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 M Antshel; Wanda Fremont; Linda E Campbell; Kathryn L McCabe; Eileen Daly; Maria Gudbrandsen; Clodagh 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; Nancy J Butcher; Fidel Vila-Rodriguez; Joanne Doherty; Adam Cunningham; Marianne B M van den Bree; David E J Linden; Hayley Moss; Michael J Owen; Kieran C Murphy; Donna M McDonald-McGinn; Beverly Emanuel; Theo G M van Erp; Jessica A Turner; Paul M Thompson; Carrie E Bearden

doi:10.1038/s41380-018-0078-5

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 M 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, Nancy J Butcher, Fidel Vila-Rodriguez, Joanne Doherty, Adam Cunningham, Marianne B M van den Bree, David E J Linden, Hayley Moss, Michael J Owen, Kieran C Murphy, Donna M McDonald-McGinn, Beverly Emanuel, Theo G M van Erp, Jessica A Turner, Paul M Thompson, Carrie E Bearden

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

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 language	English
Pages (from-to)	1822-1834
Number of pages	13
Journal	MOLECULAR PSYCHIATRY
Volume	25
Issue number	8
DOIs	https://doi.org/10.1038/s41380-018-0078-5
Publication status	Published - 13 Jun 2018

Keywords

Adolescent
Adult
Cerebral Cortex/pathology
Chromosome Deletion
DiGeorge Syndrome/genetics
Female
Gray Matter/pathology
Humans
Magnetic Resonance Imaging
Male
Psychotic Disorders/genetics
Young Adult

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10.1038/s41380-018-0078-5

Cite this

Sun, D., Ching, C. R. K., Lin, A., Forsyth, J. K., Kushan, L., Vajdi, A., Jalbrzikowski, M., Hansen, L., Villalon-Reina, J. E., Qu, X., Jonas, R. K., van Amelsvoort, T., Bakker, G., Kates, W. R., Antshel, K. M., Fremont, W., Campbell, L. E., McCabe, K. L., Daly, E., ... Bearden, C. E. (2018). Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size. MOLECULAR PSYCHIATRY, 25(8), 1822-1834. https://doi.org/10.1038/s41380-018-0078-5

@article{4e0ceb8566914589b91ceac5544f2489,

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

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.",

keywords = "Adolescent, Adult, Cerebral Cortex/pathology, Chromosome Deletion, DiGeorge Syndrome/genetics, Female, Gray Matter/pathology, Humans, Magnetic Resonance Imaging, Male, Psychotic Disorders/genetics, Young Adult",

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

year = "2018",

month = jun,

day = "13",

doi = "10.1038/s41380-018-0078-5",

language = "English",

volume = "25",

pages = "1822--1834",

journal = "MOLECULAR PSYCHIATRY",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "8",

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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, vol. 25, no. 8, pp. 1822-1834. https://doi.org/10.1038/s41380-018-0078-5

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 M

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, Nancy J

AU - Vila-Rodriguez, Fidel

AU - Doherty, Joanne

AU - Cunningham, Adam

AU - van den Bree, Marianne B M

AU - Linden, David E J

AU - Moss, Hayley

AU - Owen, Michael J

AU - Murphy, Kieran C

AU - McDonald-McGinn, Donna 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.

KW - Adolescent

KW - Adult

KW - Cerebral Cortex/pathology

KW - Chromosome Deletion

KW - DiGeorge Syndrome/genetics

KW - Female

KW - Gray Matter/pathology

KW - Humans

KW - Magnetic Resonance Imaging

KW - Male

KW - Psychotic Disorders/genetics

KW - Young Adult

U2 - 10.1038/s41380-018-0078-5

DO - 10.1038/s41380-018-0078-5

M3 - Article

C2 - 29895892

SN - 1359-4184

VL - 25

SP - 1822

EP - 1834

JO - MOLECULAR PSYCHIATRY

JF - MOLECULAR PSYCHIATRY

IS - 8

ER -