Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia Andrew K. Martin a,n, G. Robinson b, D. Reutens c, B. Mowry a,d a
University of Queensland, Queensland Brain Institute, St. Lucia, Queensland 4072, Australia University of Queensland, School of Psychology, St. Lucia, Queensland 4072, Australia c University of Queensland, Centre for Advanced Imaging, St. Lucia, Queensland 4072, Australia d University of Queensland, Queensland Centre for Mental Health Research, Wacol 4076, Queensland b
art ic l e i nf o
a b s t r a c t
Article history: Received 9 February 2015 Received in revised form 17 April 2015 Accepted 25 April 2015
Schizophrenia is a clinically heterogeneous disorder associated with broad deficits across cognitive domains. As large genomewide association studies uncover the genetic architecture of schizophrenia, the relationship between common genetic variants and clinical and cognitive characteristics will form part of an integrative approach to understanding genetic effects on the clinical phenotype. In the current study, association between common genetic risk variants and clinical and cognitive variables was investigated. Common risk variants were associated with positive symptoms and decision-making ability from the Cambridge Gambling Task with trends in other domains. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cognition Polygene risk scores Positive symptoms
1. Introduction Schizophrenia is a debilitating, chronic mental illness with cognitive dysfunction as one of its cardinal features. Heritability estimates are as high as 80% (Cardno and Gottesman, 2000) and several large studies have begun the process of understanding the complex genetic architecture of schizophrenia (Mowry and Gratten, 2013). The emerging picture is one of sobering complexity with many common variants and most likely a smaller number of rare variants. Although each common variant represents a very small increase in disease risk, aggregate measures of common variants, such as the polygenic risk score (PRS), have greater probabilistic predictive ability (Purcell et al., 2009; Wray et al., 2014). PRS are calculated based on all single nucleotide polymorphisms (SNPs) that are associated with disease risk given a certain threshold of statistical significance. However, little is known about the phenotypic characteristics associated with risk variants. Identifying associations between genetic risk variants for schizophrenia and cognition will increase our understanding of the pathway from genotype to phenotype (Gur et al., 2007). Two recent studies taking this approach found contrasting results. In a large sample of healthy older adults without schizophrenia, PRS (calculated according to Purcell et al. (2009)) was associated with greater cognitive decline
n
Corresponding author. Tel.: þ 61 7 3346 6351. E-mail addresses: [email protected], [email protected] (A.K. Martin).
(McIntosh et al., 2013), but in a smaller sample of patients with schizophrenia and age and sex matched controls, PRS was only associated with intelligence in patients (van Scheltinga et al., 2013). A recent study observed PRS to be associated with general cognitive ability and several measures of “executive” functions. However, the executive measures did not remain significant after controlling for general cognitive functioning, suggesting that PRS only affects general cognitive ability, often termed ‘g’ or fluid intelligence (Yeo et al., 2014). The Yeo et al. (2014) study also included rare copy number deletion burden across the genome with similar association identified with executive measures and general cognitive functioning. The authors suggest that both rare deletions and PRS may act on similar pathways. In the current study, associations were investigated across PRS and a broader range of cognitive domains than previously studied. PRS was determined from a large discovery sample from the Psychiatric Genomics Consortium (PGC) (34,351 cases and 110,593 controls) representing the latest and most comprehensive aggregate measure of common risk variants in schizophrenia.
2. Method 2.1. Participants Seventy-three patients with schizophrenia and GWAS data were recruited through the Queensland Centre for Mental Health Research, Brisbane. This cohort formed part of an Australian subsample (N ¼633) of a large GWAS study (Levinson et al.,
http://dx.doi.org/10.1016/j.psychres.2015.04.045 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Martin, A.K., et al., Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.045i
A.K. Martin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2
2011). Cognitive assessments were conducted blind to polygene risk score (PRS) status as these were computed after the cognitive data had been collected. Missing cognitive data on specific measures was due to patient distractibility or time constraints. A trained psychiatric nurse and a research assistant, under the supervision of a clinical neuropsychologist, carried out all neuropsychological testing. Regular meetings and supervision removed any bias between the two cognitive assessors. Testing took place at the participant's place of residence or at a hospital facility.
Table 1 Neuropsychological and clinical correlates of polygenic risk scores in patients. N
Correlation Pearson's r
Sig
Clinical Positive Neg/Dis Mood AAO
73 73 73 73
0.316 0.081 0.073 0.124
0.006 0.494 0.538 0.295
Fluid intelligence Matrix reasoning
73
0.174
0.141
Executive functions Hayling Section 2 error Stroop test Phonemic word fluency Semantic word fluency Digit-span backwards
73 66 71 71 71
0.152 0.235 0.090 0.129 0.230
0.199 0.058 0.458 0.285 0.054
Language Vocabulary Syd-Bat naming
71 71
0.290 0.230
0.013 0.054
2.3. Clinical Assessment
Episodic memory RAVLT total
71
0.113
0.346
Three clinical factors (positive, negative/disorganized, mood) were computed based on the factor analysis carried out by Fanous et al. (2012) using the Lifetime Dimensions of Psychosis Scale (LDPS) (Levinson et al., 2002). Age at onset was ascertained through medical records and both the Family Interview for Genetic Studies (FIGS) (Maxwell, 1992) and the Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994).
Processing speed Symbol–digit modalities
70
2.2. Polygene risk score Polygene risk scores (PRS) were computed from a discovery sample of 34,351 Sz cases and 110,593 controls and calculated for each individual in an independent target sample of 629 cases of which the 73 participants in this study were drawn. A detailed outline of the method and rationale for PRS is provided elsewhere (Wray et al., 2014).
2.4. Neuropsychological assessment Participants were assessed on a broad neuropsychological battery designed to test the following cognitive domains: executive functions (Hayling Sentence Completion Task, Stroop Test, Word fluency, Digit-span backwards, Decision-making), verbal memory (Rey's Auditory Verbal Learning Test), language (Syd-Bat Naming Task & Vocabulary), processing speed (Symbol–digit Modalities), and visuospatial learning (Pattern Recognition Memory, Spatial Recognition Memory, Paired Associates Learning). See Supplementary materials for more details. 2.5. Statistical analysis All analysis was conducted in SPSS version 20.0. T-test or Pearson's correlation was used to measure the difference between PRS and both sex and age. Pearson's correlation was used to find the relationship between the cognitive measure and PRS. Bonferroni was set at 0.05/14¼ 0.004 for correction for multiple comparisons. For clinical measures, significance was set at 0.05/4 ¼0.013. 3. Results PRS was positively correlated with positive symptoms but no relationships were observed for negative/disorganized or mood symptoms or AAO (see Table 1). Table 1 also provides means for performance on all measures and provides Pearson's correlation scores between PRS and all cognitive measures. PRS was significantly associated with vocabulary and CGT decision-making. After Bonferroni correction for multiple comparisons (p o0.004) only the correlation between PRS and CGT remained significant. As PRS was positively correlated with lifetime positive symptom score, this was subsequently entered into the model for the cognitive measures associated with PRS. Positive symptom score had no effect on the association between PRS and both decision-making quality and vocabulary.
0.133
0.272
Visuo-spatial learning and memory PRM 65 SRM 65 PAL errors (reversed) 64
0.227 0.004 0.145
0.069 0.973 0.253
Cambridge gambling task CGT decision-making
0.402
0.001
61
RAVLT ¼ Rey's Auditory and Verbal Learning Test; PRM¼ Pattern Recognition Memory; SRM¼ Spatial Recognition Memory; PAL¼ Paired Associates Learning; CGT ¼ Cambridge Gambling Task; AAO ¼ Age at onset; Neg/Dis¼ Negative and disorganized symptom.
4. Discussion Polygenic risk score (PRS) was negatively correlated with decision-making ability on the Cambridge Gambling Task (CGT). Nominal association was identified between PRS and vocabulary from the Weschler Abbreviated Scale of Intelligence (WASI). Lifetime positive symptom rating was positively correlated with PRS, but this did not mediate the relationship between PRS and either decision-making or vocabulary. Decision-making deficits using the CGT have previously been identified in chronic patients but not first-episode patients (Hutton et al., 2002) suggesting disease processes may influence performance. Here we show that genetic risk variants, especially PRS, may influence performance, independent from symptom effects. The decision-making component of the CGT is considered sensitive to orbitofrontal cortical (OFC) functioning (Rogers et al., 1999), although using diffusion tensor imaging (DTI) of greymatter in patients with traumatic brain injury, regional differences in the left hippocampus, striatum, ventrolateral and dorsolateral prefrontal cortex (dlPFC), were also associated with decisionmaking quality (Newcombe et al., 2011). The fact that PRS was not significantly associated with measures known to recruit dlPFC, such as those measuring fluid intelligence, working memory and executive functions (Kane and Engle, 2002), suggests the OFC, and its connections, may be disproportionately affected by common schizophrenia risk variants. The trend showing an association between measures of language and PRS, points to an early neurodevelopmental deficit, rather than greater decline after the onset of illness. Verbal knowledge is less likely to deteriorate after brain insult (Nelson and O'Connell, 1978) and less affected before the onset of psychosis (Amminger et al., 2000). Therefore, reduced performance on
Please cite this article as: Martin, A.K., et al., Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.045i
A.K. Martin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
verbal measures of general knowledge is indicative of lower premorbid cognitive function. As verbal IQ measures are considered measures of crystal intelligence and indicative of learning processes, especially in verbal domains, PRS may impact on neural processes relevant for plasticity. The current study provides novel evidence for an association between common risk variants and decision-making ablity in patients with schizophrenia. Examining the processes underlying these cognitive domains may provide evidence for brain networks or regions that are disproportionately affected by schizophrenia risk variants and provide evidence for both key cognitive markers of disease and potential pathways from genotype to phenotype. Financial disclosure This work was supported by the Australian National Health and Medical Research Council (Grant no. 631671) and the United States National Institute of Mental Health (Grant no. RO1 MH59588). Conflict of interest The authors report no conflicts of interest. Acknowledgments We would like to acknowledge all the participants and their families. We acknowledge the MGS Australian recruitment team and the MGS consortium. We thank Divya Mehta for providing the polygenic risk scores. We thank Andrea Baker, Deborah Nertney and Duncan McLean for their assistance in collecting the cognitive data. Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2015.04.045. References Amminger, G.P., Schlogelhofer, M., Lehner, T., Looser Ott, S., Friedrich, M.H., Aschauer, H.N., 2000. Premorbid performance IQ deficit in schizophrenia. Acta Psychiatrica Scandinavica 102, 414–422. Cardno, A.G., Gottesman, I.I., 2000. Twin studies of schizophrenia: from bow-andarrow concordances to star wars Mx and functional genomics. American Journal of Medical Genetics 97, 12–17. Fanous, A.H., Zhou, B., Aggen, S.H., Bergen, S.E., Amdur, R.L., Duan, J., Sanders, A.R., Shi, J., Mowry, B.J., Olincy, A., Amin, F., Cloninger, C.R., Silverman, J.M., Buccola, N.G., Byerley, W.F., Black, D.W., Freedman, R., Dudbridge, F., Holmans, P.A., Ripke, S., Gejman, P.V., Kendler, K.S., Levinson, D.F., 2012. Genome-wide association study of clinical dimensions of schizophrenia: polygenic effect on disorganized symptoms. The American Journal of Psychiatry 169, 1309–1317.
3
Gur, R.E., Calkins, M.E., Gur, R.C., Horan, W.P., Nuechterlein, K.H., Seidman, L.J., Stone, W.S., 2007. The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes. Schizophrenia Bulletin 33, 49–68. Hutton, S.B., Murphy, F.C., Joyce, E.M., Rogers, R.D., Cuthbert, I., Barnes, T.R., McKenna, P.J., Sahakian, B.J., Robbins, T.W., 2002. Decision making deficits in patients with first-episode and chronic schizophrenia. Schizophrenia Research 55, 249–257. Kane, M.J., Engle, R.W., 2002. The role of prefrontal cortex in working-memory capacity, executive attention, and general fluid intelligence: an individualdifferences perspective. Psychonomic Bulletin & Review 9, 637–671. Levinson, D.F., Duan, J., Oh, S., Wang, K., Sanders, A.R., Shi, J., Zhang, N., Mowry, B.J., Olincy, A., Amin, F., Cloninger, C.R., Silverman, J.M., Buccola, N.G., Byerley, W.F., Black, D.W., Kendler, K.S., Freedman, R., Dudbridge, F., Pe'er, I., Hakonarson, H., Bergen, S.E., Fanous, A.H., Holmans, P.A., Gejman, P.V., 2011. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. The American Journal of Psychiatry 168, 302–316. Levinson, D.F., Mowry, B.J., Escamilla, M.A., Faraone, S.V., 2002. The Lifetime Dimensions of Psychosis Scale (LDPS): description and interrater reliability. Schizophrenia Bulletin 28, 683–695. Maxwell, M.E., 1992. Family Interview for Genetic Studies (FIGS): A Manual for FIGS. Clinical Neurogenetics Branch, Intramural Research Program, NIMH, Bethesda, MD. McIntosh, A.M., Gow, A., Luciano, M., Davies, G., Liewald, D.C., Harris, S.E., Corley, J., Hall, J., Starr, J.M., Porteous, D.J., Tenesa, A., Visscher, P.M., Deary, I.J., 2013. Polygenic risk for schizophrenia is associated with cognitive change between childhood and old age. Biological Psychiatry 73, 938–943. Mowry, B.J., Gratten, J., 2013. The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants. Molecular Psychiatry 18, 38–52. Nelson, H.E., O'Connell, A., 1978. Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex; A Journal Devoted to the Study of the Nervous System and Behavior 14, 234–244. Newcombe, V.F., Outtrim, J.G., Chatfield, D.A., Manktelow, A., Hutchinson, P.J., Coles, J.P., Williams, G.B., Sahakian, B.J., Menon, D.K., 2011. Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury. Brain: A Journal of Neurology 134, 759–768. Nurnberger Jr., J.I., Blehar, M.C., Kaufmann, C.A., York-Cooler, C., Simpson, S.G., Harkavy-Friedman, J., Severe, J.B., Malaspina, D., Reich, T., 1994. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Archives of General Psychiatry 51, 849–859 (discussion 844–863). Purcell, S.M., Wray, N.R., Stone, J.L., Visscher, P.M., O'Donovan, M.C., Sullivan, P.F., Sklar, P., 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752. Rogers, R.D., Everitt, B.J., Baldacchino, A., Blackshaw, A.J., Swainson, R., Wynne, K., Baker, N.B., Hunter, J., Carthy, T., Booker, E., London, M., Deakin, J.F., Sahakian, B. J., Robbins, T.W., 1999. Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 20, 322–339. van Scheltinga, A.F., Bakker, S.C., van Haren, N.E., Derks, E.M., Buizer-Voskamp, J.E., Cahn, W., Ripke, S., Ophoff, R.A., Kahn, R.S., 2013. Schizophrenia genetic variants are not associated with intelligence. Psychological Medicine 43, 2563–2570. Wray, N.R., Lee, S.H., Mehta, D., Vinkhuyzen, A.A., Dudbridge, F., Middeldorp, C.M., 2014. Research review: polygenic methods and their application to psychiatric traits. Journal of Child Psychology and Psychiatry and Allied Disciplines 55, 1068–1087. Yeo, R.A., Gangestad, S.W., Walton, E., Ehrlich, S., Pommy, J., Turner, J.A., Liu, J., Mayer, A.R., Schulz, S.C., Ho, B.C., Bustillo, J.R., Wassink, T.H., Sponheim, S.R., Morrow, E.M., Calhoun, V.D., 2014. Genetic influences on cognitive endophenotypes in schizophrenia. Schizophrenia Research 156, 71–75.
Please cite this article as: Martin, A.K., et al., Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.045i
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia Andrew K. Martin a,n, G. Robinson b, D. Reutens c, B. Mowry a,d a
University of Queensland, Queensland Brain Institute, St. Lucia, Queensland 4072, Australia University of Queensland, School of Psychology, St. Lucia, Queensland 4072, Australia c University of Queensland, Centre for Advanced Imaging, St. Lucia, Queensland 4072, Australia d University of Queensland, Queensland Centre for Mental Health Research, Wacol 4076, Queensland b
art ic l e i nf o
a b s t r a c t
Article history: Received 9 February 2015 Received in revised form 17 April 2015 Accepted 25 April 2015
Schizophrenia is a clinically heterogeneous disorder associated with broad deficits across cognitive domains. As large genomewide association studies uncover the genetic architecture of schizophrenia, the relationship between common genetic variants and clinical and cognitive characteristics will form part of an integrative approach to understanding genetic effects on the clinical phenotype. In the current study, association between common genetic risk variants and clinical and cognitive variables was investigated. Common risk variants were associated with positive symptoms and decision-making ability from the Cambridge Gambling Task with trends in other domains. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cognition Polygene risk scores Positive symptoms
1. Introduction Schizophrenia is a debilitating, chronic mental illness with cognitive dysfunction as one of its cardinal features. Heritability estimates are as high as 80% (Cardno and Gottesman, 2000) and several large studies have begun the process of understanding the complex genetic architecture of schizophrenia (Mowry and Gratten, 2013). The emerging picture is one of sobering complexity with many common variants and most likely a smaller number of rare variants. Although each common variant represents a very small increase in disease risk, aggregate measures of common variants, such as the polygenic risk score (PRS), have greater probabilistic predictive ability (Purcell et al., 2009; Wray et al., 2014). PRS are calculated based on all single nucleotide polymorphisms (SNPs) that are associated with disease risk given a certain threshold of statistical significance. However, little is known about the phenotypic characteristics associated with risk variants. Identifying associations between genetic risk variants for schizophrenia and cognition will increase our understanding of the pathway from genotype to phenotype (Gur et al., 2007). Two recent studies taking this approach found contrasting results. In a large sample of healthy older adults without schizophrenia, PRS (calculated according to Purcell et al. (2009)) was associated with greater cognitive decline
n
Corresponding author. Tel.: þ 61 7 3346 6351. E-mail addresses: [email protected], [email protected] (A.K. Martin).
(McIntosh et al., 2013), but in a smaller sample of patients with schizophrenia and age and sex matched controls, PRS was only associated with intelligence in patients (van Scheltinga et al., 2013). A recent study observed PRS to be associated with general cognitive ability and several measures of “executive” functions. However, the executive measures did not remain significant after controlling for general cognitive functioning, suggesting that PRS only affects general cognitive ability, often termed ‘g’ or fluid intelligence (Yeo et al., 2014). The Yeo et al. (2014) study also included rare copy number deletion burden across the genome with similar association identified with executive measures and general cognitive functioning. The authors suggest that both rare deletions and PRS may act on similar pathways. In the current study, associations were investigated across PRS and a broader range of cognitive domains than previously studied. PRS was determined from a large discovery sample from the Psychiatric Genomics Consortium (PGC) (34,351 cases and 110,593 controls) representing the latest and most comprehensive aggregate measure of common risk variants in schizophrenia.
2. Method 2.1. Participants Seventy-three patients with schizophrenia and GWAS data were recruited through the Queensland Centre for Mental Health Research, Brisbane. This cohort formed part of an Australian subsample (N ¼633) of a large GWAS study (Levinson et al.,
http://dx.doi.org/10.1016/j.psychres.2015.04.045 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Martin, A.K., et al., Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.045i
A.K. Martin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2
2011). Cognitive assessments were conducted blind to polygene risk score (PRS) status as these were computed after the cognitive data had been collected. Missing cognitive data on specific measures was due to patient distractibility or time constraints. A trained psychiatric nurse and a research assistant, under the supervision of a clinical neuropsychologist, carried out all neuropsychological testing. Regular meetings and supervision removed any bias between the two cognitive assessors. Testing took place at the participant's place of residence or at a hospital facility.
Table 1 Neuropsychological and clinical correlates of polygenic risk scores in patients. N
Correlation Pearson's r
Sig
Clinical Positive Neg/Dis Mood AAO
73 73 73 73
0.316 0.081 0.073 0.124
0.006 0.494 0.538 0.295
Fluid intelligence Matrix reasoning
73
0.174
0.141
Executive functions Hayling Section 2 error Stroop test Phonemic word fluency Semantic word fluency Digit-span backwards
73 66 71 71 71
0.152 0.235 0.090 0.129 0.230
0.199 0.058 0.458 0.285 0.054
Language Vocabulary Syd-Bat naming
71 71
0.290 0.230
0.013 0.054
2.3. Clinical Assessment
Episodic memory RAVLT total
71
0.113
0.346
Three clinical factors (positive, negative/disorganized, mood) were computed based on the factor analysis carried out by Fanous et al. (2012) using the Lifetime Dimensions of Psychosis Scale (LDPS) (Levinson et al., 2002). Age at onset was ascertained through medical records and both the Family Interview for Genetic Studies (FIGS) (Maxwell, 1992) and the Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994).
Processing speed Symbol–digit modalities
70
2.2. Polygene risk score Polygene risk scores (PRS) were computed from a discovery sample of 34,351 Sz cases and 110,593 controls and calculated for each individual in an independent target sample of 629 cases of which the 73 participants in this study were drawn. A detailed outline of the method and rationale for PRS is provided elsewhere (Wray et al., 2014).
2.4. Neuropsychological assessment Participants were assessed on a broad neuropsychological battery designed to test the following cognitive domains: executive functions (Hayling Sentence Completion Task, Stroop Test, Word fluency, Digit-span backwards, Decision-making), verbal memory (Rey's Auditory Verbal Learning Test), language (Syd-Bat Naming Task & Vocabulary), processing speed (Symbol–digit Modalities), and visuospatial learning (Pattern Recognition Memory, Spatial Recognition Memory, Paired Associates Learning). See Supplementary materials for more details. 2.5. Statistical analysis All analysis was conducted in SPSS version 20.0. T-test or Pearson's correlation was used to measure the difference between PRS and both sex and age. Pearson's correlation was used to find the relationship between the cognitive measure and PRS. Bonferroni was set at 0.05/14¼ 0.004 for correction for multiple comparisons. For clinical measures, significance was set at 0.05/4 ¼0.013. 3. Results PRS was positively correlated with positive symptoms but no relationships were observed for negative/disorganized or mood symptoms or AAO (see Table 1). Table 1 also provides means for performance on all measures and provides Pearson's correlation scores between PRS and all cognitive measures. PRS was significantly associated with vocabulary and CGT decision-making. After Bonferroni correction for multiple comparisons (p o0.004) only the correlation between PRS and CGT remained significant. As PRS was positively correlated with lifetime positive symptom score, this was subsequently entered into the model for the cognitive measures associated with PRS. Positive symptom score had no effect on the association between PRS and both decision-making quality and vocabulary.
0.133
0.272
Visuo-spatial learning and memory PRM 65 SRM 65 PAL errors (reversed) 64
0.227 0.004 0.145
0.069 0.973 0.253
Cambridge gambling task CGT decision-making
0.402
0.001
61
RAVLT ¼ Rey's Auditory and Verbal Learning Test; PRM¼ Pattern Recognition Memory; SRM¼ Spatial Recognition Memory; PAL¼ Paired Associates Learning; CGT ¼ Cambridge Gambling Task; AAO ¼ Age at onset; Neg/Dis¼ Negative and disorganized symptom.
4. Discussion Polygenic risk score (PRS) was negatively correlated with decision-making ability on the Cambridge Gambling Task (CGT). Nominal association was identified between PRS and vocabulary from the Weschler Abbreviated Scale of Intelligence (WASI). Lifetime positive symptom rating was positively correlated with PRS, but this did not mediate the relationship between PRS and either decision-making or vocabulary. Decision-making deficits using the CGT have previously been identified in chronic patients but not first-episode patients (Hutton et al., 2002) suggesting disease processes may influence performance. Here we show that genetic risk variants, especially PRS, may influence performance, independent from symptom effects. The decision-making component of the CGT is considered sensitive to orbitofrontal cortical (OFC) functioning (Rogers et al., 1999), although using diffusion tensor imaging (DTI) of greymatter in patients with traumatic brain injury, regional differences in the left hippocampus, striatum, ventrolateral and dorsolateral prefrontal cortex (dlPFC), were also associated with decisionmaking quality (Newcombe et al., 2011). The fact that PRS was not significantly associated with measures known to recruit dlPFC, such as those measuring fluid intelligence, working memory and executive functions (Kane and Engle, 2002), suggests the OFC, and its connections, may be disproportionately affected by common schizophrenia risk variants. The trend showing an association between measures of language and PRS, points to an early neurodevelopmental deficit, rather than greater decline after the onset of illness. Verbal knowledge is less likely to deteriorate after brain insult (Nelson and O'Connell, 1978) and less affected before the onset of psychosis (Amminger et al., 2000). Therefore, reduced performance on
Please cite this article as: Martin, A.K., et al., Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.045i
A.K. Martin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
verbal measures of general knowledge is indicative of lower premorbid cognitive function. As verbal IQ measures are considered measures of crystal intelligence and indicative of learning processes, especially in verbal domains, PRS may impact on neural processes relevant for plasticity. The current study provides novel evidence for an association between common risk variants and decision-making ablity in patients with schizophrenia. Examining the processes underlying these cognitive domains may provide evidence for brain networks or regions that are disproportionately affected by schizophrenia risk variants and provide evidence for both key cognitive markers of disease and potential pathways from genotype to phenotype. Financial disclosure This work was supported by the Australian National Health and Medical Research Council (Grant no. 631671) and the United States National Institute of Mental Health (Grant no. RO1 MH59588). Conflict of interest The authors report no conflicts of interest. Acknowledgments We would like to acknowledge all the participants and their families. We acknowledge the MGS Australian recruitment team and the MGS consortium. We thank Divya Mehta for providing the polygenic risk scores. We thank Andrea Baker, Deborah Nertney and Duncan McLean for their assistance in collecting the cognitive data. Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2015.04.045. References Amminger, G.P., Schlogelhofer, M., Lehner, T., Looser Ott, S., Friedrich, M.H., Aschauer, H.N., 2000. Premorbid performance IQ deficit in schizophrenia. Acta Psychiatrica Scandinavica 102, 414–422. Cardno, A.G., Gottesman, I.I., 2000. Twin studies of schizophrenia: from bow-andarrow concordances to star wars Mx and functional genomics. American Journal of Medical Genetics 97, 12–17. Fanous, A.H., Zhou, B., Aggen, S.H., Bergen, S.E., Amdur, R.L., Duan, J., Sanders, A.R., Shi, J., Mowry, B.J., Olincy, A., Amin, F., Cloninger, C.R., Silverman, J.M., Buccola, N.G., Byerley, W.F., Black, D.W., Freedman, R., Dudbridge, F., Holmans, P.A., Ripke, S., Gejman, P.V., Kendler, K.S., Levinson, D.F., 2012. Genome-wide association study of clinical dimensions of schizophrenia: polygenic effect on disorganized symptoms. The American Journal of Psychiatry 169, 1309–1317.
3
Gur, R.E., Calkins, M.E., Gur, R.C., Horan, W.P., Nuechterlein, K.H., Seidman, L.J., Stone, W.S., 2007. The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes. Schizophrenia Bulletin 33, 49–68. Hutton, S.B., Murphy, F.C., Joyce, E.M., Rogers, R.D., Cuthbert, I., Barnes, T.R., McKenna, P.J., Sahakian, B.J., Robbins, T.W., 2002. Decision making deficits in patients with first-episode and chronic schizophrenia. Schizophrenia Research 55, 249–257. Kane, M.J., Engle, R.W., 2002. The role of prefrontal cortex in working-memory capacity, executive attention, and general fluid intelligence: an individualdifferences perspective. Psychonomic Bulletin & Review 9, 637–671. Levinson, D.F., Duan, J., Oh, S., Wang, K., Sanders, A.R., Shi, J., Zhang, N., Mowry, B.J., Olincy, A., Amin, F., Cloninger, C.R., Silverman, J.M., Buccola, N.G., Byerley, W.F., Black, D.W., Kendler, K.S., Freedman, R., Dudbridge, F., Pe'er, I., Hakonarson, H., Bergen, S.E., Fanous, A.H., Holmans, P.A., Gejman, P.V., 2011. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. The American Journal of Psychiatry 168, 302–316. Levinson, D.F., Mowry, B.J., Escamilla, M.A., Faraone, S.V., 2002. The Lifetime Dimensions of Psychosis Scale (LDPS): description and interrater reliability. Schizophrenia Bulletin 28, 683–695. Maxwell, M.E., 1992. Family Interview for Genetic Studies (FIGS): A Manual for FIGS. Clinical Neurogenetics Branch, Intramural Research Program, NIMH, Bethesda, MD. McIntosh, A.M., Gow, A., Luciano, M., Davies, G., Liewald, D.C., Harris, S.E., Corley, J., Hall, J., Starr, J.M., Porteous, D.J., Tenesa, A., Visscher, P.M., Deary, I.J., 2013. Polygenic risk for schizophrenia is associated with cognitive change between childhood and old age. Biological Psychiatry 73, 938–943. Mowry, B.J., Gratten, J., 2013. The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants. Molecular Psychiatry 18, 38–52. Nelson, H.E., O'Connell, A., 1978. Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex; A Journal Devoted to the Study of the Nervous System and Behavior 14, 234–244. Newcombe, V.F., Outtrim, J.G., Chatfield, D.A., Manktelow, A., Hutchinson, P.J., Coles, J.P., Williams, G.B., Sahakian, B.J., Menon, D.K., 2011. Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury. Brain: A Journal of Neurology 134, 759–768. Nurnberger Jr., J.I., Blehar, M.C., Kaufmann, C.A., York-Cooler, C., Simpson, S.G., Harkavy-Friedman, J., Severe, J.B., Malaspina, D., Reich, T., 1994. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Archives of General Psychiatry 51, 849–859 (discussion 844–863). Purcell, S.M., Wray, N.R., Stone, J.L., Visscher, P.M., O'Donovan, M.C., Sullivan, P.F., Sklar, P., 2009. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752. Rogers, R.D., Everitt, B.J., Baldacchino, A., Blackshaw, A.J., Swainson, R., Wynne, K., Baker, N.B., Hunter, J., Carthy, T., Booker, E., London, M., Deakin, J.F., Sahakian, B. J., Robbins, T.W., 1999. Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 20, 322–339. van Scheltinga, A.F., Bakker, S.C., van Haren, N.E., Derks, E.M., Buizer-Voskamp, J.E., Cahn, W., Ripke, S., Ophoff, R.A., Kahn, R.S., 2013. Schizophrenia genetic variants are not associated with intelligence. Psychological Medicine 43, 2563–2570. Wray, N.R., Lee, S.H., Mehta, D., Vinkhuyzen, A.A., Dudbridge, F., Middeldorp, C.M., 2014. Research review: polygenic methods and their application to psychiatric traits. Journal of Child Psychology and Psychiatry and Allied Disciplines 55, 1068–1087. Yeo, R.A., Gangestad, S.W., Walton, E., Ehrlich, S., Pommy, J., Turner, J.A., Liu, J., Mayer, A.R., Schulz, S.C., Ho, B.C., Bustillo, J.R., Wassink, T.H., Sponheim, S.R., Morrow, E.M., Calhoun, V.D., 2014. Genetic influences on cognitive endophenotypes in schizophrenia. Schizophrenia Research 156, 71–75.
Please cite this article as: Martin, A.K., et al., Common genetic risk variants are associated with positive symptoms and decision-making ability in patients with schizophrenia. Psychiatry Research (2015), http://dx.doi.org/10.1016/j.psychres.2015.04.045i
