Hostname: page-component-7c8c6479df-nwzlb Total loading time: 0 Render date: 2024-03-28T14:49:28.069Z Has data issue: false hasContentIssue false

Schizophrenia genetic variants are not associated with intelligence

Published online by Cambridge University Press:  15 February 2013

A. F. Terwisscha van Scheltinga*
Affiliation:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
S. C. Bakker
Affiliation:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
N. E. M. van Haren
Affiliation:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
E. M. Derks
Affiliation:
Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands
J. E. Buizer-Voskamp
Affiliation:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
W. Cahn
Affiliation:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
S. Ripke
Affiliation:
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
R. A. Ophoff
Affiliation:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands Center for Neurobehavioral Genetics, University of California, Los Angeles, USA
R. S. Kahn
Affiliation:
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands
*
*Address for correspondence: A. F. Terwisscha van Scheltinga, M.D. Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Huispostnummer A00.241, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. (Email: aterwiss@umcutrecht.nl)

Abstract

Background

Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence.

Method

IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls.

Results

Although significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R2 = 0.055, p = 2.1 × 10−7) and with IQ in the entire sample (R2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status.

Conclusions

Our data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.

Type
Original Articles
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

Andreasen, NC, Flaum, M, Arndt, S (1992). The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology? Archives of General Psychiatry 49, 615623.CrossRefGoogle ScholarPubMed
Aukes, MF, Alizadeh, BZ, Sitskoorn, MM, Kemner, C, Ophoff, RA, Kahn, RS (2009). Genetic overlap among intelligence and other candidate endophenotypes for schizophrenia? Biological Psychiatry 65, 527534.CrossRefGoogle ScholarPubMed
Boos, HB, Aleman, A, Cahn, W, Hulshoff Pol, HE, Kahn, RS (2007). Brain volumes in relatives of patients with schizophrenia: a meta-analysis? Archives of General Psychiatry 64, 297304.CrossRefGoogle ScholarPubMed
Buizer-Voskamp, JE, Muntjewerff, JW, Strengman, E, Sabatti, C, Stefansson, H, Vorstman, JA, Ophoff, RA (2011). Genome-wide analysis shows increased frequency of copy number variation deletions in Dutch schizophrenia patients? Biological Psychiatry 70, 655662.CrossRefGoogle ScholarPubMed
Cardno, AG, Marshall, EJ, Coid, B, Macdonald, AM, Ribchester, TR, Davies, NJ, Venturi, P, Jones, LA, Lewis, SW, Sham, PC, Gottesman, II, Farmer, AE, McGuffin, P, Reveley, AM, Murray, RM (1999). Heritability estimates for psychotic disorders: the Maudsley twin psychosis series? Archives of General Psychiatry 56, 162168.CrossRefGoogle ScholarPubMed
Deary, IJ, Yang, J, Davies, G, Harris, SE, Tenesa, A, Liewald, D, Luciano, M, Lopez, LM, Gow, AJ, Corley, J, Redmond, P, Fox, HC, Rowe, SJ, Haggarty, P, McNeill, G, Goddard, ME, Porteous, DJ, Whalley, LJ, Starr, JM, Visscher, PM (2012). Genetic contributions to stability and change in intelligence from childhood to old age? Nature 482, 212215.CrossRefGoogle ScholarPubMed
Elvevag, B, Goldberg, TE (2000). Cognitive impairment in schizophrenia is the core of the disorder? Critical Reviews in Neurobiology 14, 121.CrossRefGoogle ScholarPubMed
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, 460466.Google ScholarPubMed
Gottesman, II, Gould, TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions? American Journal of Psychiatry 160, 636645.CrossRefGoogle ScholarPubMed
Guilmatre, A, Dubourg, C, Mosca, AL, Legallic, S, Goldenberg, A, Drouin-Garraud, V, Layet, V, Rosier, A, Briault, S, Bonnet-Brilhault, F, Laumonnier, F, Odent, S, Le Vacon, G, Joly-Helas, G, David, V, Bendavid, C, Pinoit, JM, Henry, C, Impallomeni, C, Germano, E, Tortorella, G, Di Rosa, G, Barthelemy, C, Andres, C, Faivre, L, Frebourg, T, Saugier, VP, Campion, D (2009). Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation? Archives of General Psychiatry 66, 947956.CrossRefGoogle ScholarPubMed
Hedman, AM, van Haren, NE, van Baal, GC, Brans, RG, Hijman, R, Kahn, RS, Hulshoff Pol, HE (2012). Is there change in intelligence quotient in chronically ill schizophrenia patients? A longitudinal study in twins discordant for schizophrenia? Psychological Medicine 42, 25352541.CrossRefGoogle ScholarPubMed
Khandaker, GM, Barnett, JH, White, IR, Jones, PB (2011). A quantitative meta-analysis of population-based studies of premorbid intelligence and schizophrenia? Schizophrenia Research 132, 220227.CrossRefGoogle ScholarPubMed
Kraepelin, E (1919). Dementia Praecox and Paraphrenia. E & S Livingstone: Edinburgh.Google Scholar
Lee, SH, Decandia, TR, Ripke, S, Yang, J, Sullivan, PF, Goddard, ME, Keller, MC, Visscher, PM, Wray, NR (2012). Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs? Nature Genetics 44, 247250.CrossRefGoogle ScholarPubMed
Mesholam-Gately, RI, Giuliano, AJ, Goff, KP, Faraone, SV, Seidman, LJ (2009). Neurocognition in first-episode schizophrenia: a meta-analytic review? Neuropsychology. 23, 315336.CrossRefGoogle ScholarPubMed
Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MA, Bender, D, Maller, J, Sklar, P, de Bakker, PI, Daly, MJ, Sham, PC (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses? American Journal of Human Genetics 81, 559575.CrossRefGoogle ScholarPubMed
Reichenberg, A, Caspi, A, Harrington, H, Houts, R, Keefe, RS, Murray, RM, Poulton, R, Moffitt, TE (2010). Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: a 30-year study? American Journal of Psychiatry 167, 160169.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 Haan, 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 Hann, 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, Lasseter, VK, Laurent, C, Lawrence, J, Lencz, T, Lerer, FB, Liang, KY, Lichtenstein, P, Lieberman, JA, Linszen, DH, Lonnqvist, J, Loughland, CM, MacLean, AW, Maher, BS, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, McGhee, KA, McGrath, JJ, McIntosh, A, McLean, DE, McQuillin, A, Melle, I, Michie, PT, Milanova, V, Morris, DW, Mors, O, Mortensen, PB, Moskvina, V, Muglia, P, Myin-Germeys, I, Nertney, DA, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nothen, MM, O'Dushlaine, CT, Olincy, A, Olsen, L, O'Neill, FA, Orntoft, TF, Owen, MJ, Pantelis, C, Papadimitriou, G, Pato, MT, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, AE, Puri, V, Quested, D, Quinn, EM, Rasmussen, HB, Rethelyi, JM, Ribble, R, Rietschel, M, Riley, BP, Ruggeri, M, Schall, U, Schulze, TG, Schwab, SG, Scott, RJ, Shi, J, Sigurdsson, E, Silverman, JM, Spencer, CC, Stefansson, K, Strange, A, Strengman, E, Stroup, TS, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, JH, Timm, S, Toncheva, D, van den Oord, E, van Os, J, van Winkel, R, Veldink, J, Walsh, D, Wang, AG, Wiersma, D, Wildenauer, DB, Williams, HJ, Williams, NM, Wormley, B, Zammit, S, Sullivan, PF, O'Donovan, MC, Daly, MJ, Gejman, PV (2011). Genome-wide association study identifies five new schizophrenia loci? Nature Genetics 10, 969976.Google Scholar
Stefansson, H, Rujescu, D, Cichon, S, Pietilainen, OP, Ingason, A, Steinberg, S, Fossdal, R, Sigurdsson, E, Sigmundsson, T, Buizer-Voskamp, JE, Hansen, T, Jakobsen, KD, Muglia, P, Francks, C, Matthews, PM, Gylfason, A, Halldorsson, BV, Gudbjartsson, D, Thorgeirsson, TE, Sigurdsson, A, Jonasdottir, A, Jonasdottir, A, Bjornsson, A, Mattiasdottir, S, Blondal, T, Haraldsson, M, Magnusdottir, BB, Giegling, I, Moller, HJ, Hartmann, A, Shianna, KV, Ge, D, Need, AC, Crombie, C, Fraser, G, Walker, N, Lonnqvist, J, Suvisaari, J, Tuulio-Henriksson, A, Paunio, T, Toulopoulou, T, Bramon, E, Di Forti, M, Murray, R, Ruggeri, M, Vassos, E, Tosato, S, Walshe, M, Li, T, Vasilescu, C, Muhleisen, TW, Wang, AG, Ullum, H, Djurovic, S, Melle, I, Olesen, J, Kiemeney, LA, Franke, B, Kahn, RS, Linszen, D, van Os, J, Wiersma, D, Bruggeman, R, Cahn, W, Germeys, I, de Haan, L, Krabbendam, L, Sabatti, C, Freimer, NB, Gulcher, JR, Thorsteinsdottir, U, Kong, A, Andreassen, OA, Ophoff, RA, Georgi, A, Rietschel, M, Werge, T, Petursson, H, Goldstein, DB, Nothen, MM, Peltonen, L, Collier, DA, St Clair, D, Stefansson, K (2008). Large recurrent microdeletions associated with schizophrenia? Nature 455, 232236.CrossRefGoogle ScholarPubMed
Stinissen, J, Willems, PJ, Coetsier, P, Hulsman, WWL (1970). Manual of the Dutch Translation of the Wechsler Adult Intelligence Scale. Swets: Amsterdam, The Netherlands.Google Scholar
Terwisscha van Scheltinga, A, Bakker, S, van Haren, N, Buizer-Voskamp, J, Boos, H, Vorstman, J, Cahn, W, Hulshoff Poll, H, Ophoff, R, Kahn, R (2012 a). Association study of copy number variants with brain volume in schizophrenia patients and healthy controls? Psychiatry Research 30, 10111013.CrossRefGoogle Scholar
Terwisscha van Scheltinga, AF, Bakker, SC, van Haren, NEM, Derks, EM, Buizer-Voskamp, JE, Boos, HB, Cahn, W, Hulshoff Pol, HE, Ripke, S, Ophoff, RA, Kahn, RS; the Psychiatric GWAS Consortium (2012 b). Genetic schizophrenia risk variants jointly modulate total brain and white matter volume? Biological Psychiatry. Published online: 3 October 2012. doi:10.1016/j.biopsych.2012.08.017.Google 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, 13481355.CrossRefGoogle ScholarPubMed
van Haren, NEM, Rijsdijk, F, Schnack, HG, Picchioni, MM, Toulopoulou, T, Weisbrod, M, Sauer, H, van Erp, TG, Cannon, TD, Huttunen, MO, Boomsma, DI, Hulshoff Pol, HE, Murray, RM, Kahn, RS (2012). The genetic and environmental determinants of the association between brain abnormalities and schizophrenia: the Schizophrenia Twins and Relatives Consortium? Biological Psychiatry 71, 915921.CrossRefGoogle ScholarPubMed
Walsh, T, McClellan, JM, McCarthy, SE, Addington, AM, Pierce, SB, Cooper, GM, Nord, AS, Kusenda, M, Malhotra, D, Bhandari, A, Stray, SM, Rippey, CF, Roccanova, P, Makarov, V, Lakshmi, B, Findling, RL, Sikich, L, Stromberg, T, Merriman, B, Gogtay, N, Butler, P, Eckstrand, K, Noory, L, Gochman, P, Long, R, Chen, Z, Davis, S, Baker, C, Eichler, EE, Meltzer, PS, Nelson, SF, Singleton, AB, Lee, MK, Rapoport, JL, King, MC, Sebat, J (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia? Science 320, 539543.CrossRefGoogle ScholarPubMed
Wright, IC, Rabe-Hesketh, S, Woodruff, PW, David, AS, Murray, RM, Bullmore, ET (2000). Meta-analysis of regional brain volumes in schizophrenia? American Journal of Psychiatry 157, 1625.CrossRefGoogle ScholarPubMed
Xu, B, Roos, JL, Levy, S, van Rensburg, EJ, Gogos, JA, Karayiorgou, M (2008). Strong association of de novo copy number mutations with sporadic schizophrenia? Nature Genetics 40, 880885.CrossRefGoogle ScholarPubMed
Yeo, RA, Gangestad, SW, Liu, J, Calhoun, VD, Hutchison, KE (2011). Rare copy number deletions predict individual variation in intelligence? PloS One 6, e16339.CrossRefGoogle ScholarPubMed