Jeffrey M Friedman

The Rockefeller University, New York, New York, United States

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Publications (106)1309.02 Total impact

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    ABSTRACT: Leptin gene expression is highly correlated with cellular lipid content in adipocytes but the transcriptional mechanisms controlling leptin expression in vivo are poorly understood. In this report, we set out to identify cis- and trans-regulatory elements controlling leptin expression.
  • Jeffrey M Friedman, Christos S Mantzoros
    Metabolism: clinical and experimental 01/2015; 64(1):1-4. DOI:10.1016/j.metabol.2014.10.023 · 3.61 Impact Factor
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    ABSTRACT: Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP-transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics.
    Nature Medicine 12/2014; DOI:10.1038/nm.3730 · 28.05 Impact Factor
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    ABSTRACT: eLife digest To multiply and grow, cells need to create more of the molecules—such as proteins—that make up their structure. This only happens if the cell has a good supply of the nutrients used to build the proteins. Red blood cells are particularly sensitive to the supply of nutrients, especially iron, which is a key component of the hemoglobin molecules that enable the cells to transport oxygen around the body. A lack of iron can lead to a shortage of red blood cells and a condition called anemia. People with mild forms of anemia may feel tired or weak, but more severe forms of anemia can cause heart problems and even death. A protein called mTOR forms part of a protein complex that helps alert the cells of many different organisms to the presence of nutrients. mTOR can add phosphate groups to ribosomes—the molecular machines that translate molecules of mRNA to build proteins. In 2012, researchers developed a technique called Phospho-Trap that can isolate these phosphorylated ribosomes from cells. Cells with an activated mTOR complex express more mTOR protein and in turn have more ribosomes that are modified. Examining the mRNA molecules associated with these ribosomes can reveal which proteins are produced in greater amounts in these cells. Previous experiments using Phospho-Trap found the proteins that make up hemoglobin in unexpectedly high amounts in the mouse brain. Now, Knight et al.—and other researchers involved in the 2012 work—have established that the hemoglobin was not coming from the brain cells but from immature red blood cells circulating within the brain. These immature blood cells were found to have a highly active mTOR complex that promotes the production of hemoglobin and new blood cells. Using genetic techniques in mice, Knight et al. found that the mTOR complex can cause anemia if it is underactive or overactive. Underactive mTOR complexes cause a type of anemia that produces small red blood cells and is usually triggered by a lack of iron. This made sense because mTOR is known to regulate both protein production and cell size. Boosting the activity of the mTOR complex leads to a type of anemia in which the cells are much larger than normal, and which is normally associated with inadequate amounts of folate and B12 vitamins. When Knight et al. gave mice a drug that inhibits the mTOR protein, the mice developed anemia that resolved when the treatment stopped. However, mice that were given the mTOR inhibitor at the same time as a drug that destroys red blood cells, all died within days. Clinical trials are currently testing mTOR inhibitors as a possible cancer treatment; however, a common side effect of chemotherapy is that it stops new red blood cells being produced. Knight et al. suggest that the red blood cells of patients in these clinical trials must be closely monitored before deciding whether to continue the treatment further. DOI: http://dx.doi.org/10.7554/eLife.01913.002
    eLife Sciences 09/2014; 3:e01913. DOI:10.7554/eLife.01913 · 8.52 Impact Factor
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    Keith Tan, Zachary A. Knight, Jeffrey M. Friedman
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    ABSTRACT: While the SCN controls the circadian clock, further evidence suggests the existence of a food-entrainable oscillator (FEO) that links behavior to changes in food availability such as during restricted feeding (RF). We found that the activity of AgRP/NPY neurons changed rhythmically during RF suggesting that these neurons are a component of the FEO. We next ablated AgRP/NPY neurons in neonates with diphtheria toxin resulting in the loss of ∼ 50% of AgRP/NPY neurons. Body weight and food intake were unchanged in adult animals after neonatal ablation, as were the responses to leptin treatment, leptin withdrawal, food deprivation and ghrelin treatment. However, ablated animals showed 30% mortality within 4 days of RF. Moreover, the recovery of body weight and food intake in surviving animals lagged behind controls with an absence of food anticipatory activity even after three days. These findings identify AgRP/NPY neurons as a key cellular component of the food-entrained oscillator.
    07/2014; 3(7). DOI:10.1016/j.molmet.2014.07.002
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    ABSTRACT: The complexity and cellular heterogeneity of neural circuitry presents a major challenge to understanding the role of discrete neural populations in controlling behavior. While neuroanatomical methods enable high-resolution mapping of neural circuitry, these approaches do not allow systematic molecular profiling of neurons based on their connectivity. Here, we report the development of an approach for molecularly profiling projective neurons. We show that ribosomes can be tagged with a camelid nanobody raised against GFP and that this system can be engineered to selectively capture translating mRNAs from neurons retrogradely labeled with GFP. Using this system, we profiled neurons projecting to the nucleus accumbens. We then used an AAV to selectively profile midbrain dopamine neurons projecting to the nucleus accumbens. By comparing the captured mRNAs from each experiment, we identified a number of markers specific to VTA dopaminergic projection neurons. The current method provides a means for profiling neurons based on their projections.
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    ABSTRACT: eLife digest Sales of full-sugar fizzy drinks are almost triple those of diet versions, providing real-world confirmation of the laboratory finding that humans, as well as animals, prefer sugar to artificial sweeteners. However, it is not simply that sugary things taste better. Mice with a mutation that prevents them from perceiving sweet tastes still prefer the natural sugar sucrose over the artificial sweetener sucralose. This is because sugar, unlike artificial sweeteners, has nutritional value, and both humans and animals find it rewarding to consume foods with a high caloric content. Consuming sugar has been known to cause certain parts of the brain to release more of the chemical transmitter dopamine, which is used to signal reward, but exactly how this process produces a preference for sugar has been unclear. Now, Domingos et al. have revealed that a brain region called the lateral hypothalamus is responsible for this effect. This region of the brain—which helps to control appetite and which is also connected to the brain’s reward system—normally contains cells called MCH neurons. Domingos et al. show that the natural preference for sucrose over sucralose can be reversed by stimulating the MCH neurons with light, which in turn stimulates dopamine release in reward centers in the brain. Moreover, mutant mice that do not have any MCH neurons in the lateral hypothalamus show a reduced preference for sucrose over sucralose, compared to normal mice, and they release less dopamine than normal mice when they consume sucrose. By demonstrating that MCH neurons are both necessary and sufficient for sensing the nutritional value of sugar, these results provide new insights into the biological basis of sugar cravings. However, given the health implications of excessive sugar consumption, they may ultimately be used to find ways to make sugar less desirable, or to make artificial sweeteners more closely mimic the real thing. DOI: http://dx.doi.org/10.7554/eLife.01462.002
    eLife Sciences 12/2013; 2:e01462. DOI:10.7554/eLife.01462 · 8.52 Impact Factor
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    ABSTRACT: Leptin-deficient patients report higher “liking” ratings for food, and leptin replacement therapy normalizes these ratings even before weight loss is achieved. Since animals cannot report their ratings, we studied the relationship between leptin and food reward in leptin-deficient ob/ob mice using a optogenetic assay that quantifies the reward value of sucrose. In this assay, mice chose between one sipper dispensing the artificial sweetener sucralose coupled to optogenetic activation of dopaminergic (DA) neurons, and another sipper dispensing sucrose. We found that the reward value of sucrose was high under a state of leptin deficiency, as well as at a dose of leptin that does not suppress food intake (12.5 ng/h). Treatment with higher doses of leptin decreased the reward value of sucrose before weight loss was achieved (100 ng/h), as seen in leptin-deficient patients. These results phenocopy in mice the behavior of leptin-deficient patients.
    12/2013; 3(1). DOI:10.1016/j.molmet.2013.10.007
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    ABSTRACT: Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context-detecting function of the brain's mesolimbic circuit.
    Nature Neuroscience 11/2013; DOI:10.1038/nn.3591 · 14.98 Impact Factor
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    ABSTRACT: WNIN/Obese (WNIN/Ob) rat a new mutant model of metabolic syndrome was identified in 1996 from an inbred Wistar rat strain, WNIN. So far several papers are published on this model highlighting its physical, biochemical and metabolic traits. WNIN/Ob is leptin resistant with unaltered leptin or its receptor coding sequences - the two well-known candidate genes for obesity. Genotyping analysis of F2 progeny (raised from WNIN/Ob × Fisher - 344) in the present study localized the mutation to a recombinant region of 14.15cM on chromosome 5. This was further corroborated by QTL analysis for body weight, which narrowed this region to 4.43 cM with flanking markers D5Rat256 & D5Wox37. Interval mapping of body weight QTL shows that the LOD score peak maps upstream of leptin receptor and shows an additive effect suggesting this as a novel mutation and signifying the model as a valuable resource for studies on obesity and metabolic syndrome.
    PLoS ONE 10/2013; 8(10):e77679. DOI:10.1371/journal.pone.0077679 · 3.53 Impact Factor
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    ABSTRACT: Obesity and diabetes are particularly high in indigenous populations exposed to a Western diet and lifestyle. We describe the prevalence of obesity, diabetes, hyperglycemia, dyslipidemia, and hypertension in one such population, the Micronesian island of Kosrae. Longitudinal screenings for metabolic traits were conducted on adult Kosraens ò 20 years of age in 1994 and again in 2001. Data was obtained on 3,106 Kosraens, comprising ˜80% of the adult population. Diabetes was diagnosed using World Health Organization guidelines. Prevalences of obesity, hyperglycemia, dyslipidemia, and hypertension were assessed. The overall age-adjusted prevalence of diabetes increased from 14% to 21%. The most significant change observed in the population was increases in obesity and hyperglycemia, especially among young Kosraens and women. Obesity age-adjusted prevalence increased from 45% to 62%, and hyperglycemia age-adjusted prevalence increased from 19% to 44%. Of note, Kosraens as a group had unusually low high density lipoprotein (HDL) levels with 80% classified as low HDL by NCEP-ATPIII criteria, despite lacking the usually accompanying increase in triglycerides. Comparison to reports from other populations shows that Kosrae experiences one of the highest rates of obesity, hyperglycemia, and low HDL globally while maintaining relatively healthy levels of triglycerides. Our study shows a dramatic increase in obesity and hyperglycemia in Kosrae in just 7 years and forebodes significantly increased health risks for this part of the world.
    Obesity 04/2013; 21(9). DOI:10.1002/oby.20041 · 4.39 Impact Factor
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    Zhiying Li, Sarah F Schmidt, Jeffrey M Friedman
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    ABSTRACT: Treatment of ob/ob mice with a Cannabinoid receptor 1 (Cnr1) antagonist reduces food intake suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knock-out ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced insulin-like growth factor 1 levels without alterations of growth hormone levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist which had no effect on glucose metabolism suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also show similar leptin senstivity as ob/ob mice suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data further suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-1 axis and improve β bell function and glucose homeostasis in the setting of leptin deficiency.
    Diabetes 02/2013; 62(7). DOI:10.2337/db12-0901 · 8.47 Impact Factor
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    ABSTRACT: Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence-in real time-linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.
    Nature 12/2012; 493(7433). DOI:10.1038/nature11713 · 42.35 Impact Factor
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    ABSTRACT: The mammalian brain is composed of thousands of interacting neural cell types. Systematic approaches to establish the molecular identity of functional populations of neurons would advance our understanding of neural mechanisms controlling behavior. Here, we show that ribosomal protein S6, a structural component of the ribosome, becomes phosphorylated in neurons activated by a wide range of stimuli. We show that these phosphorylated ribosomes can be captured from mouse brain homogenates, thereby enriching directly for the mRNAs expressed in discrete subpopulations of activated cells. We use this approach to identify neurons in the hypothalamus regulated by changes in salt balance or food availability. We show that galanin neurons are activated by fasting and that prodynorphin neurons restrain food intake during scheduled feeding. These studies identify elements of the neural circuit that controls food intake and illustrate how the activity-dependent capture of cell-type-specific transcripts can elucidate the functional organization of a complex tissue.
    Cell 11/2012; 151(5):1126-37. DOI:10.1016/j.cell.2012.10.039 · 33.12 Impact Factor
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    Jeffrey M Friedman
    BMC proceedings 06/2012; 6(3). DOI:10.1186/1753-6561-6-S3-O6
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    ABSTRACT: Medical applications of nanotechnology typically focus on drug delivery and biosensors. Here, we combine nanotechnology and bioengineering to demonstrate that nanoparticles can be used to remotely regulate protein production in vivo. We decorated a modified temperature-sensitive channel, TRPV1, with antibody-coated iron oxide nanoparticles that are heated in a low-frequency magnetic field. When local temperature rises, TRPV1 gates calcium to stimulate synthesis and release of bioengineered insulin driven by a Ca(2+)-sensitive promoter. Studying tumor xenografts expressing the bioengineered insulin gene, we show that exposure to radio waves stimulates insulin release from the tumors and lowers blood glucose in mice. We further show that cells can be engineered to synthesize genetically encoded ferritin nanoparticles and inducibly release insulin. These approaches provide a platform for using nanotechnology to activate cells.
    Science 05/2012; 336(6081):604-8. DOI:10.1126/science.1216753 · 31.48 Impact Factor
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    ABSTRACT: Obesity is characterized by an expansion of white adipose tissue mass that results from an increase in the size and the number of adipocytes. However, the mechanisms responsible for the formation of adipocytes during development and the molecular mechanisms regulating their increase and maintenance in adulthood are poorly understood. Here, we report the use of leptin-luciferase BAC transgenic mice to track white adipose tissue (WAT) development and guide the isolation and molecular characterization of adipocytes during development using DNA microarrays. These data reveal distinct transcriptional programs that are regulated during murine WAT development in vivo. By using a de novo cis-regulatory motif discovery tool (FIRE), we identify two early gene clusters whose promoters show significant enrichment for NRF2/ETS transcription factor binding sites. We further demonstrate that Ets transcription factors, but not Nrf2, are regulated during early adipogenesis and that Ets2 is essential for the normal progression of the adipocyte differentiation program in vitro. These data identify ETS2 as a functionally important transcription factor in adipogenesis and its possible role in regulating adipose tissue mass in adults can now be tested. Our approach also provides the basis for elucidating the function of other gene networks during WAT development in vivo. Finally these data confirm that although gene expression during adipogenesis in vitro recapitulates many of the patterns of gene expression in vivo, there are additional developmental transitions in pre and post-natal adipose tissue that are not evident in cell culture systems.
    Development 11/2011; 138(21):4709-19. DOI:10.1242/dev.067710 · 6.27 Impact Factor
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    ABSTRACT: Obese, leptin deficient obob mice have profoundly decreased activity and increased food seeking behavior. The decreased activity has been attributed to obesity. In mice, we tested the hypothesis that leptin increases total locomotor activity but inhibits food anticipatory activity. We also sought to determine if leptin induced increases in total locomotor activity are independent of changes in body weight and obesity. We studied obob mice and also created a novel transgenic mouse where leptin is over-expressed in a tetracycline-off system and can be abruptly and non-invasively suppressed by doxycycline within few hours. The studies were performed using two independent behavioral assays: home cage activity (HCA) and running wheel activity (RWA). Systemic administration of leptin (150 ng/hr) to obob mice produced a 122%±30% (mean ± SEM) increase (p≤0.01) in locomotor activity within 2 days In addition, cerebroventricular administration of leptin (5 ng/hr) also produced an early and progressive increase in total locomotor activity beginning on the 1st day (+28±8%; p≤0.05) and increasing to +69±23% on day 3 without a decrease in body weight during this time. The increase in activity was restricted to the dark phase. Conversely, in a tet-off transgenic obob mouse line, acute leptin suppression reduced spontaneous locomotor activity. To further define activities that are leptin regulated, we assayed food anticipatory activity (FAA) and found that it was markedly augmented in obob mice compared to wild type mice (+38±6.7 in obob vs +20±6.3% in wild type at peak; mean ± SEM; p≤0.001) and abolished by leptin. Although melanocortin-3 receptors (MC3R) reportedly mediate FAA, we found augmented FAA and preserved inhibitory effects of leptin on FAA in MC3R-/-obob mice. In summary, this study demonstrates that total activity and FAA are regulated independently by leptin. Leptin, acting in the central nervous system and at physiologic levels, produces early increases in locomotor activity before substantial weight loss. In contrast, leptin suppresses augmented food anticipatory activity in obob mice.
    PLoS ONE 08/2011; 6(8):e23364. DOI:10.1371/journal.pone.0023364 · 3.53 Impact Factor
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    ABSTRACT: Rare variants affecting phenotype pose a unique challenge for human genetics. Although genome-wide association studies have successfully detected many common causal variants, they are underpowered in identifying disease variants that are too rare or population-specific to be imputed from a general reference panel and thus are poorly represented on commercial SNP arrays. We set out to overcome these challenges and detect association between disease and rare alleles using SNP arrays by relying on long stretches of genomic sharing that are identical by descent. We have developed an algorithm, DASH, which builds upon pairwise identical-by-descent shared segments to infer clusters of individuals likely to be sharing a single haplotype. DASH constructs a graph with nodes representing individuals and links on the basis of such segments spanning a locus and uses an iterative minimum cut algorithm to identify densely connected components. We have applied DASH to simulated data and diverse GWAS data sets by constructing haplotype clusters and testing them for association. In simulations we show this approach to be significantly more powerful than single-marker testing in an isolated population that is from Kosrae, Federated States of Micronesia and has abundant IBD, and we provide orthogonal information for rare, recent variants in the outbred Wellcome Trust Case-Control Consortium (WTCCC) data. In both cohorts, we identified a number of haplotype associations, five such loci in the WTCCC data and ten in the isolated, that were conditionally significant beyond any individual nearby markers. We have replicated one of these loci in an independent European cohort and identified putative structural changes in low-pass whole-genome sequence of the cluster carriers.
    The American Journal of Human Genetics 06/2011; 88(6):706-17. DOI:10.1016/j.ajhg.2011.04.023 · 10.99 Impact Factor
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    ABSTRACT: The potential benefits of using population isolates in genetic mapping, such as reduced genetic, phenotypic and environmental heterogeneity, are offset by the challenges posed by the large amounts of direct and cryptic relatedness in these populations confounding basic assumptions of independence. We have evaluated four representative specialized methods for association testing in the presence of relatedness; (i) within-family (ii) within- and between-family and (iii) mixed-models methods, using simulated traits for 2906 subjects with known genome-wide genotype data from an extremely isolated population, the Island of Kosrae, Federated States of Micronesia. We report that mixed models optimally extract association information from such samples, demonstrating 88% power to rank the true variant as among the top 10 genome-wide with 56% achieving genome-wide significance, a >80% improvement over the other methods, and demonstrate that population isolates have similar power to non-isolate populations for observing variants of known effects. We then used the mixed-model method to reanalyze data for 17 published phenotypes relating to metabolic traits and electrocardiographic measures, along with another 8 previously unreported. We replicate nine genome-wide significant associations with known loci of plasma cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, thyroid stimulating hormone, homocysteine, C-reactive protein and uric acid, with only one detected in the previous analysis of the same traits. Further, we leveraged shared identity-by-descent genetic segments in the region of the uric acid locus to fine-map the signal, refining the known locus by a factor of 4. Finally, we report a novel associations for height (rs17629022, P< 2.1 × 10⁻⁸).
    Human Molecular Genetics 02/2011; 20(4):827-39. DOI:10.1093/hmg/ddq510 · 6.68 Impact Factor

Publication Stats

20k Citations
1,309.02 Total Impact Points

Institutions

  • 1991–2015
    • The Rockefeller University
      • • Laboratory of Molecular Genetics
      • • Laboratory of Sensory Neuroscience
      • • Laboratory of Molecular Biology
      New York, New York, United States
  • 2013
    • New York State
      New York, New York, United States
  • 2011
    • Columbia University
      • Department of Computer Science
      New York City, NY, United States
  • 1992–2009
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • CUNY Graduate Center
      New York, New York, United States
  • 2002
    • University of Wisconsin, Madison
      • Department of Biochemistry
      Madison, MS, United States