Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: A report from the Cognitive Genomics consorTium (COGENT)

T. Lencz, E. Knowles, G. Davies, S. Guha, D. C. Liewald, J. M. Starr, S. Djurovic, I. Melle, K. Sundet, A. Christoforou, I. Reinvang, S. Mukherjee, Pamela Derosse, A. Lundervold, V. M. Steen, M. John, T. Espeseth, K. Räikkönen, E. Widen, A. PalotieJ. G. Eriksson, I. Giegling, B. Konte, M. Ikeda, P. Roussos, S. Giakoumaki, K. E. Burdick, A. Payton, W. Ollier, M. Horan, G. Donohoe, D. Morris, A. Corvin, M. Gill, N. Pendleton, N. Iwata, A. Darvasi, P. Bitsios, D. Rujescu, J. Lahti, S. L. Hellard, M. C. Keller, O. A. Andreassen, I. J. Deary, D. C. Glahn, A. K. Malhotra

Research output: Contribution to journalArticle

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Abstract

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (∼5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Original languageEnglish
Pages (from-to)168-174
Number of pages7
JournalMolecular Psychiatry
Volume19
Issue number2
DOIs
Publication statusPublished - 01-02-2014

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Aptitude
Genomics
Molecular Biology
Schizophrenia
Genome-Wide Association Study
Endophenotypes
Single Nucleotide Polymorphism
Meta-Analysis
Alleles
Phenotype

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Lencz, T. ; Knowles, E. ; Davies, G. ; Guha, S. ; Liewald, D. C. ; Starr, J. M. ; Djurovic, S. ; Melle, I. ; Sundet, K. ; Christoforou, A. ; Reinvang, I. ; Mukherjee, S. ; Derosse, Pamela ; Lundervold, A. ; Steen, V. M. ; John, M. ; Espeseth, T. ; Räikkönen, K. ; Widen, E. ; Palotie, A. ; Eriksson, J. G. ; Giegling, I. ; Konte, B. ; Ikeda, M. ; Roussos, P. ; Giakoumaki, S. ; Burdick, K. E. ; Payton, A. ; Ollier, W. ; Horan, M. ; Donohoe, G. ; Morris, D. ; Corvin, A. ; Gill, M. ; Pendleton, N. ; Iwata, N. ; Darvasi, A. ; Bitsios, P. ; Rujescu, D. ; Lahti, J. ; Hellard, S. L. ; Keller, M. C. ; Andreassen, O. A. ; Deary, I. J. ; Glahn, D. C. ; Malhotra, A. K. / Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia : A report from the Cognitive Genomics consorTium (COGENT). In: Molecular Psychiatry. 2014 ; Vol. 19, No. 2. pp. 168-174.
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abstract = "It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (∼5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.",
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Lencz, T, Knowles, E, Davies, G, Guha, S, Liewald, DC, Starr, JM, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, Mukherjee, S, Derosse, P, Lundervold, A, Steen, VM, John, M, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Ikeda, M, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Horan, M, Donohoe, G, Morris, D, Corvin, A, Gill, M, Pendleton, N, Iwata, N, Darvasi, A, Bitsios, P, Rujescu, D, Lahti, J, Hellard, SL, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC & Malhotra, AK 2014, 'Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: A report from the Cognitive Genomics consorTium (COGENT)', Molecular Psychiatry, vol. 19, no. 2, pp. 168-174. https://doi.org/10.1038/mp.2013.166

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia : A report from the Cognitive Genomics consorTium (COGENT). / Lencz, T.; Knowles, E.; Davies, G.; Guha, S.; Liewald, D. C.; Starr, J. M.; Djurovic, S.; Melle, I.; Sundet, K.; Christoforou, A.; Reinvang, I.; Mukherjee, S.; Derosse, Pamela; Lundervold, A.; Steen, V. M.; John, M.; Espeseth, T.; Räikkönen, K.; Widen, E.; Palotie, A.; Eriksson, J. G.; Giegling, I.; Konte, B.; Ikeda, M.; Roussos, P.; Giakoumaki, S.; Burdick, K. E.; Payton, A.; Ollier, W.; Horan, M.; Donohoe, G.; Morris, D.; Corvin, A.; Gill, M.; Pendleton, N.; Iwata, N.; Darvasi, A.; Bitsios, P.; Rujescu, D.; Lahti, J.; Hellard, S. L.; Keller, M. C.; Andreassen, O. A.; Deary, I. J.; Glahn, D. C.; Malhotra, A. K.

In: Molecular Psychiatry, Vol. 19, No. 2, 01.02.2014, p. 168-174.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia

T2 - A report from the Cognitive Genomics consorTium (COGENT)

AU - Lencz, T.

AU - Knowles, E.

AU - Davies, G.

AU - Guha, S.

AU - Liewald, D. C.

AU - Starr, J. M.

AU - Djurovic, S.

AU - Melle, I.

AU - Sundet, K.

AU - Christoforou, A.

AU - Reinvang, I.

AU - Mukherjee, S.

AU - Derosse, Pamela

AU - Lundervold, A.

AU - Steen, V. M.

AU - John, M.

AU - Espeseth, T.

AU - Räikkönen, K.

AU - Widen, E.

AU - Palotie, A.

AU - Eriksson, J. G.

AU - Giegling, I.

AU - Konte, B.

AU - Ikeda, M.

AU - Roussos, P.

AU - Giakoumaki, S.

AU - Burdick, K. E.

AU - Payton, A.

AU - Ollier, W.

AU - Horan, M.

AU - Donohoe, G.

AU - Morris, D.

AU - Corvin, A.

AU - Gill, M.

AU - Pendleton, N.

AU - Iwata, N.

AU - Darvasi, A.

AU - Bitsios, P.

AU - Rujescu, D.

AU - Lahti, J.

AU - Hellard, S. L.

AU - Keller, M. C.

AU - Andreassen, O. A.

AU - Deary, I. J.

AU - Glahn, D. C.

AU - Malhotra, A. K.

PY - 2014/2/1

Y1 - 2014/2/1

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