A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence

Cabana‐Domínguez, Judit; Roncero, Carlos; Grau-López, Lara; Rodríguez-Cintas, Laia; Barral, Carmen; Abad, Alfonso Carlos; Erikson, Galina; Torrico, Bàrbara; Arenas, C.; Casas, Miquel; Ribasés, Marta; Cormand, Bru; Fernàndez‐Castillo, Noèlia

doi:10.1038/srep31033

Cited by 8 publications

(4 citation statements)

References 69 publications

(78 reference statements)

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“…So far, only one copy number variant (CNV) has been found associated with cocaine dependence, a large polymorphic CNV that partially spans the NSF gene, involved in synaptic vesicle turnover [38]. In this study, individuals with a low number of copies showed a quicker transition from cocaine use to dependence than individuals with a high number of copies.…”

Section: Genetic Architecture Of Cocaine Addictionmentioning

confidence: 73%

Molecular genetics of cocaine use disorders in humans

et al. 2021

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Drug addiction, one of the major health problems worldwide, is characterized by the loss of control in drug intake, craving, and withdrawal. At the individual level, drugs of abuse produce serious consequences on health and have a negative impact on the family environment and on interpersonal and work relationships. At a wider scale, they have significant socio-economic and public health consequences and they cause delinquency and citizen insecurity. Cocaine, a psychostimulant substance, is one of the most used illicit drugs, especially in America, Western Europe, and Australia. Cocaine use disorders (CUD) are complex multifactorial conditions driven by both genetic and environmental influences. Importantly, not all people who use cocaine develop CUD, and this is due, at least in part, to biological factors that are encoded in the genome of individuals. Acute and repeated use of cocaine induces epigenetic and gene expression changes responsible for the neuronal adaptations and the remodeling of brain circuits that lead to the transition from use to abuse or dependence. The purpose of this review is to delineate such factors, which should eventually help to understand the inter-individual variability in the susceptibility to cocaine addiction. Heritability estimates for CUD are high and genetic risk factors for cocaine addiction have been investigated by candidate gene association studies (CGAS) and genome-wide association studies (GWAS), reviewed here. Also, the high comorbidity that exists between CUD and several other psychiatric disorders is well known and includes phenotypes like schizophrenia, aggression, antisocial or risk-taking behaviors. Such comorbidities are associated with a worse lifetime trajectory, and here we report shared genetic factors that may contribute to them. Gene expression changes and epigenetic modifications induced by cocaine use and chronic abuse in humans are addressed by reviewing transcriptomic studies performed on neuronal cells and on postmortem brains. We report some genes which expression is altered by cocaine that also bear genetic risk variants for the disorder. Finally, we have a glance to the pharmacogenetics of CUD treatments, still in early stages. A better understanding of the genetic underpinnings of CUD will foster the search of effective treatments and help to move forward to personalized medicine.

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Section: Genetic Architecture Of Cocaine Addictionmentioning

confidence: 73%

Molecular genetics of cocaine use disorders in humans

et al. 2021

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“…The original NSF locus is full length, while the subsequent NSF copy number repeats truncate near exon 13 and do not encode full-length NSF transcripts (59,60). A recent study reported a correlation between this human NSF copy number variation and drug dependency (60). Notably, no residue substitutions were reported among human NSF alleles, and, to the best of our knowledge, no naturally occurring NSF protein variants from any organism have previously been reported.…”

Section: Discussionmentioning

confidence: 87%

“…The 1,000 Human Genomes Project showed that, in certain human ethnicities, NSF copy number expansions of up to three repeats are not uncommon (59). The original NSF locus is full length, while the subsequent NSF copy number repeats truncate near exon 13 and do not encode full-length NSF transcripts (59,60). A recent study reported a correlation between this human NSF copy number variation and drug dependency (60).…”

Section: Discussionmentioning

confidence: 99%

An atypical N-ethylmaleimide sensitive factor enables the viability of nematode-resistant Rhg1 soybeans

Bayless

Zapotocny

Grunwald

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

102

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N-ethylmaleimide sensitive factor (NSF) and α-soluble NSF attachment protein (α-SNAP) are essential eukaryotic housekeeping proteins that cooperatively function to sustain vesicular trafficking. The "resistance to 1" () locus of soybean () confers resistance to soybean cyst nematode, a highly damaging soybean pest. loci encode repeat copies of atypical α-SNAP proteins that are defective in promoting NSF function and are cytotoxic in certain contexts. Here, we discovered an unusual allele (-associated NSF on chromosome 07; ) in germplasm. NSF protein modeling to mammalian NSF/α-SNAP complex structures indicated that at least three of the five NSF polymorphisms reside adjacent to the α-SNAP binding interface. NSF exhibited stronger in vitro binding with resistance-type α-SNAPs. NSF coexpression was more protective against α-SNAP cytotoxicity, relative to WT NSF Investigation of a previously reported segregation distortion between chromosome 18 and a chromosome 07 interval now known to contain the NSF gene revealed 100% coinheritance of the allele with disease resistance alleles, across 855 soybean accessions and in all examined progeny from biparental crosses. Additionally, we show that some-mediated resistance is associated with depletion of WT α-SNAP abundance via selective loss of WT α-SNAP loci. Hence atypical coevolution of the soybean SNARE-recycling machinery has balanced the acquisition of an otherwise disruptive housekeeping protein, enabling a valuable disease resistance trait. Our findings further indicate that successful engineering of -related resistance in plants will require a compatible NSF partner for the resistance-conferring α-SNAP.

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“…γ duplications increase transcript levels of the pseudogene NSFP1 that contains the first 13 exons of NSF . Although the effect on protein stability is still unknown, the CNVs in this locus are associated with cocaine dependence [ 58 ].…”

Section: Introductionmentioning

confidence: 99%

Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases

Pedicone,

Weitzman,

Renton

et al. 2024

Mol Neurodegeneration

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A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases. Graphical Abstract

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A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence

Cited by 8 publications

References 69 publications

Molecular genetics of cocaine use disorders in humans

Molecular genetics of cocaine use disorders in humans

An atypical N-ethylmaleimide sensitive factor enables the viability of nematode-resistant Rhg1 soybeans

Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases

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