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. 2016 Aug 8;6:31033.
doi: 10.1038/srep31033.

A Highly Polymorphic Copy Number Variant in the NSF Gene Is Associated With Cocaine Dependence

Free PMC article

A Highly Polymorphic Copy Number Variant in the NSF Gene Is Associated With Cocaine Dependence

Judit Cabana-Domínguez et al. Sci Rep. .
Free PMC article


Cocaine dependence is a complex psychiatric disorder involving both genetic and environmental factors. Several neurotransmitter systems mediate cocaine's effects, dependence and relapse, being the components of the neurotransmitter release machinery good candidates for the disorder. Previously, we identified a risk haplotype for cocaine dependence in the NSF gene, encoding the protein N-Ethylmaleimide-Sensitive Factor essential for synaptic vesicle turnover. Here we examined the possible contribution to cocaine dependence of a large copy number variant (CNV) that encompasses part of the NSF gene. We performed a case-control association study in a discovery sample (359 cases and 356 controls) and identified an association between cocaine dependence and the CNV (P = 0.013), that was confirmed in the replication sample (508 cases and 569 controls, P = 7.1e-03) and in a pooled analysis (P = 1.8e-04), with an over-representation of low number of copies in cases. Subsequently, we studied the functional impact of the CNV on gene expression and found that the levels of two NSF transcripts were significantly increased in peripheral blood mononuclear cells (PBMC) along with the number of copies of the CNV. These results, together with a previous study from our group, support the role of NSF in the susceptibility to cocaine dependence.


Figure 1
Figure 1. Delimitation of the CNV region.
(a) Representation of the 3′ end of the CNV spanning the NSF gene. The CNV is indicated with a grey box, exons with black boxes, and triangles show the position of primers used in qRT-PCR assays. The location of SNP rs183211 is indicated. (b) Number of individuals grouped by copies of the NSF CNV in exons 2 and 13 and in intron 13.
Figure 2
Figure 2. Schematic representation of the CNV region.
(a) Representation of genes NSF (ENSG00000073969), ARL17A (ENSG00000185829) and LRRC37A2 (ENSG00000238083). Exons are indicated with black boxes, CNV is indicated with a grey box. The location of the two SNPs previously associated with cocaine dependence is indicated. (b) Schema of genetic context of the three possible alleles of the CNV in this region: 1, 2 or 3 repeats.
Figure 3
Figure 3. Time between initial consumption and onset of cocaine dependence (years) in individuals with low (2 or 3) and high (4, 5 or 6) number of copies of the NSF CNV.
Figure 4
Figure 4. Correlation between the number of copies of the CNV and gene expression.
(a) Structure of transcripts detected by qRT-PCR assay. CNV is indicated with a grey box, exons are indicated with boxes in black for the NSF gene (ENSG00000073969) and in grey for NSF transcripts: NSF_001 (ENST00000398238), NSFP1_001 (ENST00000570034), NSF_002 (ENST00000486366) and NSF_003 (ENST00000465370). Arrows indicate the position of qRT-PCR primers sets used to detect the different transcripts: “a” for NSF_001 + NSFP_001, “b” for NSF_001, “c” for NSF_002 and “d” for NSF_003. (b) Blox plot for mRNA expression levels of each transcript in individuals with low and high number of copies. Linear regression showing the correlation between number of copies and transcript expression levels. Spearman’s rank correlation coefficients (ρ) are shown inside the graphs. (**P < 0.001; ***P < 0.0001).

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