Abstract
The synaptosomal-associated protein of 25 kDa (SNAP-25) gene plays an integral role in synaptic transmission, and is differentially expressed in the mammalian brain in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra and cerebellar granular cells. Recent studies have suggested a possible involvement of SNAP-25 in learning and memory, both of which are key components of human intelligence. In addition, the SNAP-25 gene lies in a linkage area implicated previously in human intelligence. In two independent family-based Dutch samples of 391 (mean age 12.4 years) and 276 (mean age 37.3 years) subjects, respectively, we genotyped 12 single-nucleotide polymorphisms (SNPs) in the SNAP-25 gene on 20p12–20p11.2. From all individuals, standardized intelligence measures were available. Using a family-based association test, a strong association was found between three SNPs in the SNAP-25 gene and intelligence, two of which showed association in both independent samples. The strongest, replicated association was found between SNP rs363050 and performance IQ (PIQ), where the A allele was associated with an increase of 2.84 PIQ points (P=0.0002). Variance in this SNP accounts for 3.4 % of the phenotypic variance in PIQ.
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References
Bartels M, Rietveld M, Van Baal GCM, Boomsma DI . Genetic and environmental influences on the development of intelligence. Behav Genet 2002; 32: 237–249.
McGue M, Bouchard Jr TJ, Iacono WG, Lykken DT . Behavioral genetics of cognitive ability: a life-span perspective. In: Plomin R, McClearn GE (eds). Nature, Nurture, and Psychology. American Psychological Association: Washington, DC, 1993, pp 59–76.
Posthuma D, Luciano M, Geus EJ, Wright MJ, Slagboom PE, Montgomery GW et al. A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. Am J Hum Genet 2005; 77: 318–326.
Buyske S, Bates M, Gharani N, Matise T, Tischfield J, Manowitz P . Cognitive traits link to human chromosomal regions. Behav Genet 2006; 36: 65–76.
Dick D, Aliev F, Bierut L, Goate A, Rice J, Hinrichs A et al. Linkage analyses of IQ in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Behav Genet 2006; 36: 77–86.
Luciano M, Wright MJ, Duffy DL, Wainwright MA, Zhu G, Evans DM et al. Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q. Behavior Genetics 2006. Behav Genet 2006; 36: 45–55.
Wainwright M, Wright M, Luciano M, Montgomery G, Geffen G, Martin N . A linkage study of academic skills defined by the Queensland core skills test. Behav Genet 2006; 36: 56–64.
Squire LR, Kandel ER (eds). Memory: From Mind to Molecules. Scientific American Library: New York, 1999.
Kim JJ, Rison RA, Fanselow MS . Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. Behav Neurosci 1993; 107: 1093–1098.
Logue SF, Paylor R, Wehner JM . Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task. Behav Neurosci 1997; 111: 104–113.
Morris RG, Garrud P, Rawlins JN, O'Keefe J . Place navigation impaired in rats with hippocampal lesions. Nature 1982; 297: 681–683.
Phillips RG, LeDoux JE . Lesions of the fornix but not the entorhinal or perirhinal cortex interfere with contextual fear conditioning. J Neurosci 1995; 15: 5308–5315.
Sandin J, Ogren SO, Terenius L . Nociceptin/orphanin FQ modulates spatial learning via ORL-1 receptors in the dorsal hippocampus of the rat. Brain Res 2004; 997: 222.
Selden NR, Everitt BJ, Jarrard LE, Robbins TW . Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience 1991; 42: 335–350.
Sutherland RJ, Kolb B, Whishaw IQ . Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat. Neurosci Lett 1982; 31: 271–276.
Geddes JW, Hess EJ, Hart RA, Kesslak JP, Cotman CW, Wilson MC . Lesions of hippocampal circuitry define synaptosomal-associated protein-25 (SNAP-25) as a novel presynaptic marker. Neuroscience 1990; 38: 515–525.
Oyler GA, Higgins GA, Hart RA, Battenberg E, Billingsley M, Bloom FE et al. The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations. J Cell Biol 1989; 109: 3039–3052.
Frassoni C, Inverardi F, Coco S, Ortino B, Grumelli C, Pozzi D et al. Analysis of SNAP-25 immunoreactivity in hippocampal inhibitory neurons during development in culture and in situ. Neuroscience 2005; 131: 813.
Horikawa HP, Saisu H, Ishizuka T, Sekine Y, Tsugita A, Odani S et al. A complex of rab3A, SNAP-25, VAMP/synaptobrevin-2 and syntaxins in brain presynaptic terminals. FEBS Lett 1993; 330: 236–240.
Seagar M, Takahashi M . Interactions between presynaptic calcium channels and proteins implicated in synaptic vesicle trafficking and exocytosis. J Bioenerg Biomembr 1998; 30: 347–356.
Osen-Sand A, Catsicas M, Staple JK, Jones KA, Ayala G, Knowles J et al. Inhibition of axonal growth by SNAP-25 antisense oligonucleotides in vitro and in vivo. Nature 1993; 364: 445–448.
Grosse G, Grosse J, Tapp R, Kuchinke J, Gorsleben M, Fetter I et al. SNAP-25 requirement for dendritic growth of hippocampal neurons. J Neurosci Res 1999; 56: 539–546.
Hou Q, Gao X, Zhang X, Kong L, Wang X, Bian W et al. SNAP-25 in hippocampal CA1 region is involved in memory consolidation. Eur J Neurosci 2004; 20: 1593–1603.
Roberts LA, Morris BJ, O'Shaughnessy CT . Involvement of two isoforms of SNAP-25 in the expression of long-term potentiation in the rat hippocampus. NeuroReport 1998; 9: 33–36.
Bliss TV, Collingridge GL . A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993; 361: 31–39.
Martin SJ, Grimwood PD, Morris RG . Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 2000; 23: 649–711.
Morris RG . Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J Neurosci 1989; 9: 3040–3057.
Morris RG, Anderson E, Lynch GS, Baudry M . Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 1986; 319: 774–776.
Lander E, Kruglyak L . Genetic dissection of complex traits: guideline for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Boomsma DI . Twin registers in Europe: an overview. Twin Res 1998; 1: 34–51.
Polderman TJC, Stins JF, Posthuma D, Gosso MF, Verhulst FC, Boomsma DI . The phenotypic and genotypic relation between working memory speed and capacity. Available online, 3 May 2006: doi:10.1016/J.intell.2006.03.010.
Wechsler D (ed). Wechsler Intelligence Scale for Children-Revised (WISC-R). Swets & Zeitlinger: Lisse, 1986.
Wechsler D (ed). WAIS-III Wechsler Adult Intelligence Scale. Psychological Corporation: San Antonio, TX, 1997.
Meulenbelt I, Droog S, Trommelen GJ, Boomsma DI, Slagboom PE . High-yield noninvasive human genomic DNA isolation method for genetic studies in geographically dispersed families and populations. Am J Hum Genet 1995; 57: 1252–1254.
Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.
Ardlie KG, Kruglyak L, Seielstad M . Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 2002; 3: 299–309.
Excoffier L, Slatkin M . Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.
Gudbjartsson DF, Thorvaldsson T, Kong A, Gunnarsson G, Ingolfsdottir A . Allegro version 2. Nat Genet 2005; 37: 1015–1016.
Abecasis GR, Cardon LR, Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.
Fulker DW, Cherny SS, Sham PC, Hewitt JK . Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet 1999; 64: 259–267.
Posthuma D, de Geus EJ, Boomsma DI, Neale MC . Combined linkage and association tests in mx. Behav Genet 2004; 34: 179–196.
Bark IC, Wilson MC . Human cDNA clones encoding two different isoforms of the nerve terminal protein SNAP-25. Gene 1994; 139: 291–292.
Low P, Norlin T, Risinger C, Larhammar D, Pieribone VA, Shupliakov O et al. Inhibition of neurotransmitter release in the lamprey reticulospinal synapse by antibody-mediated disruption of SNAP-25 function. Eur J Cell Biol 1999; 78: 787–793.
Bark C, Wilson MC . Alternative splicing generates a variant SNAP-25 protein during development. Soc Neurosci Abstr 1991; 17: 531.
Hess DT, Slater TM, Wilson MC, Skene JH . The 25 kDa synaptosomal-associated protein SNAP-25 is the major methionine-rich polypeptide in rapid axonal transport and a major substrate for palmitoylation in adult CNS. J Neurosci 1992; 12: 4634–4641.
Bark IC, Hahn KM, Ryabinin AE, Wilson MC . Differential expression of SNAP-25 protein isoforms during divergent vesicle fusion events of neural development. Proc Natl Acad Sci USA 1995; 92: 1510–1514.
Steffensen SC, Wilson MC, Henriksen SJ . Coloboma contiguous gene deletion encompassing Snap alters hippocampal plasticity. Synapse 1996; 22: 281–289.
Heyser CJ, Wilson MC, Gold LH . Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones. Brain Res Dev Brain Res 1995; 89: 264–269.
Snell GD, Bunker HP . Coloboma linkage. Mouse News Lett 1967; 37: 34.
Brophy K, Hawi Z, Kirley A, Fitzgerald M, Gill M . Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population. Mol Psychiatry 2002; 7: 913–917.
Feng Y, Crosbie J, Wigg K, Pathare T, Ickowicz A, Schachar R et al. The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder. Mol Psychiatry 2005; 10: 998–1005.
Kustanovich V, Merriman B, McGough J, McCracken JT, Smalley SL, Nelson SF . Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder. Mol Psychiatry 2003; 8: 309–315.
Mill J, Curran S, Kent L, Gould A, Huckett L, Richards S et al. Association study of a SNAP-25 microsatellite and attention deficit hyperactivity disorder. Am J Med Genet 2002; 114: 269–271.
Xu X, Knight J, Brookes K, Mill J, Sham P, Craig I et al. DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder: no evidence for association. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 115–118.
Acknowledgements
This study was supported by the Universitair Stimulerings Fonds (Grant no. 96/22), the Human Frontiers of Science Program (Grant no. rg0154/1998-B) and the Netherlands Organization for Scientific Research (NWO) Grants 904-57-94 and NWO/SPI 56-464-14192. DP was supported by GenomEUtwin Grant EU/QLRT-2001-01254 and by NWO/MaGW Vernieuwingsimpuls 016-065-318. This study was supported by the Centre for Medical Systems Biology (CMSB), a centre of excellence approved by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). We thank Saskia van Mil and David Sondervan from the Medical Genomics Laboratory for technical support, and Zoltan Bochdanovits for valuable comments. We also like to thank the families from the Netherland Twin Registry (NTR) who participated in this study.
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Gosso, M., de Geus, E., van Belzen, M. et al. The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts. Mol Psychiatry 11, 878–886 (2006). https://doi.org/10.1038/sj.mp.4001868
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DOI: https://doi.org/10.1038/sj.mp.4001868