The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking

Kim, Hye-Jin; Chun, Younghwa; Che, Lihua; Kim, Jeongbeom; Lee, Sung-Joong; Lee, Soojin

doi:10.1016/j.bbrc.2016.12.043

Cited by 34 publications

(36 citation statements)

References 24 publications

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“…Specific variants in NEGR1 gene locus have been implicated in human obesity, body mass index 32,33 and psychological traits commonly linked with eating disorders 34 . The body mass phenotype could be related to the interaction of NEGR1 with the Niemann-Pick disease Type C2 (NPC2) protein that alters cholesterol transport 35 .…”

Section: Introductionmentioning

confidence: 99%

Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders

Singh

Mohan

Kaare

et al. 2019

Sci Rep

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Neuronal growth regulator 1 (NEGR1) belongs to the immunoglobulin (IgLON) superfamily of cell adhesion molecules involved in cortical layering. Recent functional and genomic studies implicate the role of NEGR1 in a wide spectrum of psychiatric disorders, such as major depression, schizophrenia and autism. Here, we investigated the impact of Negr1 deficiency on brain morphology, neuronal properties and social behavior of mice. In situ hybridization shows Negr1 expression in the brain nuclei which are central modulators of cortical-subcortical connectivity such as the island of Calleja and the reticular nucleus of thalamus. Brain morphological analysis revealed neuroanatomical abnormalities in Negr1 −/− mice, including enlargement of ventricles and decrease in the volume of the whole brain, corpus callosum, globus pallidus and hippocampus. Furthermore, decreased number of parvalbumin-positive inhibitory interneurons was evident in Negr1 −/− hippocampi. Behaviorally, Negr1 −/− mice displayed hyperactivity in social interactions and impairments in social hierarchy. Finally, Negr1 deficiency resulted in disrupted neurite sprouting during neuritogenesis. Our results provide evidence that NEGR1 is required for balancing the ratio of excitatory/inhibitory neurons and proper formation of brain structures, which is prerequisite for adaptive behavioral profiles. Therefore, Negr1 −/− mice have a high potential to provide new insights into the neural mechanisms of neuropsychiatric disorders.

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Section: Introductionmentioning

confidence: 99%

Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders

Singh

Mohan

Kaare

et al. 2019

Sci Rep

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“…NEGR1 is expressed in the rat brain. It has been proposed that NEGR1 could modulate the intracellular cholesterol trafficking, suggesting its implication in human obesity ( Kim et al, 2017 ). NEGR1 was associated with obesity ( Thorleifsson et al, 2009 ; Willer et al, 2009 ).…”

Section: Genes Associated With Obesity and Neurodegenerative And Neurmentioning

confidence: 99%

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

2020

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Obesity is a multifactorial disease in which environmental conditions and several genes play an important role in the development of this disease. Obesity is associated with neurodegenerative diseases (Alzheimer, Parkinson, and Huntington diseases) and with neurodevelopmental diseases (autism disorder, schizophrenia, and fragile X syndrome). Some of the environmental conditions that lead to obesity are physical activity, alcohol consumption, socioeconomic status, parent feeding behavior, and diet. Interestingly, some of these environmental conditions are shared with neurodegenerative and neurodevelopmental diseases. Obesity impairs neurodevelopment abilities as memory and fine-motor skills. Moreover, maternal obesity affects the cognitive function and mental health of the offspring. The common biological mechanisms involved in obesity and neurodegenerative/neurodevelopmental diseases are insulin resistance, pro-inflammatory cytokines, and oxidative damage, among others, leading to impaired brain development or cell death. Obesogenic environmental conditions are not the only factors that influence neurodegenerative and neurodevelopmental diseases. In fact, several genes implicated in the leptin–melanocortin pathway ( LEP , LEPR , POMC , BDNF , MC4R , PCSK1 , SIM1 , BDNF , TrkB , etc.) are associated with obesity and neurodegenerative and neurodevelopmental diseases. Moreover, in the last decades, the discovery of new genes associated with obesity ( FTO, NRXN3, NPC1, NEGR1, MTCH2, GNPDA2 , among others) and with neurodegenerative or neurodevelopmental diseases ( APOE, CD38, SIRT1, TNF α, PAI-1, TREM2, SYT4, FMR1, TET3 , among others) had opened new pathways to comprehend the common mechanisms involved in these diseases. In conclusion, the obesogenic environmental conditions, the genes, and the interaction gene–environment would lead to a better understanding of the etiology of these diseases.

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“…Firstly, rs10889923 maps on an intron for NEGR1 (neuronal growth receptor 1), a very important gene many times linked to obesity, body mass index, triglycerides, cholesterol, etc. and many other phenotypes highly correlated with hypertension 66,67,68 . Even though NEGR1 has been associated with many phenotypes in the GWAS Catalog, no GWAS has yet been able to directly link it to hypertension.…”

Section: Snp Selection Performance On Wtccc Datamentioning

confidence: 99%

DeepCOMBI: Explainable artificial intelligence for the analysis and discovery in genome-wide association studies

Mieth

Rozier

Rodríguez

et al. 2020

Preprint

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Deep learning algorithms have revolutionized data science in many fields by greatly improving prediction performances in comparison to conventional approaches. Recently, explainable artificial intelligence (XAI) has emerged as a novel area of research that goes beyond pure prediction improvement. Knowledge embodied in deep learning methodologies is extracted by interpreting their results. We investigate such explanations to explore the genetic architectures of phenotypes in genome-wide association studies. Instead of testing each position in the genome individually, the novel three-step algorithm, called DeepCOMBI, first trains a neural network for the classification of subjects into their respective phenotypes. Second, it explains the classifiers’ decisions by applying layerwise relevance propagation as one example from the pool of XAI techniques. The resulting importance scores are eventually used to determine a subset of most relevant locations for multiple hypothesis testing in the third step. The performance of DeepCOMBI in terms of power and precision is investigated on generated datasets and a 2007 WTCCC study. Verification of the latter is achieved by validating all findings with independent studies published up until 2020. DeepCOMBI is shown to outperform ordinary raw p-value thresholding as well as other baseline methods. Moreover, two novel disease associations (rs10889923 for hypertension and rs4769283 for type 1 diabetes) were identified.

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The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking

Cited by 34 publications

References 24 publications

Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders

Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

DeepCOMBI: Explainable artificial intelligence for the analysis and discovery in genome-wide association studies

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