Publications by authors named "Margaux Keller"

27 Publications

  • Page 1 of 1

Preventing Postoperative Nausea and Vomiting During an Ondansetron Shortage.

AANA J 2021 Apr;89(2):161-167

is the executive director of the TriService Nursing Research Program, Bethesda, Maryland.

Postoperative nausea and vomiting (PONV) degrades patient experience and increases healthcare costs. Estimates of PONV range from 10% to 80%. The Apfel Simplified Score is an evidence-based instrument for determining individual risk of PONV. Scoring enables anesthesia providers to match antiemetic strategies with the calculated risk of PONV. Data were collected across 3 times. After the Apfel scoring system was automated into the electronic medical record, providers were more likely to increase PONV prophylaxis for patients at highest risk and reduce prophylaxis for patients at lowest risk. Rates of PONV remained similar at baseline (34.7%) and in the early postimplementation period (38.8%); a modest reduction was observed in the final period (26.5%). Intravenous ondansetron, the most common antiemetic at baseline, was not available in the early postimplementation period, which may partially explain the initial increase in PONV. While ondansetron was unavailable, providers began using 3 other antiemetics, a practice that persisted once intravenous ondansetron returned. The Apfel score is an evidence-based tool that providers can use to reduce the risk of PONV. This electronic tool and the reminder cards have been shared across the US Military Health System, fostering an organizational culture that values targeted prophylaxis for PONV.
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April 2021

Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium.

Hum Mol Genet 2017 06;26(11):2156-2163

Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA.

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P =1.27 × 10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.
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http://dx.doi.org/10.1093/hmg/ddx091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075215PMC
June 2017

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.

Am J Hum Genet 2017 Jan 22;100(1):51-63. Epub 2016 Dec 22.

Icahn Institute for Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.
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http://dx.doi.org/10.1016/j.ajhg.2016.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223059PMC
January 2017

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

Am J Hum Genet 2016 Jul 16;99(1):56-75. Epub 2016 Jun 16.

Division of General Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
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http://dx.doi.org/10.1016/j.ajhg.2016.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005440PMC
July 2016

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Nat Genet 2015 Nov 28;47(11):1294-1303. Epub 2015 Sep 28.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
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http://dx.doi.org/10.1038/ng.3412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661791PMC
November 2015

Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.

Am J Clin Nutr 2015 Nov 9;102(5):1266-78. Epub 2015 Sep 9.

Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland;

Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

Conclusion: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
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http://dx.doi.org/10.3945/ajcn.114.101238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625584PMC
November 2015

Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study.

Lancet Neurol 2015 Oct 10;14(10):1002-9. Epub 2015 Aug 10.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Background: Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts.

Methods: We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD).

Findings: In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900-0·946) with high sensitivity (0·834, 95% CI 0·711-0·883) and specificity (0·903, 95% CI 0·824-0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867-0·921) in the PDBP cohort, 0·998 (0·992-1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896-0·962) in LABS-PD, and 0·939 (0·891-0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003).

Interpretation: Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions.

Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.
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http://dx.doi.org/10.1016/S1474-4422(15)00178-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575273PMC
October 2015

Baseline genetic associations in the Parkinson's Progression Markers Initiative (PPMI).

Mov Disord 2016 Jan 13;31(1):79-85. Epub 2015 Aug 13.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Background: The Parkinson's Progression Marker Initiative is an international multicenter study whose main goal is investigating markers for Parkinson's disease (PD) progression as part of a path to a treatment for the disease. This manuscript describes the baseline genetic architecture of this study, providing not only a catalog of disease-linked variants and mutations, but also quantitative measures with which to adjust for population structure.

Methods: Three hundred eighty-three newly diagnosed typical PD cases, 65 atypical PD and 178 healthy controls, from the Parkinson's Progression Marker Initiative study have been genotyped on the NeuroX or Immunochip arrays. These data are freely available to all researchers interested in pursuing PD research within the Parkinson's Progression Marker Initiative.

Results: The Parkinson's Progression Marker Initiative represents a study population with low genetic heterogeneity. We recapitulate known PD associations from large-scale genome-wide association studies and refine genetic risk score models for PD predictability (area under the curve, ∼0.74). We show the presence of six LRRK2 p.G2019S and nine GBA p.N370S mutation carriers.

Conclusions: The Parkinson's Progression Marker Initiative study and its genetic data are useful in studies of PD biomarkers. The genetic architecture described here will be useful in the analysis of myriad biological and clinical traits within this study.
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http://dx.doi.org/10.1002/mds.26374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724309PMC
January 2016

Genetic risk and age in Parkinson's disease: Continuum not stratum.

Mov Disord 2015 May 17;30(6):850-4. Epub 2015 Mar 17.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Background: Recent genomewide association study meta-analyses have identified 28 loci associated with risk of Parkinson's disease (PD). We sought to investigate whether these genetic risk factors are associated with PD age at onset.

Methods: Genetic risk scores from these loci were calculated for 6,249 cases. Linear regression tested associations between cumulative genetic risk and PD age at onset.

Results: Increasing genetic risk scores were associated with earlier age at onset (beta = -0.10, P = 2.92 × 10(-8) , adjusted r(2)  = 0.27). Single standard deviation increase in genetic risk score is associated with 37.44 d earlier age at onset. Highest genetic risk was found at 31 to 60 y, onset slightly below average age at onset (AAO).

Conclusions: Common genetic risk factors have a small but consistent association with AAO in PD.
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http://dx.doi.org/10.1002/mds.26192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217457PMC
May 2015

NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases.

Neurobiol Aging 2015 Mar 4;36(3):1605.e7-12. Epub 2014 Aug 4.

Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317375PMC
March 2015

Trans-ethnic meta-analysis of white blood cell phenotypes.

Hum Mol Genet 2014 Dec 5;23(25):6944-60. Epub 2014 Aug 5.

Department of Epidemiology Department of Medicine, Brown University, Providence, RI, USA.

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.
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http://dx.doi.org/10.1093/hmg/ddu401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245044PMC
December 2014

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.

Nat Genet 2014 Sep 27;46(9):989-93. Epub 2014 Jul 27.

The Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA.

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
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http://dx.doi.org/10.1038/ng.3043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146673PMC
September 2014

Genome-wide analysis of the heritability of amyotrophic lateral sclerosis.

JAMA Neurol 2014 Sep;71(9):1123-34

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.

Importance: Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.

Objective: To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.

Design, Setting, And Participants: We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.

Main Outcomes And Measures: A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.

Results: With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.

Conclusions And Relevance: We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.
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http://dx.doi.org/10.1001/jamaneurol.2014.1184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566960PMC
September 2014

Assessment of Parkinson's disease risk loci in Greece.

Neurobiol Aging 2014 Feb 27;35(2):442.e9-442.e16. Epub 2013 Sep 27.

Reta Lila Weston Laboratories and Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.

Genome-wide association studies (GWAS) have been shown to be a powerful approach to identify risk loci for neurodegenerative diseases. Recent GWAS in Parkinson's disease (PD) have been successful in identifying numerous risk variants pointing to novel pathways potentially implicated in the pathogenesis of PD. Contributing to these GWAS efforts, we performed genotyping of previously identified risk alleles in PD patients and control subjects from Greece. We showed that previously published risk profiles for Northern European and American populations are also applicable to the Greek population. In addition, although our study was largely underpowered to detect individual associations, we replicated 5 of 32 previously published risk variants with nominal p values <0.05. Genome-wide complex trait analysis revealed that known risk loci explain disease risk in 1.27% of Greek PD patients. Collectively, these results indicate that there is likely a substantial genetic component to PD in Greece, similarly to other worldwide populations, that remains to be discovered.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830580PMC
February 2014

Genetic comorbidities in Parkinson's disease.

Hum Mol Genet 2014 Feb 20;23(3):831-41. Epub 2013 Sep 20.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.
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http://dx.doi.org/10.1093/hmg/ddt465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888265PMC
February 2014

Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

Am J Hum Genet 2013 Sep 22;93(3):545-54. Epub 2013 Aug 22.

Department of Epidemiology, University of North Carolina at Chapel Hill, NC 27599, USA.

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 × 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.
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http://dx.doi.org/10.1016/j.ajhg.2013.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769920PMC
September 2013

Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.

JAMA Neurol 2013 Oct;70(10):1268-76

Importance: Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders.

Objective: To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD.

Design: Combined GWA analysis.

Setting: Data sets from the United Kingdom, Germany, France, and the United States.

Participants: Thousands of patients with AD or PD and their controls.

Main Outcomes And Measures: Meta-analysis of GWA studies of AD and PD.

Methods: To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD.

Results: Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD.

Conclusions And Relevance: Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.
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http://dx.doi.org/10.1001/jamaneurol.2013.448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978422PMC
October 2013

Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.

PLoS Med 2013 4;10(6):e1001462. Epub 2013 Jun 4.

Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy.

Background: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.

Methods And Findings: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron.

Conclusions: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
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http://dx.doi.org/10.1371/journal.pmed.1001462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672214PMC
March 2014

A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies.

JAMA Neurol 2013 Jun;70(6):727-35

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Importance: While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.

Objective: To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.

Setting: Eleven centers from sites around the world performing genotyping.

Participants: Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.

Main Outcome Measures: Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores.

Conclusions And Relevance: Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
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http://dx.doi.org/10.1001/jamaneurol.2013.1925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841974PMC
June 2013

Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network.

Hum Mol Genet 2013 Jun 26;22(12):2529-38. Epub 2013 Feb 26.

Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA.

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.
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http://dx.doi.org/10.1093/hmg/ddt087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658166PMC
June 2013

Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.

Am J Hum Genet 2013 Jan 13;92(1):5-14. Epub 2012 Dec 13.

Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.

Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.
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http://dx.doi.org/10.1016/j.ajhg.2012.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542456PMC
January 2013

Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.

PLoS One 2012 7;7(12):e50198. Epub 2012 Dec 7.

Department of Genetics, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA.

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050198PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517599PMC
May 2013

Candidate gene association study of BMI-related loci, weight, and adiposity in old age.

J Gerontol A Biol Sci Med Sci 2013 Jun 16;68(6):661-6. Epub 2012 Nov 16.

Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD 20892, USA.

Most genome-wide association studies are confined to middle-aged populations. It is unclear whether associations between single nucleotide polymorphisms (SNPs) and obesity persist in old age. We aimed to relate 10 body mass index (BMI)-associated SNPs to weight, BMI, % fat, visceral and subcutaneous adipose tissue in Health ABC and AGES-Reykjavik comprising 4,846 individuals of European Ancestry, and 1,139 African Americans over age 65. SNPs were scaled using effect estimates from candidate SNPs. In Health ABC, a SNP near GNPDA2 was modestly associated with weight and SAT area (p = .008, p = .001). Risk score (sum of scaled SNPs) was associated with weight, BMI, and SAT area (p < .0001 for all), but neither GNPDA2 nor risk score was associated with weight, BMI, visceral adippose tissue, subcutaneous adipose tissue, or % fat in AGES-Reykjavik. In African Americans, a SNP near SEC16B was weakly associated with weight (p = .04). In this sample of older adults, no BMI-associated SNPs were associated with weight or adiposity.
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http://dx.doi.org/10.1093/gerona/gls227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660116PMC
June 2013

Genome wide assessment of young onset Parkinson's disease from Finland.

PLoS One 2012 24;7(7):e41859. Epub 2012 Jul 24.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.

In the current study we undertook a series of experiments to test the hypothesis that a monogenic cause of disease may be detectable within a cohort of Finnish young onset Parkinson's disease patients. In the first instance we performed standard genome wide association analyses, and subsequent risk profile analysis. In addition we performed a series of analyses that involved testing measures of global relatedness within the cases compared to controls, searching for excess homozygosity in the cases, and examining the cases for signs of excess local genomic relatedness using a sliding window approach. This work suggested that the previously identified common, low risk alleles, and the risk models associated with these alleles, were generalizable to the Finnish Parkinson's disease population. However, we found no evidence that would suggest a single common high penetrance mutation exists in this cohort of young onset patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041859PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404082PMC
February 2013

Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease.

Hum Mol Genet 2012 Nov 13;21(22):4996-5009. Epub 2012 Aug 13.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
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http://dx.doi.org/10.1093/hmg/dds335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576713PMC
November 2012

Use of support vector machines for disease risk prediction in genome-wide association studies: concerns and opportunities.

Hum Mutat 2012 Dec 3;33(12):1708-18. Epub 2012 Aug 3.

Center for Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tübingen, Germany.

The success of genome-wide association studies (GWAS) in deciphering the genetic architecture of complex diseases has fueled the expectations whether the individual risk can also be quantified based on the genetic architecture. So far, disease risk prediction based on top-validated single-nucleotide polymorphisms (SNPs) showed little predictive value. Here, we applied a support vector machine (SVM) to Parkinson disease (PD) and type 1 diabetes (T1D), to show that apart from magnitude of effect size of risk variants, heritability of the disease also plays an important role in disease risk prediction. Furthermore, we performed a simulation study to show the role of uncommon (frequency 1-5%) as well as rare variants (frequency <1%) in disease etiology of complex diseases. Using a cross-validation model, we were able to achieve predictions with an area under the receiver operating characteristic curve (AUC) of ~0.88 for T1D, highlighting the strong heritable component (∼90%). This is in contrast to PD, where we were unable to achieve a satisfactory prediction (AUC ~0.56; heritability ~38%). Our simulations showed that simultaneous inclusion of uncommon and rare variants in GWAS would eventually lead to feasible disease risk prediction for complex diseases such as PD. The used software is available at http://www.ra.cs.uni-tuebingen.de/software/MACLEAPS/.
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http://dx.doi.org/10.1002/humu.22161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968822PMC
December 2012

Large C9orf72 repeat expansions are not a common cause of Parkinson's disease.

Neurobiol Aging 2012 Oct 20;33(10):2527.e1-2. Epub 2012 Jun 20.

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

The concept of a pathological overlap between neurodegenerative disorders is gaining momentum. We sought to determine the contribution of C9orf72 repeat expansions, recently discovered as a cause of frontotemporal dementia and amyotrophic lateral sclerosis, in a large number of Parkinson's disease patients. No large expansions were identified in our cohort.
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http://dx.doi.org/10.1016/j.neurobiolaging.2012.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545506PMC
October 2012