (SNPs) in SORCS1 and renal function in large cohorts of European and African ancestry. The experimental data from the rat combined with association results from different ethnic groups indicates a role for SORCS1 in maintaining proper renal function.
    Physiological Genomics 06/2013; DOI:10.1152/physiolgenomics.00089.2013 · 2.81 Impact Factor
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    ABSTRACT: Anophthalmia and microphthalmia (A/M) represent severe developmental ocular malformations. Currently, mutations in known genes explain less than 40% of A/M cases. We performed whole genome copy number variation analysis in sixty patients affected with isolated or syndromic A/M. Pathogenic deletions of 3q26 (SOX2) were identified in four independent patients with syndromic microphthalmia. Other variants of interest included regions with a known role in human disease (likely pathogenic) as well as novel rearrangements (uncertain significance). A 2.2-Mb duplication of 3q29 in a patient with nonsyndromic anophthalmia and an 877-kb duplication of 11p13 (PAX6) and a 1.4-Mb deletion of 17q11.2 (NF1) in two independent probands with syndromic microphthalmia and other ocular defects were identified; while ocular anomalies have been previously associated with 3q29 duplications, PAX6 duplications, and NF1 mutations in some cases, the ocular phenotypes observed here are more severe than previously reported. Three novel regions of possible interest included a 2q14.2 duplication which cosegregated with microphthalmia/microcornea and congenital cataracts in one family, and 2q21 and 15q26 duplications in two additional cases; each of these regions contains genes that are active during vertebrate ocular development. Overall, this study identified causative copy number mutations and regions with a possible role in ocular disease in 17% of A/M cases.
    Clinical Genetics 05/2013; 84(5). DOI:10.1111/cge.12202 · 3.65 Impact Factor
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    ABSTRACT: Background Metabolic syndrome (MetS) is an aberration associated with increased risk for cancer and inflammation. Adiponectin, an adipocyte-produced abundant protein hormone, has countering effect on the diabetogenic and atherogenic components of MetS. Plasma levels of adiponectin are negatively correlated with onset of cancer and cancer patient mortality. We previously performed microsatellite linkage analyses using adiponectin as a surrogate marker and revealed two QTLs on chr5 (5p14) and chr14 (14q13). Methods Using individuals from 85 extended families that contributed to the linkage and who were measured for 42 clinical and biologic MetS phenotypes, we tested QTL-based SNP associations, peripheral white blood cell (PWBC) gene expression, and the effects of cis-acting SNPs on gene expression to discover genomic elements that could affect the pathophysiology and complications of MetS. Results Adiponectin levels were found to be highly intercorrelated phenotypically with the majority of MetS traits. QTL-specific haplotype-tagging SNPs associated with MetS phenotypes were annotated to 14 genes whose function could influence MetS biology as well as oncogenesis or inflammation. These were mechanistically categorized into four groups: cell-cell adhesion and mobility, signal transduction, transcription and protein sorting. Four genes were highly prioritized: cadherin 18 (CDH18), myosin X (MYO10), anchor protein 6 of AMPK (AKAP6), and neuronal PAS domain protein 3 (NPAS3). PWBC expression was detectable only for the following genes with multi-organ or with multi-function properties: NPAS3, MARCH6, MYO10 and FBXL7. Strong evidence of cis-effects on the expression of MYO10 in PWBC was found with SNPs clustered near the gene’s transcription start site. MYO10 expression in PWBC was marginally correlated with body composition (p= 0.065) and adipokine levels in the periphery (p = 0.064). Variants of genes AKAP6, NPAS3, MARCH6 and FBXL7 have been previously reported to be associated with insulin resistance, inflammatory markers or adiposity studies using genome-wide approaches whereas associations of CDH18 and MYO10 with MetS traits have not been reported before. Conclusions Adiponectin QTLs-based SNP association and mRNA expression identified genes that could mediate the association between MetS and cancer or inflammation.
    BMC Medical Genomics 04/2013; 6(1):14. DOI:10.1186/1755-8794-6-14 · 3.91 Impact Factor

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3k Citations
812.94 Total Impact Points

Institutions

  • 2002–2015
    • Medical College of Wisconsin
      • • Department of Pediatrics
      • • Human and Molecular Genetics Center
      • • Division of Cardiovascular Medicine
      Milwaukee, Wisconsin, United States
  • 2005–2013
    • University of Wisconsin - Milwaukee
      Milwaukee, Wisconsin, United States
  • 2011
    • Children's Hospital of Wisconsin
      Madison, Wisconsin, United States
  • 2004
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2000
    • Loyola University Chicago
      Chicago, Illinois, United States
  • 1998–2000
    • University of Münster
      • Institute of Epidemiology and Social Medicine
      Münster, North Rhine-Westphalia, Germany
  • 1998–1999
    • Universität Regensburg
      • Department of Internal Medicine II
      Ratisbon, Bavaria, Germany