Daniel Mirel

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States

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Publications (153)

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    Full-text Dataset · Mar 2015
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    [Show abstract] [Hide abstract] ABSTRACT: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    Full-text Article · Mar 2015 · The American Journal of Human Genetics
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    [Show abstract] [Hide abstract] ABSTRACT: ContextIt is important to identify the patients at highest risk of fractures. A recent large-scale meta-analysis identified 63 autosomal SNPs associated with bone mineral density (BMD), of which 16 were also associated with fracture risk. Based on these findings two genetic risk scores (GRS63 and GRS16) were developed.Objective To determine the clinical usefulness of these GRS for the prediction of BMD, BMD change and fracture risk in elderly subjects.Design, Settings and ParticipantsTwo male (MrOS US, MrOS Sweden) and one female (SOF) large prospective cohorts of older subjects.Main Outcome MeasuresBMD, BMD change and radiographically and/or medically confirmed incident fractures (8,067 subjects, 2,185 incident non-vertebral or vertebral fractures).ResultsGRS63 was associated with BMD (≅3% of the variation explained), but not with BMD change.Both GRS63 and GRS16 were associated with fractures. After BMD-adjustment, the effect sizes for these associations were substantially reduced.Similar results were found using an unweighted GRS63 and an unweighted GRS16 compared to those found using the corresponding weighted risk scores.Only minor improvements in C-statistics (AUC) for fractures were seen when the GRSs were added to a base model (age, weight and height) and no significant improvements in C-statistics were seen when they were added to a model further adjusted for BMD. Net reclassification improvements with the addition of the GRSs to a base model were modest and substantially attenuated in BMD-adjusted models.Conclusions and RelevanceGRS63 is associated with BMD, but not BMD change, suggesting that the genetic determinants of BMD differ from those of BMD change. When BMD is known, the clinical utility of the two GRSs for fracture prediction is limited in elderly subjects. © 2014 American Society for Bone and Mineral Research
    Full-text Article · Jan 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    D R Crosslin · D S Carrell · A Burt · [...] · G P Jarvik
    [Show abstract] [Hide abstract] ABSTRACT: Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22 981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.Genes and Immunity advance online publication, 9 October 2014; doi:10.1038/gene.2014.51.
    Full-text Article · Oct 2014 · Genes and immunity
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    [Show abstract] [Hide abstract] ABSTRACT: Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
    Full-text Article · Feb 2014 · PLoS ONE
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    Full-text Dataset · Dec 2013
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    Full-text Dataset · Dec 2013
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    [Show abstract] [Hide abstract] ABSTRACT: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
    Full-text Article · Dec 2013 · Nature
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    Full-text Dataset · Dec 2013
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    Full-text Dataset · Dec 2013
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    Full-text Dataset · Dec 2013
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    Full-text Dataset · Dec 2013
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    Full-text Dataset · Dec 2013
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    Full-text Dataset · Dec 2013
  • Article · Aug 2013 · Cancer Research
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    [Show abstract] [Hide abstract] ABSTRACT: Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.
    Full-text Article · Jul 2013 · Diabetes
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    Dataset: Figure S2
    [Show abstract] [Hide abstract] ABSTRACT: Bias in point estimates of odds ratio for various φ and γca with k = .01, R = 4, m = .3, RRAA = 3 and a multiplicative disease risk model. (EPS)
    Full-text Dataset · Jun 2013
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    [Show abstract] [Hide abstract] ABSTRACT: The feasibility of using imperfectly phenotyped "silver standard" samples identified from electronic medical record diagnoses is considered in genetic association studies when these samples might be combined with an existing set of samples phenotyped with a gold standard technique. An analytic expression is derived for the power of a chi-square test of independence using either research-quality case/control samples alone, or augmented with silver standard data. The subset of the parameter space where inclusion of silver standard samples increases statistical power is identified. A case study of dementia subjects identified from electronic medical records from the Electronic Medical Records and Genomics (eMERGE) network, combined with subjects from two studies specifically targeting dementia, verifies these results.
    Full-text Article · Jun 2013 · PLoS ONE
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    Dataset: Figure S1
    [Show abstract] [Hide abstract] ABSTRACT: P-values from null models in simulation are approximately uniformly distributed. (EPS)
    Full-text Dataset · Jun 2013
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    Dataset: Document S1
    [Show abstract] [Hide abstract] ABSTRACT: ICD-9 Codes and Medications defining silver standard cases from EMR. (XLS)
    Full-text Dataset · Jun 2013

Publication Stats

6k Citations

Institutions

  • 2009
    • Broad Institute of MIT and Harvard
      • Program in Medical and Population Genetics
      Cambridge, Massachusetts, United States
  • 2007
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2002
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 2001
    • Stanford University
      Stanford, California, United States