Erratum: Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Sniekers, Suzanne; Stringer, Sven; Watanabe, Kyoko; Jansen, Philip R.; Coleman, Jonathan R. I.; Krapohl, Eva; Taskesen, Erdogan; Hammerschlag, Anke R.; Okbay, Aysu; Zabaneh, Delilah; Amin, Najaf; Breen, Gerome; Cesarini, David; Chabris, Christopher F.; Iacono, William G.; Ikram, M. Arfan; Johannesson, Magnus; Koellinger, Philipp; Lee, James J.; Magnusson, Patrik K. E.; McGue, Matt; Miller, Mike; Ollier, William; Payton, Antony; Pendleton, Neil; Plomin, Robert; Rietveld, Cornelius A.; Tiemeier, Henning; Duijn, Cornelia M. van; Posthuma, Daniëlle

doi:10.1038/ng1017-1558c

Cited by 145 publications

(12 citation statements)

References 44 publications

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“…Large-scale genome-wide association studies (GWAS) indicate polymorphisms present in the NEGR1 gene to be associated with the risk for SCZ 18 , MDD 19 and AD 20 . Variations in NEGR1 are linked with human intelligence 21 and dyslexia 22 . Polymorphisms in NEGR1 have also been implicated in low white matter integrity, which could be the underlying risk factor for many psychiatric phenotypes 23 .…”

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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“…For example, polymorphisms in the human LSAMP gene have been associated with major depressive disorder (Koido et al, 2012 ) and schizophrenia (Koido et al, 2014 ). Gene variants in a regulatory region upstream of the NEGR1 gene have been associated with major depressive disorder (Hyde et al, 2016 ) but also with low white matter integrity (Dennis et al, 2014 ) and intelligence (Sniekers et al, 2017 ). Neuropsychiatric problems and learning difficulties were further reported in two siblings with a mono-allelic microdeletion of chromosome 1p31.1 involving only the NEGR1 gene (Genovese et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene

Singh

Loreth

Pöttker

et al. 2018

Front. Mol. Neurosci.

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Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been implicated in neuronal growth and connectivity. In addition, genetic variants in or near the NEGR1 locus have been associated with obesity and more recently with learning difficulties, intellectual disability and psychiatric disorders. However, experimental evidence is lacking to support a possible link between NEGR1, neuronal growth and behavioral abnormalities. Initial expression analysis of NEGR1 mRNA in C57Bl/6 wildtype (WT) mice by in situ hybridization demonstrated marked expression in the entorhinal cortex (EC) and dentate granule cells. In co-cultures of cortical neurons and NSC-34 cells overexpressing NEGR1, neurite growth of cortical neurons was enhanced and distal axons occupied an increased area of cells overexpressing NEGR1. Conversely, in organotypic slice co-cultures, Negr1-knockout (KO) hippocampus was less permissive for axons grown from EC of β-actin-enhanced green fluorescent protein (EGFP) mice compared to WT hippocampus. Neuroanatomical analysis revealed abnormalities of EC axons in the hippocampal dentate gyrus (DG) of Negr1-KO mice including increased numbers of axonal projections to the hilus. Neurotransmitter receptor ligand binding densities, a proxy of functional neurotransmitter receptor abundance, did not show differences in the DG of Negr1-KO mice but altered ligand binding densities to NMDA receptor and muscarinic acetylcholine receptors M1 and M2 were found in CA1 and CA3. Activity behavior, anxiety-like behavior and sensorimotor gating were not different between genotypes. However, Negr1-KO mice exhibited impaired social behavior compared to WT littermates. Moreover, Negr1-KO mice showed reversal learning deficits in the Morris water maze and increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. Thus, our results from neuronal growth assays, neuroanatomical analyses and behavioral assessments provide first evidence that deficiency of the psychiatric disease-associated Negr1 gene may affect neuronal growth and behavior. These findings might be relevant to further evaluate the role of NEGR1 in cognitive and psychiatric disorders.

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“…However, our study spotlights the first functional study of a single mutation in Mint2 that has significant impact on synaptic function. Recently Mint1, structurally similar to Mint2, was identified as one of the 52 genes linked to human intelligence highlighting the importance of the Mint family of adaptor proteins influencing and shaping intelligence 38 . The validation and mechanistic role of new genes such as MINT2 associated with ASD will directly lead to a better understanding of the molecular pathways underlying ASD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function

Lin

Henry

Reißner

et al. 2019

Sci Rep

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MINT2/APBA2 is a synaptic adaptor protein involved in excitatory synaptic transmission. Several nonsynonymous coding variants in MINT2 have been identified in autism spectrum disorders (ASDs); however, these rare variants have not been examined functionally and the pathogenic mechanisms are unknown. Here, we examined the synaptic effects of rat Mint2 N723S mutation (equivalent to autism-linked human MINT2 N722S mutation) which targets a conserved asparagine residue in the second PDZ domain of Mint2 that binds to neurexin-1α (Nrxn1α), a presynaptic cell-adhesion protein implicated in ASDs. We show the N723S mutation impairs Nrxn1α stabilization and trafficking to the membrane while binding to Nrxn1α remains unaffected. Using time-lapse imaging in primary mouse neurons, we found that the N723S mutant had more immobile puncta at neuronal processes compared to Mint2 wild type. We therefore, reasoned that the N723S mutant may alter the co-transport of Nrxn1α at axonal processes to presynaptic terminals. Indeed, we found the N723S mutation affected Nrxn1α localization at presynaptic terminals which correlated with a decrease in Nrxn-mediated synaptogenesis and miniature event frequency in excitatory synapses. Together, our data reveal Mint2 N723S leads to neuronal dysfunction, in part due to alterations in Nrxn1α surface trafficking and synaptic function of Mint2.

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Erratum: Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Cited by 145 publications

References 44 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

Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene

A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function

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