Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis

Eva Velthorst; Sean Froudist-Walsh; Eli Stahl; Douglas Ruderfer; Ilyan Ivanov; Joseph Buxbaum; iPSYCH-Broad ASD Group, the IMAGEN consortium; Tobias Banaschewski; Arun L.W. Bokde; Uli Bromberg; Christian Büchel; Erin Burke Quinlan; Sylvane Desrivières; Herta Flor; Vincent Frouin; Hugh Garavan; Penny Gowland; Andreas Heinz; Bernd Ittermann; Marie Laure Paillère Martinot; Eric Artiges; Frauke Nees; Dimitri Papadopoulos Orfanos; Tomáš Paus; Luise Poustka; Sarah Hohmann; Juliane H. Fröhner; Michael N. Smolka; Henrik Walter; Robert Whelan; Gunter Schumann; Abraham Reichenberg; Anders D. Børglum; Jakob Grove; Manuel Mattheisen; Thomas Werge; Preben Bo Mortensen; Marianne Giørtz Pedersen; Carsten Bøcker Pedersen; Ole Mors; Merete Nordentoft; David M. Hougaard; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Christine Søholm Hansen; Mark J. Daly; Benjamin M. Neale; Elise B. Robinson; Felecia Cerrato; Ashley Dumont; Jacqueline Goldstein

doi:10.1038/s41398-018-0229-0

Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis

Eva Velthorst^*, Sean Froudist-Walsh, Eli Stahl, Douglas Ruderfer, Ilyan Ivanov, Joseph Buxbaum, iPSYCH-Broad ASD Group, the IMAGEN consortium, Tobias Banaschewski, Arun L.W. Bokde, Uli Bromberg, Christian Büchel, Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Marie Laure Paillère MartinotEric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Sarah Hohmann, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Gunter Schumann, Abraham Reichenberg, Anders D. Børglum, Jakob Grove, Manuel Mattheisen, Thomas Werge, Preben Bo Mortensen, Marianne Giørtz Pedersen, Carsten Bøcker Pedersen, Ole Mors, Merete Nordentoft, David M. Hougaard, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Christine Søholm Hansen, Mark J. Daly, Benjamin M. Neale, Elise B. Robinson, Felecia Cerrato, Ashley Dumont, Jacqueline Goldstein

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

8 Citationer (Scopus)

31 Downloads (Pure)

Abstract

While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.

Originalsprog	Engelsk
Artikelnummer	204
Tidsskrift	Translational Psychiatry
Vol/bind	8
Udgave nummer	1
ISSN	2158-3188
DOI	https://doi.org/10.1038/s41398-018-0229-0
Status	Udgivet - 2018

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10.1038/s41398-018-0229-0

Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosisForlagets udgivne version, 776 KB

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Velthorst, E., Froudist-Walsh, S., Stahl, E., Ruderfer, D., Ivanov, I., Buxbaum, J., iPSYCH-Broad ASD Group, the IMAGEN consortium, Banaschewski, T., Bokde, A. L. W., Bromberg, U., Büchel, C., Burke Quinlan, E., Desrivières, S., Flor, H., Frouin, V., Garavan, H., Gowland, P., Heinz, A., Ittermann, B., ... Goldstein, J. (2018). Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis. Translational Psychiatry, 8(1), [204]. https://doi.org/10.1038/s41398-018-0229-0

Velthorst, E, Froudist-Walsh, S, Stahl, E, Ruderfer, D, Ivanov, I, Buxbaum, J, iPSYCH-Broad ASD Group, the IMAGEN consortium, Banaschewski, T, Bokde, ALW, Bromberg, U, Büchel, C, Burke Quinlan, E, Desrivières, S, Flor, H, Frouin, V, Garavan, H, Gowland, P, Heinz, A, Ittermann, B, Paillère Martinot, ML, Artiges, E, Nees, F, Papadopoulos Orfanos, D, Paus, T, Poustka, L, Hohmann, S, Fröhner, JH, Smolka, MN, Walter, H, Whelan, R, Schumann, G, Reichenberg, A, Børglum, AD, Grove, J, Mattheisen, M, Werge, T, Mortensen, PB, Pedersen, MG, Pedersen, CB, Mors, O, Nordentoft, M, Hougaard, DM, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Hansen, CS, Daly, MJ, Neale, BM, Robinson, EB, Cerrato, F, Dumont, A & Goldstein, J 2018, 'Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis', Translational Psychiatry, bind 8, nr. 1, 204. https://doi.org/10.1038/s41398-018-0229-0

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title = "Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis",

abstract = "While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.",

author = "Eva Velthorst and Sean Froudist-Walsh and Eli Stahl and Douglas Ruderfer and Ilyan Ivanov and Joseph Buxbaum and {iPSYCH-Broad ASD Group, the IMAGEN consortium} and Tobias Banaschewski and Bokde, {Arun L.W.} and Uli Bromberg and Christian B{\"u}chel and {Burke Quinlan}, Erin and Sylvane Desrivi{\`e}res and Herta Flor and Vincent Frouin and Hugh Garavan and Penny Gowland and Andreas Heinz and Bernd Ittermann and {Paill{\`e}re Martinot}, {Marie Laure} and Eric Artiges and Frauke Nees and {Papadopoulos Orfanos}, Dimitri and Tom{\'a}{\v s} Paus and Luise Poustka and Sarah Hohmann and Fr{\"o}hner, {Juliane H.} and Smolka, {Michael N.} and Henrik Walter and Robert Whelan and Gunter Schumann and Abraham Reichenberg and B{\o}rglum, {Anders D.} and Jakob Grove and Manuel Mattheisen and Thomas Werge and Mortensen, {Preben Bo} and Pedersen, {Marianne Gi{\o}rtz} and Pedersen, {Carsten B{\o}cker} and Ole Mors and Merete Nordentoft and Hougaard, {David M.} and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-Hansen and Hansen, {Christine S{\o}holm} and Daly, {Mark J.} and Neale, {Benjamin M.} and Robinson, {Elise B.} and Felecia Cerrato and Ashley Dumont and Jacqueline Goldstein",

year = "2018",

doi = "10.1038/s41398-018-0229-0",

language = "English",

volume = "8",

journal = "Translational Psychiatry",

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TY - JOUR

T1 - Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis

AU - Velthorst, Eva

AU - Froudist-Walsh, Sean

AU - Stahl, Eli

AU - Ruderfer, Douglas

AU - Ivanov, Ilyan

AU - Buxbaum, Joseph

AU - iPSYCH-Broad ASD Group, the IMAGEN consortium

AU - Banaschewski, Tobias

AU - Bokde, Arun L.W.

AU - Bromberg, Uli

AU - Büchel, Christian

AU - Burke Quinlan, Erin

AU - Desrivières, Sylvane

AU - Flor, Herta

AU - Frouin, Vincent

AU - Garavan, Hugh

AU - Gowland, Penny

AU - Heinz, Andreas

AU - Ittermann, Bernd

AU - Paillère Martinot, Marie Laure

AU - Artiges, Eric

AU - Nees, Frauke

AU - Papadopoulos Orfanos, Dimitri

AU - Paus, Tomáš

AU - Poustka, Luise

AU - Hohmann, Sarah

AU - Fröhner, Juliane H.

AU - Smolka, Michael N.

AU - Walter, Henrik

AU - Whelan, Robert

AU - Schumann, Gunter

AU - Reichenberg, Abraham

AU - Børglum, Anders D.

AU - Grove, Jakob

AU - Mattheisen, Manuel

AU - Werge, Thomas

AU - Mortensen, Preben Bo

AU - Pedersen, Marianne Giørtz

AU - Pedersen, Carsten Bøcker

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Hansen, Christine Søholm

AU - Daly, Mark J.

AU - Neale, Benjamin M.

AU - Robinson, Elise B.

AU - Cerrato, Felecia

AU - Dumont, Ashley

AU - Goldstein, Jacqueline

PY - 2018

Y1 - 2018

N2 - While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.

AB - While psychotic experiences (PEs) are assumed to represent psychosis liability, general population studies have not been able to establish significant associations between polygenic risk scores (PRS) and PEs. Previous work suggests that PEs may only represent significant risk when accompanied by social impairment. Leveraging data from the large longitudinal IMAGEN cohort, including 2096 14-year old adolescents that were followed-up to age 18, we tested whether the association between polygenic risk and PEs is mediated by (increasing) impairments in social functioning and social cognitive processes. Using structural equation modeling (SEM) for the subset of participants (n = 643) with complete baseline and follow-up data, we examined pathways to PEs. We found that high polygenic risk for schizophrenia (p = 0.014), reduced brain activity to emotional stimuli (p = 0.009) and social impairments in late adolescence (p < 0.001; controlling for functioning in early adolescence) each independently contributed to the severity of PEs at age 18. The pathway between polygenic risk for autism spectrum disorder and PEs was mediated by social impairments in late adolescence (indirect pathway; p = 0.025). These findings point to multiple direct and indirect pathways to PEs, suggesting that different processes are in play, depending on genetic loading, and environment. Our results suggest that treatments targeting prevention of social impairment may be particularly promising for individuals at genetic risk for autism in order to minimize risk for psychosis.

U2 - 10.1038/s41398-018-0229-0

DO - 10.1038/s41398-018-0229-0

M3 - Journal article

C2 - 30258131

AN - SCOPUS:85054049851

SN - 2158-3188

VL - 8

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

M1 - 204

ER -

Genetic risk for schizophrenia and autism, social impairment and developmental pathways to psychosis

Abstract

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