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; Gail 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 Palotie; J 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

doi: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)

T Lencz, E Knowles, Gail 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

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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 language	English
Pages (from-to)	168-174
Number of pages	7
Journal	Molecular Psychiatry
Volume	19
Issue number	2
DOIs	https://doi.org/10.1038/mp.2013.166
Publication status	Published - Feb 2014

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10.1038/mp.2013.166

8 Finished

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Maclullich, A.
1/09/13 → 31/08/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
A Hundred at Ninety: the common cause Hypothesis of Ageing tested in four waves of the Lothian Birth Cohort 1921
Deary, I., Bates, T., Gow, A. & Starr, J.
UK central government bodies/local authorities, health and hospital authorities
1/01/11 → 31/12/12
Project: Research

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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, P., Lundervold, A., Steen, V. M., John, M., Espeseth, T., Räikkönen, K., Widen, E., ... Malhotra, A. K. (2014). Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Molecular Psychiatry, 19(2), 168-174. https://doi.org/10.1038/mp.2013.166

Lencz, T ; Knowles, E ; Davies, Gail ; 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.

@article{135a28fc203d4218b08e4450903d81ee,

title = "Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT)",

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.",

author = "T Lencz and E Knowles and Gail Davies and S Guha and Liewald, {D C} and Starr, {J M} and S Djurovic and I Melle and K Sundet and A Christoforou and I Reinvang and S Mukherjee and Pamela Derosse and A Lundervold and Steen, {V M} and M John and T Espeseth and K R{\"a}ikk{\"o}nen and E Widen and A Palotie and Eriksson, {J G} and I Giegling and B Konte and M Ikeda and P Roussos and S Giakoumaki and Burdick, {K E} and A Payton and W Ollier and M Horan and G Donohoe and D Morris and A Corvin and M Gill and N Pendleton and N Iwata and A Darvasi and P Bitsios and D Rujescu and J Lahti and Hellard, {S L} and Keller, {M C} and Andreassen, {O A} and Deary, {I J} and Glahn, {D C} and Malhotra, {A K}",

year = "2014",

month = feb,

doi = "10.1038/mp.2013.166",

language = "English",

volume = "19",

pages = "168--174",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

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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, Gail; 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, 02.2014, p. 168-174.

Research output: Contribution to journal › Article › peer-review

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, Gail

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

Y1 - 2014/2

N2 - 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.

AB - 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.

U2 - 10.1038/mp.2013.166

DO - 10.1038/mp.2013.166

M3 - Article

C2 - 24342994

VL - 19

SP - 168

EP - 174

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 2

ER -

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

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Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

A Hundred at Ninety: the common cause Hypothesis of Ageing tested in four waves of the Lothian Birth Cohort 1921

Cite this