Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size

Daqiang Sun, Christopher R.K. Ching, Amy Lin, Jennifer K. Forsyth, Leila Kushan, Ariana Vajdi, Maria Jalbrzikowski, Laura Hansen, Julio E. Villalon-Reina, Xiaoping Qu, Rachel K. Jonas, Therese van Amelsvoort, Geor Bakker, Wendy R. Kates, Kevin Martin Antshel, Wanda Fremont, Linda E. Campbell, Kathryn L. McCabe, Eileen Daly, Maria GudbrandsenClodagh M. Murphy, Declan Murphy, Michael Craig, Jacob Vorstman, Ania Fiksinski, Sanne Koops, Kosha Ruparel, David R. Roalf, Raquel E. Gur, J. Eric Schmitt, Tony J. Simon, Naomi J. Goodrich-Hunsaker, Courtney A. Durdle, Anne S. Bassett, Eva W.C. Chow, N. J. Butcher, Fidel Vila-Rodriguez, Joanne Doherty, Adam Cunningham, M. B.M. van Den Bree, David E.J. Linden, Hayley Moss, Michael J. Owen, Kieran C. Murphy, D. M. McDonald-McGinn, Beverly Emanuel, Theo G.M. van Erp, Jessica A. Turner, Paul M. Thompson, Carrie E. Bearden

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jun 13 2018

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DiGeorge Syndrome
Psychotic Disorders
Schizophrenia
Temporal Lobe
Meta-Analysis
Brain
Biological Models
Gyrus Cinguli

ASJC Scopus subject areas

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

Cite this

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome : Convergence with idiopathic psychosis and effects of deletion size. / Sun, Daqiang; Ching, Christopher R.K.; Lin, Amy; Forsyth, Jennifer K.; Kushan, Leila; Vajdi, Ariana; Jalbrzikowski, Maria; Hansen, Laura; Villalon-Reina, Julio E.; Qu, Xiaoping; Jonas, Rachel K.; van Amelsvoort, Therese; Bakker, Geor; Kates, Wendy R.; Antshel, Kevin Martin; Fremont, Wanda; Campbell, Linda E.; McCabe, Kathryn L.; Daly, Eileen; Gudbrandsen, Maria; Murphy, Clodagh M.; Murphy, Declan; Craig, Michael; Vorstman, Jacob; Fiksinski, Ania; Koops, Sanne; Ruparel, Kosha; Roalf, David R.; Gur, Raquel E.; Schmitt, J. Eric; Simon, Tony J.; Goodrich-Hunsaker, Naomi J.; Durdle, Courtney A.; Bassett, Anne S.; Chow, Eva W.C.; Butcher, N. J.; Vila-Rodriguez, Fidel; Doherty, Joanne; Cunningham, Adam; van Den Bree, M. B.M.; Linden, David E.J.; Moss, Hayley; Owen, Michael J.; Murphy, Kieran C.; McDonald-McGinn, D. M.; Emanuel, Beverly; van Erp, Theo G.M.; Turner, Jessica A.; Thompson, Paul M.; Bearden, Carrie E.

In: Molecular Psychiatry, 13.06.2018, p. 1-13.

Research output: Contribution to journalArticle

Sun, D, Ching, CRK, Lin, A, Forsyth, JK, Kushan, L, Vajdi, A, Jalbrzikowski, M, Hansen, L, Villalon-Reina, JE, Qu, X, Jonas, RK, van Amelsvoort, T, Bakker, G, Kates, WR, Antshel, KM, Fremont, W, Campbell, LE, McCabe, KL, Daly, E, Gudbrandsen, M, Murphy, CM, Murphy, D, Craig, M, Vorstman, J, Fiksinski, A, Koops, S, Ruparel, K, Roalf, DR, Gur, RE, Schmitt, JE, Simon, TJ, Goodrich-Hunsaker, NJ, Durdle, CA, Bassett, AS, Chow, EWC, Butcher, NJ, Vila-Rodriguez, F, Doherty, J, Cunningham, A, van Den Bree, MBM, Linden, DEJ, Moss, H, Owen, MJ, Murphy, KC, McDonald-McGinn, DM, Emanuel, B, van Erp, TGM, Turner, JA, Thompson, PM & Bearden, CE 2018, 'Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size', Molecular Psychiatry, pp. 1-13. https://doi.org/10.1038/s41380-018-0078-5
Sun, Daqiang ; Ching, Christopher R.K. ; Lin, Amy ; Forsyth, Jennifer K. ; Kushan, Leila ; Vajdi, Ariana ; Jalbrzikowski, Maria ; Hansen, Laura ; Villalon-Reina, Julio E. ; Qu, Xiaoping ; Jonas, Rachel K. ; van Amelsvoort, Therese ; Bakker, Geor ; Kates, Wendy R. ; Antshel, Kevin Martin ; Fremont, Wanda ; Campbell, Linda E. ; McCabe, Kathryn L. ; Daly, Eileen ; Gudbrandsen, Maria ; Murphy, Clodagh M. ; Murphy, Declan ; Craig, Michael ; Vorstman, Jacob ; Fiksinski, Ania ; Koops, Sanne ; Ruparel, Kosha ; Roalf, David R. ; Gur, Raquel E. ; Schmitt, J. Eric ; Simon, Tony J. ; Goodrich-Hunsaker, Naomi J. ; Durdle, Courtney A. ; Bassett, Anne S. ; Chow, Eva W.C. ; Butcher, N. J. ; Vila-Rodriguez, Fidel ; Doherty, Joanne ; Cunningham, Adam ; van Den Bree, M. B.M. ; Linden, David E.J. ; Moss, Hayley ; Owen, Michael J. ; Murphy, Kieran C. ; McDonald-McGinn, D. M. ; Emanuel, Beverly ; van Erp, Theo G.M. ; Turner, Jessica A. ; Thompson, Paul M. ; Bearden, Carrie E. / Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome : Convergence with idiopathic psychosis and effects of deletion size. In: Molecular Psychiatry. 2018 ; pp. 1-13.
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abstract = "The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9{\%} female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9{\%} female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8{\%} accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.",
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TY - JOUR

T1 - Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome

T2 - Convergence with idiopathic psychosis and effects of deletion size

AU - Sun, Daqiang

AU - Ching, Christopher R.K.

AU - Lin, Amy

AU - Forsyth, Jennifer K.

AU - Kushan, Leila

AU - Vajdi, Ariana

AU - Jalbrzikowski, Maria

AU - Hansen, Laura

AU - Villalon-Reina, Julio E.

AU - Qu, Xiaoping

AU - Jonas, Rachel K.

AU - van Amelsvoort, Therese

AU - Bakker, Geor

AU - Kates, Wendy R.

AU - Antshel, Kevin Martin

AU - Fremont, Wanda

AU - Campbell, Linda E.

AU - McCabe, Kathryn L.

AU - Daly, Eileen

AU - Gudbrandsen, Maria

AU - Murphy, Clodagh M.

AU - Murphy, Declan

AU - Craig, Michael

AU - Vorstman, Jacob

AU - Fiksinski, Ania

AU - Koops, Sanne

AU - Ruparel, Kosha

AU - Roalf, David R.

AU - Gur, Raquel E.

AU - Schmitt, J. Eric

AU - Simon, Tony J.

AU - Goodrich-Hunsaker, Naomi J.

AU - Durdle, Courtney A.

AU - Bassett, Anne S.

AU - Chow, Eva W.C.

AU - Butcher, N. J.

AU - Vila-Rodriguez, Fidel

AU - Doherty, Joanne

AU - Cunningham, Adam

AU - van Den Bree, M. B.M.

AU - Linden, David E.J.

AU - Moss, Hayley

AU - Owen, Michael J.

AU - Murphy, Kieran C.

AU - McDonald-McGinn, D. M.

AU - Emanuel, Beverly

AU - van Erp, Theo G.M.

AU - Turner, Jessica A.

AU - Thompson, Paul M.

AU - Bearden, Carrie E.

PY - 2018/6/13

Y1 - 2018/6/13

N2 - The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

AB - The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

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