bdnf - brain derived neurotrophic factor
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Publication
Journal: Journal of Neuroscience Research
May/13/2007
Abstract
Brain-derived neurotrophic factor (BDNF) has important functions in the development of the nervous system and in brain plasticity-related processes such as memory, learning, and drug addiction. Despite the fact that the function and regulation of rodent BDNF gene expression have received close attention during the last decade, knowledge of the structural organization of mouse and rat BDNF gene has remained incomplete. We have identified and characterized several mouse and rat BDNF transcripts containing novel 5' untranslated exons and introduced a new numbering system for mouse and rat BDNF exons. According to our results both mouse and rat BDNF gene consist of eight 5' untranslated exons and one protein coding 3' exon. Transcription of the gene results in BDNF transcripts containing one of the eight 5' exons spliced to the protein coding exon and in a transcript containing only 5' extended protein coding exon. We also report the distinct tissue-specific expression profiles of each of the mouse and rat 5' exon-specific transcripts in different brain regions and nonneural tissues. In addition, we show that kainic acid-induced seizures that lead to changes in cellular Ca(2+) levels as well as inhibition of DNA methylation and histone deacetylation contribute to the differential regulation of the expression of BDNF transcripts. Finally, we confirm that mouse and rat BDNF gene loci do not encode antisense mRNA transcripts, suggesting that mechanisms of regulation for rodent and human BDNF genes differ substantially.
Publication
Journal: Nature
February/21/2001
Abstract
The precise hierarchy of ancient divergence events that led to the present assemblage of modern placental mammals has been an area of controversy among morphologists, palaeontologists and molecular evolutionists. Here we address the potential weaknesses of limited character and taxon sampling in a comprehensive molecular phylogenetic analysis of 64 species sampled across all extant orders of placental mammals. We examined sequence variation in 18 homologous gene segments (including nearly 10,000 base pairs) that were selected for maximal phylogenetic informativeness in resolving the hierarchy of early mammalian divergence. Phylogenetic analyses identify four primary superordinal clades: (I) Afrotheria (elephants, manatees, hyraxes, tenrecs, aardvark and elephant shrews); (II) Xenarthra (sloths, anteaters and armadillos); (III) Glires (rodents and lagomorphs), as a sister taxon to primates, flying lemurs and tree shrews; and (IV) the remaining orders of placental mammals (cetaceans, artiodactyls, perissodactyls, carnivores, pangolins, bats and core insectivores). Our results provide new insight into the pattern of the early placental mammal radiation.
Publication
Journal: Journal of Neuroscience
October/28/2008
Abstract
Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. Contextual fear learning induced differential regulation of exon-specific bdnf mRNAs (I, IV, VI, IX) that was associated with changes in bdnf DNA methylation and altered local chromatin structure. Infusions of zebularine (a DNA methyltransferase inhibitor) significantly altered bdnf DNA methylation and triggered changes in exon-specific bdnf mRNA levels, indicating that altered DNA methylation is sufficient to drive differential bdnf transcript regulation in the hippocampus. In addition, NMDA receptor blockade prevented memory-associated alterations in bdnf DNA methylation, resulting in a block of altered bdnf gene expression in hippocampus and a deficit in memory formation. These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.
Publication
Journal: Journal of Neuroscience
June/9/2005
Abstract
A variation in the BDNF gene (val66met) affects the function of BDNF in neurons, predicts variation in human memory, and is associated with several neurological and psychiatric disorders. Here, we show that, in magnetic resonance imaging scans of a large sample of normal individuals, this polymorphism affects the anatomy of the hippocampus and prefrontal cortex, identifying a genetic mechanism of variation in brain morphology related to learning and memory.
Publication
Journal: Human Genetics
August/24/2009
Abstract
Quantitative genetic studies (i.e., twin and adoption studies) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder (ADHD). Over the past 15 years, considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD. The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies. The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results. Significant associations were identified for several candidate genes including DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25. Further, significant heterogeneity was observed for the associations between ADHD and DAT1, DRD4, DRD5, DBH, ADRA2A, 5HTT, TPH2, MAOA, and SNAP25, suggesting that future studies should explore potential moderators of these associations (e.g., ADHD subtype diagnoses, gender, exposure to environmental risk factors). We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD.
Publication
Journal: Journal of Neurochemistry
October/21/2002
Abstract
To determine the role of brain-derived neurotrophic factor (BDNF) in the enhancement of hippocampal neurogenesis resulting from dietary restriction (DR), heterozygous BDNF knockout (BDNF +/-) mice and wild-type mice were maintained for 3 months on DR or ad libitum (AL) diets. Mice were then injected with bromodeoxyuridine (BrdU) and killed either 1 day or 4 weeks later. Levels of BDNF protein in neurons throughout the hippocampus were decreased in BDNF +/- mice, but were increased by DR in wild-type mice and to a lesser amount in BDNF +/- mice. One day after BrdU injection the number of BrdU-labeled cells in the dentate gyrus of the hippocampus was significantly decreased in BDNF +/- mice maintained on the AL diet, suggesting that BDNF signaling is important for proliferation of neural stem cells. DR had no effect on the proliferation of neural stem cells in wild-type or BDNF +/- mice. Four weeks after BrdU injection, numbers of surviving labeled cells were decreased in BDNF +/- mice maintained on either AL or DR diets. DR significantly improved survival of newly generated cells in wild-type mice, and also improved their survival in BDNF +/- mice, albeit to a lesser extent. The majority of BrdU-labeled cells in the dentate gyrus exhibited a neuronal phenotype at the 4-week time point. The reduced neurogenesis in BDNF +/- mice was associated with a significant reduction in the volume of the dentate gyrus. These findings suggest that BDNF plays an important role in the regulation of the basal level of neurogenesis in dentate gyrus of adult mice, and that by promoting the survival of newly generated neurons BDNF contributes to the enhancement of neurogenesis induced by DR.
Publication
Journal: EMBO Journal
July/26/1984
Abstract
We report the purification from pig brain of a factor supporting the survival of, and fibre outgrowth from, cultured embryonic chick sensory neurons. The purified factor migrates as one single band, mol. wt. 12 300, on gel electrophoresis in the presence of sodium dodecylsulphate (SDS) and is a basic molecule (pI greater than or equal to 10.1). Approximately 1 microgram factor was isolated from 1.5 kg brain. The final degree of purification was estimated to be 1.4 X 10(6)-fold, and the specific activity 0.4 ng/ml/unit, which is similar to that of nerve growth factor (NGF) using the same assay system. This factor is the first neurotrophic factor to be purified since NGF, from which it is clearly distinguished because it has different antigenic and functional properties.
Publication
Journal: Nature Neuroscience
August/13/2003
Abstract
The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
Publication
Journal: Biological Psychiatry
August/21/2003
Abstract
BACKGROUND
Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD).
METHODS
We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method.
RESULTS
We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment.
CONCLUSIONS
Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients.
Publication
Journal: Cell
July/24/2008
Abstract
The brain produces two brain-derived neurotrophic factor (BDNF) transcripts, with either short or long 3' untranslated regions (3' UTRs). The physiological significance of the two forms of mRNAs encoding the same protein is unknown. Here, we show that the short and long 3' UTR BDNF mRNAs are involved in different cellular functions. The short 3' UTR mRNAs are restricted to somata, whereas the long 3' UTR mRNAs are also localized in dendrites. In a mouse mutant where the long 3' UTR is truncated, dendritic targeting of BDNF mRNAs is impaired. There is little BDNF in hippocampal dendrites despite normal levels of total BDNF protein. This mutant exhibits deficits in pruning and enlargement of dendritic spines, as well as selective impairment in long-term potentiation in dendrites, but not somata, of hippocampal neurons. These results provide insights into local and dendritic actions of BDNF and reveal a mechanism for differential regulation of subcellular functions of proteins.
Publication
Journal: Molecular Endocrinology
February/20/2002
Abstract
Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.
Authors
Publication
Journal: Archives of general psychiatry
September/9/2003
Abstract
BACKGROUND
Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions.
METHODS
These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase-polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas.
RESULTS
Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain.
CONCLUSIONS
Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.
Publication
Journal: Journal of Neuroscience
September/12/2005
Abstract
Antidepressants increase proliferation of neuronal progenitor cells and expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. We investigated the role of BDNF signaling in antidepressant-induced neurogenesis by using transgenic mice with either reduced BDNF levels (BDNF+/-) or impaired trkB activation (trkB.T1-overexpressing mice). In both transgenic strains, chronic (21 d) imipramine treatment increased the number of bromodeoxyuridine (BrdU)-positive cells to degree similar to that seen in wild-type mice 24 h after BrdU administration, although the basal proliferation rate was increased in both transgenic strains. Three weeks after BrdU administration and the last antidepressant injection, the amount of newborn (BrdU- or TUC-4-positive) cells was significantly reduced in both BDNF+/- and trkB.T1-overexpressing mice, which suggests that normal BDNF signaling is required for the long-term survival of newborn hippocampal neurons. Moreover, the antidepressant-induced increase in the surviving BrdU-positive neurons seen in wild-type mice 3 weeks after treatment was essentially lost in mice with reduced BDNF signaling. Furthermore, we observed that chronic treatment with imipramine or fluoxetine produced a temporally similar increase in both BrdU-positive and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeled neurons in the dentate gyrus, indicating that these drugs simultaneously increase both neurogenesis and neuronal elimination. These data suggest that antidepressants increase turnover of hippocampal neurons rather than neurogenesis per se and that BDNF signaling is required for the long-term survival of newborn neurons in mouse hippocampus.
Publication
Journal: Neurobiology of Learning and Memory
June/15/2008
Abstract
It is generally believed that late-phase long-term potentiation (L-LTP) and long-term memory (LTM) require new protein synthesis. Although the full complement of proteins mediating the long-lasting changes in synaptic efficacy have yet to be identified, several lines of evidence point to a crucial role for activity-induced brain-derived neurotrophic factor (BDNF) expression in generating sustained structural and functional changes at hippocampal synapses thought to underlie some forms of LTM. In particular, BDNF is sufficient to induce the transformation of early to late-phase LTP in the presence of protein synthesis inhibitors, and inhibition of BDNF signaling impairs LTM. Despite solid evidence for a critical role of BDNF in L-LTP and LTM, many issues are not resolved. Given that BDNF needs to be processed in Golgi outposts localized at the branch point of one or few dendrites, a conceptually challenging problem is how locally synthesized BDNF in dendrites could ensure synapse-specific modulation of L-LTP. An interesting alternative is that BDNF-TrkB signaling is involved in synaptic tagging, a prominent hypothesis that explains how soma-derived protein could selectively modulate the tetanized (tagged) synapse. Finally, specific roles of BDNF in the acquisition, retention or extinction of LTM remain to be established.
Publication
Journal: Neuron
March/29/2006
Abstract
Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MeCP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in Mecp2 mutant mice, and deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the Mecp2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in Mecp2 mutants. Our results provide in vivo evidence for a functional interaction between Mecp2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.
Publication
Journal: EMBO Journal
April/26/2000
Abstract
Brain-derived neurotrophic factor (BDNF) was studied initially for its role in sensory neuron development. Ablation of this gene in mice leads to death shortly after birth, and abnormalities have been found in both the peripheral and central nervous systems. BDNF and its tyrosine kinase receptor, TrkB, are expressed in hypothalamic nuclei associated with satiety and locomotor activity. In heterozygous mice, BDNF gene expression is reduced and we find that all heterozygous mice exhibit abnormalities in eating behavior or locomotor activity. We also observe this phenotype in independently derived inbred and hybrid BDNF mutant strains. Infusion with BDNF or NT4/5 can transiently reverse the eating behavior and obesity. Thus, we identify a novel non-neurotrophic function for neurotrophins and indicate a role in behavior that is remarkably sensitive to alterations in BDNF activity.
Publication
Journal: Neuron
September/16/2008
Abstract
Adult hippocampal neurogenesis is stimulated by chronic administration of antidepressants (ADs) and by voluntary exercise. Neural progenitor cells (NPCs) in the dentate gyrus (DG) that are capable of continuous proliferation and neuronal differentiation are the source of such structural plasticity. Here we report that mice lacking the receptor tyrosine kinase TrkB in hippocampal NPCs have impaired proliferation and neurogenesis. When exposed to chronic ADs or wheel-running, no increase in proliferation or neurogenesis is observed. Ablation of TrkB also renders these mice behaviorally insensitive to antidepressive treatment in depression- and anxiety-like paradigms. In contrast, mice lacking TrkB only in differentiated DG neurons display typical neurogenesis and respond normally to chronic ADs. Thus, our data establish an essential cell-autonomous role for TrkB in regulating hippocampal neurogenesis and behavioral sensitivity to antidepressive treatments, and support the notion that impairment of the neurogenic niche is an etiological factor for refractory responses to an antidepressive regimen.
Publication
Journal: Science
May/26/2004
Abstract
The idea that new memories undergo a time-dependent consolidation process after acquisition has received considerable experimental support. More controversial has been the demonstration that established memories, once recalled, become labile and sensitive to disruption, requiring "reconsolidation" to become permanent. By infusing antisense oligodeoxynucleotides into the hippocampus of rats, we show that consolidation and reconsolidation are doubly dissociable component processes of memory. Consolidation involves brain-derived neurotrophic factor (BDNF) but not the transcription factor Zif268, whereas reconsolidation recruits Zif268 but not BDNF. These findings confirm a requirement for BDNF specifically in memory consolidation and also resolve the role of Zif268 in brain plasticity, learning, and memory.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
September/20/2009
Abstract
Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Ass plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Ass or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brain-derived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.
Publication
Journal: Nature
October/16/1989
Abstract
During the development of the vertebrate nervous system, many neurons depend for survival on interactions with their target cells. Specific proteins are thought to be released by the target cells and to play an essential role in these interactions. So far, only one such protein, nerve growth factor, has been fully characterized. This has been possible because of the extraordinarily (and unexplained) large quantities of this protein in some adult tissues that are of no relevance to the developing nervous system. Whereas the dependency of many neurons on their target cells for normal development, and the restricted neuronal specificity of nerve growth factor have long suggested the existence of other such proteins, their low abundance has rendered their characterization difficult. Here we report the full primary structure of brain-derived neurotrophic factor. This very rare protein is known to promote the survival of neuronal populations that are all located either in the central nervous system or directly connected with it. The messenger RNA for brain-derived neurotrophic factor was found predominantly in the central nervous system, and the sequence of the protein indicates that it is structurally related to nerve growth factor. These results establish that these two neurotrophic factors are related both functionally and structurally.
Publication
Journal: Science
April/1/2008
Abstract
Long-term potentiation (LTP) at glutamatergic synapses is considered to underlie learning and memory and is associated with the enlargement of dendritic spines. Because the consolidation of memory and LTP require protein synthesis, it is important to clarify how protein synthesis affects spine enlargement. In rat brain slices, the repetitive pairing of postsynaptic spikes and two-photon uncaging of glutamate at single spines (a spike-timing protocol) produced both immediate and gradual phases of spine enlargement in CA1 pyramidal neurons. The gradual enlargement was strongly dependent on protein synthesis and brain-derived neurotrophic factor (BDNF) action, often associated with spine twitching, and was induced specifically at the spines that were immediately enlarged by the synaptic stimulation. Thus, this spike-timing protocol is an efficient trigger for BDNF secretion and induces protein synthesis-dependent long-term enlargement at the level of single spines.
Publication
Journal: Nature
April/27/1994
Abstract
During vertebrate development, neuronal survival depends on target-derived neurotrophic factors. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, can prevent the death of particular peripheral sensory neurons in vitro, and of central motor neurons as well as dopaminergic and cholinergic neurons of the basal forebrain during development. It also prevents the death of motor neurons and midbrain dopaminergic neurons induced by lesions. Here we show that mutant mice lacking BDNF have severe deficiencies in coordination and balance, associated with excessive degeneration in several sensory ganglia including the vestibular ganglion. The few remaining vestibular axons fail to contact the vestibular sensory epithelia, and terminate in the adjacent connective tissue. Survival of sympathetic, midbrain dopaminergic and motor neurons is not affected. These results indicate that BDNF is required for the survival and target innervation of particular neuronal populations.
Publication
Journal: Science
March/8/2010
Abstract
Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.
Publication
Journal: Nature Genetics
June/17/2013
Abstract
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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