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

Johan H. Thygesen; Amelia Presman; Jasmine Harju-Seppänen; Haritz Irizar; Rebecca Jones; Karoline Kuchenbaecker; Kuang Lin; Behrooz Z. Alizadeh; Isabelle Austin-Zimmerman; Agna Bartels-Velthuis; Anjali Bhat; Richard Bruggeman; Wiepke Cahn; Stella Calafato; Benedicto Crespo-Facorro; Liewe de Haan; Sonja M. C. de Zwarte; Marta di Forti; Álvaro Díez-Revuelta; Jeremy Hall; Mei-Hua Hall; Conrad Iyegbe; Assen Jablensky; Rene Kahn; Luba Kalaydjieva; Eugenia Kravariti; Stephen Lawrie; Jurjen J. Luykx; Igancio Mata; Colm McDonald; Andrew M. McIntosh; Andrew McQuillin; Rebecca Muir; Roel Ophoff; Marco Picchioni; Diana P. Prata; Siri Ranlund; Dan Rujescu; Bart P. F. Rutten; Katja Schulze; Madiha Shaikh; Frederike Schirmbeck; Claudia J. P. Simons; Timothea Toulopoulou; Therese van Amelsvoort; Neeltje van Haren; Jim van Os; Ruud van Winkel; Evangelos Vassos; Muriel Walshe; Matthias Weisbrod; Eirini Zartaloudi; Vaughan Bell; John Powell; Cathryn M. Lewis; Robin M. Murray; Elvira Bramon

doi:https://doi.org/10.1038/s41380-020-0820-7

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

Johan H. Thygesen, Amelia Presman, Jasmine Harju-Seppänen, Haritz Irizar, Rebecca Jones, Karoline Kuchenbaecker, Kuang Lin, Behrooz Z. Alizadeh, Isabelle Austin-Zimmerman, Agna Bartels-Velthuis, Anjali Bhat, Richard Bruggeman, Wiepke Cahn, Stella Calafato, Benedicto Crespo-Facorro, Liewe de Haan, Sonja M. C. de Zwarte, Marta di Forti, Álvaro Díez-Revuelta, Jeremy HallMei-Hua Hall, Conrad Iyegbe, Assen Jablensky, Rene Kahn, Luba Kalaydjieva, Eugenia Kravariti, Stephen Lawrie, Jurjen J. Luykx, Igancio Mata, Colm McDonald, Andrew M. McIntosh, Andrew McQuillin, Rebecca Muir, Roel Ophoff, Marco Picchioni, Diana P. Prata, Siri Ranlund, Dan Rujescu, Bart P. F. Rutten, Katja Schulze, Madiha Shaikh, Frederike Schirmbeck, Claudia J. P. Simons, Timothea Toulopoulou, Therese van Amelsvoort, Neeltje van Haren, Jim van Os, Ruud van Winkel, Evangelos Vassos, Muriel Walshe, Matthias Weisbrod, Eirini Zartaloudi, Vaughan Bell, John Powell, Cathryn M. Lewis, Robin M. Murray, Elvira Bramon

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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.

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

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Thygesen, J. H., Presman, A., Harju-Seppänen, 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., Díez-Revuelta, Á., ... 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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title = "Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study",

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.",

author = "Thygesen, {Johan H.} and Amelia Presman and Jasmine Harju-Sepp{\"a}nen and Haritz Irizar and Rebecca Jones and Karoline Kuchenbaecker and Kuang Lin and Alizadeh, {Behrooz Z.} and Isabelle Austin-Zimmerman and Agna Bartels-Velthuis and Anjali Bhat and Richard Bruggeman and Wiepke Cahn and Stella Calafato and Benedicto Crespo-Facorro and {de Haan}, Liewe and {de Zwarte}, {Sonja M. C.} and {di Forti}, Marta and {\'A}lvaro D{\'i}ez-Revuelta and Jeremy Hall and Mei-Hua Hall and Conrad Iyegbe and Assen Jablensky and Rene Kahn and Luba Kalaydjieva and Eugenia Kravariti and Stephen Lawrie and Luykx, {Jurjen J.} and Igancio Mata and Colm McDonald and McIntosh, {Andrew M.} and Andrew McQuillin and Rebecca Muir and Roel Ophoff and Marco Picchioni and Prata, {Diana P.} and Siri Ranlund and Dan Rujescu and Rutten, {Bart P. F.} and Katja Schulze and Madiha Shaikh and Frederike Schirmbeck and Simons, {Claudia J. P.} and Timothea Toulopoulou and {van Amelsvoort}, Therese and {van Haren}, Neeltje and {van Os}, Jim and {van Winkel}, Ruud and Evangelos Vassos and Muriel Walshe and Matthias Weisbrod and Eirini Zartaloudi and Vaughan Bell and John Powell and Lewis, {Cathryn M.} and Murray, {Robin M.} and Elvira Bramon",

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journal = "Molecular psychiatry",

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Thygesen, JH, Presman, A, Harju-Seppänen, 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, Díez-Revuelta, Á, Hall, J, Hall, M-H, 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, Weisbrod, M, Zartaloudi, E, Bell, V, Powell, J, Lewis, CM, Murray, RM & 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

TY - JOUR

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

AU - Thygesen, Johan H.

AU - Presman, Amelia

AU - Harju-Seppänen, Jasmine

AU - Irizar, Haritz

AU - Jones, Rebecca

AU - Kuchenbaecker, Karoline

AU - Lin, Kuang

AU - Alizadeh, Behrooz Z.

AU - Austin-Zimmerman, Isabelle

AU - Bartels-Velthuis, Agna

AU - Bhat, Anjali

AU - Bruggeman, Richard

AU - Cahn, Wiepke

AU - Calafato, Stella

AU - Crespo-Facorro, Benedicto

AU - de Haan, Liewe

AU - de Zwarte, Sonja M. C.

AU - di Forti, Marta

AU - Díez-Revuelta, Álvaro

AU - Hall, Jeremy

AU - Hall, Mei-Hua

AU - Iyegbe, Conrad

AU - Jablensky, Assen

AU - Kahn, Rene

AU - Kalaydjieva, Luba

AU - Kravariti, Eugenia

AU - Lawrie, Stephen

AU - Luykx, Jurjen J.

AU - Mata, Igancio

AU - McDonald, Colm

AU - McIntosh, Andrew M.

AU - McQuillin, Andrew

AU - Muir, Rebecca

AU - Ophoff, Roel

AU - Picchioni, Marco

AU - Prata, Diana P.

AU - Ranlund, Siri

AU - Rujescu, Dan

AU - Rutten, Bart P. F.

AU - Schulze, Katja

AU - Shaikh, Madiha

AU - Schirmbeck, Frederike

AU - Simons, Claudia J. P.

AU - Toulopoulou, Timothea

AU - van Amelsvoort, Therese

AU - van Haren, Neeltje

AU - van Os, Jim

AU - van Winkel, Ruud

AU - Vassos, Evangelos

AU - Walshe, Muriel

AU - Weisbrod, Matthias

AU - Zartaloudi, Eirini

AU - Bell, Vaughan

AU - Powell, John

AU - Lewis, Cathryn M.

AU - Murray, Robin M.

AU - Bramon, Elvira

PY - 2021/9

Y1 - 2021/9

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.

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U2 - https://doi.org/10.1038/s41380-020-0820-7

DO - https://doi.org/10.1038/s41380-020-0820-7

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C2 - 32719466

SN - 1359-4184

VL - 26

SP - 5307

EP - 5319

JO - Molecular psychiatry

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ER -

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

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