Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

J.H. Thygesen; A. Presman; J. Harju-Seppanen; H. Irizar; R. Jones; K. Kuchenbaecker; K. Lin; B.Z. Alizadeh; I. Austin-Zimmerman; A. Bartels-Velthuis; A. Bhat; R. Bruggeman; W. Cahn; S. Calafato; B. Crespo-Facorro; L. de Haan; S.M.C. de Zwarte; M. Di Forti; A. Diez-Revuelta; J. Hall; M.H. Hall; C. Iyegbe; A. Jablensky; R. Kahn; L. Kalaydjieva; E. Kravariti; S. Lawrie; J.J. Luykx; I. Mata; C. McDonald; A.M. McIntosh; A. McQuillin; R. Muir; R. Ophoff; M. Picchioni; D.P. Prata; S. Ranlund; D. Rujescu; B.P.F. Rutten; K. Schulze; M. Shaikh; F. Schirmbeck; C.J.P. Simons; T. Toulopoulou; T. van Amelsvoort; N. van Haren; J. van Os; R. van Winkel; E. Vassos; M. Walshe; Elvira Bramon

doi:10.1038/s41380-020-0820-7

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

J.H. Thygesen, A. Presman, J. Harju-Seppanen, H. Irizar, R. Jones, K. Kuchenbaecker, K. Lin, B.Z. Alizadeh, I. Austin-Zimmerman, A. Bartels-Velthuis, A. Bhat, R. Bruggeman, W. Cahn, S. Calafato, B. Crespo-Facorro, L. de Haan, S.M.C. de Zwarte, M. Di Forti, A. Diez-Revuelta, J. HallM.H. Hall, C. Iyegbe, A. Jablensky, R. Kahn, L. Kalaydjieva, E. Kravariti, S. Lawrie, J.J. Luykx, I. Mata, C. McDonald, A.M. McIntosh, A. McQuillin, R. Muir, R. Ophoff, M. Picchioni, D.P. Prata, S. Ranlund, D. Rujescu, B.P.F. Rutten, K. Schulze, M. Shaikh, F. Schirmbeck, C.J.P. Simons, T. Toulopoulou, T. van Amelsvoort, N. van Haren, J. van Os, R. van Winkel, E. Vassos, M. Walshe, Elvira Bramon^*

^*Corresponding author for this work

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

6 Citations (Web of Science)

Abstract

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Original language	English
Pages (from-to)	5307-5319
Number of pages	13
Journal	Molecular Psychiatry
Volume	26
Issue number	9
Early online date	27 Jul 2020
DOIs	https://doi.org/10.1038/s41380-020-0820-7
Publication status	Published - Sep 2021

Keywords

16p11.2
ability
association
deficits
deletions
duplications
phenotype
risk
schizophrenia
verbal memory
DUPLICATIONS
PHENOTYPE
SCHIZOPHRENIA
RISK
ABILITY
16P11.2
VERBAL MEMORY
DEFICITS
ASSOCIATION
DELETIONS

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10.1038/s41380-020-0820-7

Cite this

Thygesen, J. H., Presman, A., Harju-Seppanen, J., Irizar, H., Jones, R., Kuchenbaecker, K., Lin, K., Alizadeh, B. Z., Austin-Zimmerman, I., Bartels-Velthuis, A., Bhat, A., Bruggeman, R., Cahn, W., Calafato, S., Crespo-Facorro, B., de Haan, L., de Zwarte, S. M. C., Di Forti, M., Diez-Revuelta, A., ... Bramon, E. (2021). Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study. Molecular Psychiatry, 26(9), 5307-5319. https://doi.org/10.1038/s41380-020-0820-7

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abstract = "The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.",

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author = "J.H. Thygesen and A. Presman and J. Harju-Seppanen and H. Irizar and R. Jones and K. Kuchenbaecker and K. Lin and B.Z. Alizadeh and I. Austin-Zimmerman and A. Bartels-Velthuis and A. Bhat and R. Bruggeman and W. Cahn and S. Calafato and B. Crespo-Facorro and {de Haan}, L. and {de Zwarte}, S.M.C. and {Di Forti}, M. and A. Diez-Revuelta and J. Hall and M.H. Hall and C. Iyegbe and A. Jablensky and R. Kahn and L. Kalaydjieva and E. Kravariti and S. Lawrie and J.J. Luykx and I. Mata and C. McDonald and A.M. McIntosh and A. McQuillin and R. Muir and R. Ophoff and M. Picchioni and D.P. Prata and S. Ranlund and D. Rujescu and B.P.F. Rutten and K. Schulze and M. Shaikh and F. Schirmbeck and C.J.P. Simons and T. Toulopoulou and {van Amelsvoort}, T. and {van Haren}, N. and {van Os}, J. and {van Winkel}, R. and E. Vassos and M. Walshe and Elvira Bramon",

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Thygesen, JH, Presman, A, Harju-Seppanen, J, Irizar, H, Jones, R, Kuchenbaecker, K, Lin, K, Alizadeh, BZ, Austin-Zimmerman, I, Bartels-Velthuis, A, Bhat, A, Bruggeman, R, Cahn, W, Calafato, S, Crespo-Facorro, B, de Haan, L, de Zwarte, SMC, Di Forti, M, Diez-Revuelta, A, Hall, J, Hall, MH, Iyegbe, C, Jablensky, A, Kahn, R, Kalaydjieva, L, Kravariti, E, Lawrie, S, Luykx, JJ, Mata, I, McDonald, C, McIntosh, AM, McQuillin, A, Muir, R, Ophoff, R, Picchioni, M, Prata, DP, Ranlund, S, Rujescu, D, Rutten, BPF, Schulze, K, Shaikh, M, Schirmbeck, F, Simons, CJP, Toulopoulou, T, van Amelsvoort, T, van Haren, N, van Os, J, van Winkel, R, Vassos, E, Walshe, M & Bramon, E 2021, 'Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study', Molecular Psychiatry, vol. 26, no. 9, pp. 5307-5319. https://doi.org/10.1038/s41380-020-0820-7

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T1 - Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

AU - Thygesen, J.H.

AU - Presman, A.

AU - Harju-Seppanen, J.

AU - Irizar, H.

AU - Jones, R.

AU - Kuchenbaecker, K.

AU - Lin, K.

AU - Alizadeh, B.Z.

AU - Austin-Zimmerman, I.

AU - Bartels-Velthuis, A.

AU - Bhat, A.

AU - Bruggeman, R.

AU - Cahn, W.

AU - Calafato, S.

AU - Crespo-Facorro, B.

AU - de Haan, L.

AU - de Zwarte, S.M.C.

AU - Di Forti, M.

AU - Diez-Revuelta, A.

AU - Hall, J.

AU - Hall, M.H.

AU - Iyegbe, C.

AU - Jablensky, A.

AU - Kahn, R.

AU - Kalaydjieva, L.

AU - Kravariti, E.

AU - Lawrie, S.

AU - Luykx, J.J.

AU - Mata, I.

AU - McDonald, C.

AU - McIntosh, A.M.

AU - McQuillin, A.

AU - Muir, R.

AU - Ophoff, R.

AU - Picchioni, M.

AU - Prata, D.P.

AU - Ranlund, S.

AU - Rujescu, D.

AU - Rutten, B.P.F.

AU - Schulze, K.

AU - Shaikh, M.

AU - Schirmbeck, F.

AU - Simons, C.J.P.

AU - Toulopoulou, T.

AU - van Amelsvoort, T.

AU - van Haren, N.

AU - van Os, J.

AU - van Winkel, R.

AU - Vassos, E.

AU - Walshe, M.

AU - Bramon, Elvira

PY - 2021/9

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N2 - The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

AB - The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

KW - 16p11.2

KW - ability

KW - association

KW - deficits

KW - deletions

KW - duplications

KW - phenotype

KW - risk

KW - schizophrenia

KW - verbal memory

KW - DUPLICATIONS

KW - PHENOTYPE

KW - SCHIZOPHRENIA

KW - RISK

KW - ABILITY

KW - 16P11.2

KW - VERBAL MEMORY

KW - DEFICITS

KW - ASSOCIATION

KW - DELETIONS

U2 - 10.1038/s41380-020-0820-7

DO - 10.1038/s41380-020-0820-7

M3 - Article

C2 - 32719466

VL - 26

SP - 5307

EP - 5319

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

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ER -