Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-26T08:23:57.241Z Has data issue: false hasContentIssue false
  • English
  • Français

The one and the many: effects of the cell adhesion molecule pathway on neuropsychological function in psychosis

Published online by Cambridge University Press:  28 November 2013

A. Hargreaves ,
R. Anney ,
C. O'Dushlaine ,
K. K. Nicodemus ,
M. Gill ,
A. Corvin ,
D. Morris ,
Gary Donohoe ,
Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ)  and
Wellcome Trust Case Control Consortium 2
A. Hargreaves
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
R. Anney
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
C. O'Dushlaine
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
K. K. Nicodemus
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
M. Gill
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
A. Corvin
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
D. Morris
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland
Gary Donohoe*
Affiliation:
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, Republic of Ireland School of Psychology, National University of Ireland, Galway, Republic of Ireland
*
*Address for correspondence: Professor G. Donohoe, National University of Ireland, Galway, Republic of Ireland. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Genetic studies of single gene variants have been criticized as providing a simplistic characterization of the genetic basis of illness risk that ignores the effects of other variants within the same biological pathways. Of candidate biological pathways for schizophrenia (SZ), the cell adhesion molecule (CAM) pathway has repeatedly been linked to both psychosis and neurocognitive dysfunction. Here we tested, using risk allele scores derived from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ), whether alleles within the CAM pathway were correlated with poorer neuropsychological function in patients.

Method

In total, 424 patients with psychosis were assessed in areas of cognitive ability typically found to be impaired in SZ: intelligence quotient, memory, working memory and attentional control. CAM pathway genes were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Alleles within these genes identified as significantly associated with SZ risk in the PGC-SCZ were then used to calculate a CAM pathway-based polygenic risk allele score for each patient and these scores were tested for association with cognitive ability.

Results

Increased CAM pathway polygenic risk scores were significantly associated with poorer performance on measures of memory and attention, explaining 1–3% of variation on these measures. Notably, the most strongly associated single nucleotide polymorphism (SNP) in the CAM pathway (rs9272105 within HLA-DQA1) explained a similar amount of variance in attentional control, but not memory, as the polygenic risk analysis.

Conclusions

These data support a role for the CAM pathway in cognitive function, both at the level of individual SNPs and the wider pathway. In so doing these data highlight the value of pathway-based polygenic risk score studies as well as single gene studies for understanding SZ-associated deficits in cognition.

Keywords

Cell adhesion moleculescognitiongeneHLA-DQA1pathwaypsychosisschizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 10 , July 2014 , pp. 2177 - 2187
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bellenguez, C, Bevan, S, Gschwendtner, A, Spencer, CC, Burgess, AI, Pirinen, M, Jackson, CA, Traylor, M, Strange, A, Su, Z, Band, G, Syme, PD, Malik, R, Pera, J, Norrving, B, Lemmens, R, Freeman, C, Schanz, R, James, T, Poole, D, Murphy, L, Segal, H, Cortellini, L, Cheng, YC, Woo, D, Nalls, MA, Muller-Myhsok, B, Meisinger, C, Seedorf, U, Ross-Adams, H, Boonen, S, Wloch-Kopec, D, Valant, V, Slark, J, Furie, K, Delavaran, H, Langford, C, Deloukas, P, Edkins, S, Hunt, S, Gray, E, Dronov, S, Peltonen, L, Gretarsdottir, S, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Boncoraglio, GB, Parati, EA, Attia, J, Holliday, E, Levi, C, Franzosi, MG, Goel, A, Helgadottir, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Mathew, CG, Palmer, CN, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Worrall, BB, Kittner, SJ, Mitchell, BD, Kissela, B, Meschia, JF, Thijs, V, Lindgren, A, Macleod, MJ, Slowik, A, Walters, M, Rosand, J, Sharma, P, Farrall, M, Sudlow, CL, Rothwell, PM, Dichgans, M, Donnelly, P, Markus, HS (2012). Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nature Genetics 44, 328–333.CrossRefGoogle ScholarPubMed
Cambon, K, Hansen, SM, Venero, C, Herrero, AI, Skibo, G, Berezin, V, Bock, E, Sandi, C (2004). A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation. Journal of Neuroscience 24, 4197–4204.CrossRefGoogle ScholarPubMed
Cornblatt, BA, Risch, NJ, Faris, G, Friedman, D, Erlenmeyer-Kimling, L (1988). The Continuous Performance Test, identical pairs version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Research 26, 223–238.Google Scholar
Cummings, E, Donohoe, G, Hargreaves, A, Moore, S, Fahey, C, Dinan, TG, McDonald, C, O'Callaghan, E, O'Neill, FA, Waddington, JL, Murphy, KC, Morris, DW, Gill, M, Corvin, A (2013). Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137. Neuroscience Letters 532, 33–38.CrossRefGoogle ScholarPubMed
Dean, C, Scholl, FG, Choih, J, DeMaria, S, Berger, J, Isacoff, E, Scheiffele, P (2003). Neurexin mediates the assembly of presynaptic terminals. Nature Neuroscience 6, 708–716.Google Scholar
First, M, Spitzer, R, Gibbon, M, Williams, J (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). Biometrics Research, New York State Psychiatric Institute: New York.Google Scholar
Fowler, T, Zammit, S, Owen, MJ, Rasmussen, F (2012). A population-based study of shared genetic variation between premorbid IQ and psychosis among male twin pairs and sibling pairs from Sweden. Archives of General Psychiatry 69, 460–466.Google Scholar
Friedman, JI, Vrijenhoek, T, Markx, S, Janssen, IM, van der Vliet, WA, Faas, BH, Knoers, NV, Cahn, W, Kahn, RS, Edelmann, L, Davis, KL, Silverman, JM, Brunner, HG, van Kessel, AG, Wijmenga, C, Ophoff, RA, Veltman, JA (2008). CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Molecular Psychiatry 13, 261–266.CrossRefGoogle Scholar
Greenwood, TA, Lazzeroni, LC, Murray, SS, Cadenhead, KS, Calkins, ME, Dobie, DJ, Green, MF, Gur, RE, Gur, RC, Hardiman, G, Kelsoe, JR, Leonard, S, Light, GA, Nuechterlein, KH, Olincy, A, Radant, AD, Schork, NJ, Seidman, LJ, Siever, LJ, Silverman, JM, Stone, WS, Swerdlow, NR, Tsuang, DW, Tsuang, MT, Turetsky, BI, Freedman, R, Braff, DL (2011). Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. American Journal of Psychiatry 168, 930–946.CrossRefGoogle Scholar
International Schizophrenia Consortium; Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752.Google ScholarPubMed
Irish Schizophrenia Genomics Consortium (2012). Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biological Psychiatry 72, 620–628.Google Scholar
Jia, P, Wang, L, Fanous, AH, Chen, X, Kendler, KS, Zhao, Z (2012). A bias-reducing pathway enrichment analysis of genome-wide association data confirmed association of the MHC region with schizophrenia. Journal of Medical Genetics 49, 96–103.Google Scholar
Kirov, G, Pocklington, AJ, Holmans, P, Ivanov, D, Ikeda, M, Ruderfer, D, Moran, J, Chambert, K, Toncheva, D, Georgieva, L, Grozeva, D, Fjodorova, M, Wollerton, R, Rees, E, Nikolov, I, van de Lagemaat, LN, Bayes, A, Fernandez, E, Olason, PI, Bottcher, Y, Komiyama, NH, Collins, MO, Choudhary, J, Stefansson, K, Stefansson, H, Grant, SG, Purcell, S, Sklar, P, O'Donovan, MC, Owen, MJ (2012). De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Molecular Psychiatry 17, 142–153.CrossRefGoogle ScholarPubMed
Kos, M, van den Brink, D, Snijders, TM, Rijpkema, M, Franke, B, Fernandez, G, Hagoort, P (2012). CNTNAP2 and language processing in healthy individuals as measured with ERPs. PLOS ONE 7, e46995.Google Scholar
Lips, ES, Cornelisse, LN, Toonen, RF, Min, JL, Hultman, CM, Holmans, PA, O'Donovan, MC, Purcell, SM, Smit, AB, Verhage, M, Sullivan, PF, Visscher, PM, Posthuma, D (2012). Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Molecular Psychiatry 17, 996–1006.Google Scholar
McGuffin, P, Farmer, A, Harvey, I (1991). A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system. Archives of General Psychiatry 48, 764–770.Google Scholar
McIntosh, AM, Gow, A, Luciano, M, Davies, G, Liewald, DC, Harris, SE, Corley, J, Hall, J, Starr, JM, Porteous, DJ, Tenesa, A, Visscher, PM, Deary, IJ (2013). Polygenic risk for schizophrenia is associated with cognitive change between childhood and old age. Biological Psychiatry 73, 938–943.Google Scholar
O'Dushlaine, C, Kenny, E, Heron, E, Donohoe, G, Gill, M, Morris, D, Corvin, A (2011). Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Molecular Psychiatry 16, 286–292.CrossRefGoogle ScholarPubMed
Ripke, S, Sanders, AR, Kendler, KS, Levinson, DF, Sklar, P, Holmans, PA, Lin, DY, Duan, J, Ophoff, RA, Andreassen, OA, Scolnick, E, Cichon, S, St Clair, D, Corvin, A, Gurling, H, Werge, T, Rujescu, D, Blackwood, DH, Pato, CN, Malhotra, AK, Purcell, S, Dudbridge, F, Neale, BM, Rossin, L, Visscher, PM, Posthuma, D, Ruderfer, DM, Fanous, A, Stefansson, H, Steinberg, S, Mowry, BJ, Golimbet, V, De Hert, M, Jonsson, EG, Bitter, I, Pietilainen, OP, Collier, DA, Tosato, S, Agartz, I, Albus, M, Alexander, M, Amdur, RL, Amin, F, Bass, N, Bergen, SE, Black, DW, Borglum, AD, Brown, MA, Bruggeman, R, Buccola, NG, Byerley, WF, Cahn, W, Cantor, RM, Carr, VJ, Catts, SV, Choudhury, K, Cloninger, CR, Cormican, P, Craddock, N, Danoy, PA, Datta, S, de Haan, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Donohoe, G, Duong, L, Dwyer, S, Fink-Jensen, A, Freedman, R, Freimer, NB, Friedl, M, Georgieva, L, Giegling, I, Gill, M, Glenthoj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, AM, Henskens, FA, Hougaard, DM, Hultman, CM, Ingason, A, Jablensky, AV, Jakobsen, KD, Jay, M, Jurgens, G, Kahn, RS, Keller, MC, Kenis, G, Kenny, E, Kim, Y, Kirov, GK, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, et al. (2011). Genome-wide association study identifies five new schizophrenia loci. Nature Genetics 43, 969–976.Google Scholar
Robbins, TW, James, M, Owen, AM, Sahakian, BJ, McInnes, L, Rabbitt, P (1994). Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5, 266–281.Google Scholar
Robertson, I (1994). Sustained Attention to Response Task (SART). Trinity College Dublin: Dublin.Google Scholar
Rujescu, D, Ingason, A, Cichon, S, Pietilainen, OP, Barnes, MR, Toulopoulou, T, Picchioni, M, Vassos, E, Ettinger, U, Bramon, E, Murray, R, Ruggeri, M, Tosato, S, Bonetto, C, Steinberg, S, Sigurdsson, E, Sigmundsson, T, Petursson, H, Gylfason, A, Olason, PI, Hardarsson, G, Jonsdottir, GA, Gustafsson, O, Fossdal, R, Giegling, I, Moller, HJ, Hartmann, AM, Hoffmann, P, Crombie, C, Fraser, G, Walker, N, Lonnqvist, J, Suvisaari, J, Tuulio-Henriksson, A, Djurovic, S, Melle, I, Andreassen, OA, Hansen, T, Werge, T, Kiemeney, LA, Franke, B, Veltman, J, Buizer-Voskamp, JE, Sabatti, C, Ophoff, RA, Rietschel, M, Nothen, MM, Stefansson, K, Peltonen, L, St Clair, D, Stefansson, H, Collier, DA (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics 18, 988–996.Google Scholar
Seshadri, S, DeStefano, AL, Au, R, Massaro, JM, Beiser, AS, Kelly-Hayes, M, Kase, CS, D'Agostino, RB Sr, Decarli, C, Atwood, LD, Wolf, PA (2007). Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham Study. BMC Medical Genetics 8 (Suppl. 1), S15.Google Scholar
Shatz, CJ (2009). MHC class I: an unexpected role in neuronal plasticity. Neuron 64, 40–45.CrossRefGoogle ScholarPubMed
Soronen, P, Ollila, HM, Antila, M, Silander, K, Palo, OM, Kieseppa, T, Lonnqvist, J, Peltonen, L, Tuulio-Henriksson, A, Partonen, T, Paunio, T (2010). Replication of GWAS of bipolar disorder: association of SNPs near CDH7 with bipolar disorder and visual processing. MolecularPsychiatry 15, 4–6.Google ScholarPubMed
SPSS (2008). SPSS 16.0 Command Syntax Reference. SPSS Inc.: Chicago.Google Scholar
Sun, C, Cheng, MC, Qin, R, Liao, DL, Chen, TT, Koong, FJ, Chen, G, Chen, CH (2011). Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Human Molecular Genetics 20, 3042–3051.CrossRefGoogle ScholarPubMed
Toulopoulou, T, Picchioni, M, Rijsdijk, F, Hua-Hall, M, Ettinger, U, Sham, P, Murray, R (2007). Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Archives of General Psychiatry 64, 1348–1355.Google Scholar
Voineskos, AN, Lett, TA, Lerch, JP, Tiwari, AK, Ameis, SH, Rajji, TK, Muller, DJ, Mulsant, BH, Kennedy, JL (2011). Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders. PLoS One 6, e20982.Google Scholar
Wang, K, Zhang, H, Ma, D, Bucan, M, Glessner, JT, Abrahams, BS, Salyakina, D, Imielinski, M, Bradfield, JP, Sleiman, PM, Kim, CE, Hou, C, Frackelton, E, Chiavacci, R, Takahashi, N, Sakurai, T, Rappaport, E, Lajonchere, CM, Munson, J, Estes, A, Korvatska, O, Piven, J, Sonnenblick, LI, Alvarez Retuerto, AI, Herman, EI, Dong, H, Hutman, T, Sigman, M, Ozonoff, S, Klin, A, Owley, T, Sweeney, JA, Brune, CW, Cantor, RM, Bernier, R, Gilbert, JR, Cuccaro, ML, McMahon, WM, Miller, J, State, MW, Wassink, TH, Coon, H, Levy, SE, Schultz, RT, Nurnberger, JI, Haines, JL, Sutcliffe, JS, Cook, EH, Minshew, NJ, Buxbaum, JD, Dawson, G, Grant, SF, Geschwind, DH, Pericak-Vance, MA, Schellenberg, GD, Hakonarson, H (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528–533.Google Scholar
Wechsler, D (1997 a). Wechsler Adult Intelligence Test, 3rd edn (WAIS-III). Harcourt Assessment: San Antonio.Google Scholar
Wechsler, D (1997 b). Wechsler Memory Scale, 3rd edn (WAIS-III). The Psychological Corporation: San Antonio.Google Scholar
Supplementary material: File

Hargreaves et al. Supplementary Material

Supplementary Material

Download Hargreaves et al. Supplementary Material(File)
File 68.6 KB