Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

International 22q11.2DS Brain and Behavior Consortium; Rosemarie Fritsch

doi:10.1038/s41380-020-0654-3

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

International 22q11.2DS Brain and Behavior Consortium, Rosemarie Fritsch

Facultad de Medicina

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

74 Scopus citations

Abstract

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p_adj = 6.73 × 10⁻⁶). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Original language	English
Pages (from-to)	4496-4510
Number of pages	15
Journal	Molecular Psychiatry
Volume	26
Issue number	8
DOIs	https://doi.org/10.1038/s41380-020-0654-3
State	Published - Aug 2021

Bibliographical note

Funding Information:
to DG, U01 MH087626 to MEC, RSG, RCG, and REG, U54HD090260 to AD, TG, BEM, and YZ, UO1-MH191719 and R01 MH087636-01A1 to TBC, BSE, AJ, BL, DMM-M, DEM, EMM, HIS, RJS, OT, MU, and EHZ, Van de Werf fund for cardiovascular research to JB, IWT 131625 to WD, Wellcome Trust grant 102428/Z/13/Z to TM and NMW, and Canadian Institutes of Health Research grants MOP-79518, MOP-89066, MOP-97800 and MOP-111238, a McLaughlin Centre Accelerator grant, the Canada Research Chairs program, and Dalglish Chair to ASB. The authors thank all individuals with 22q11.2 deletion syndrome and their families for their generous contributions to this and related research studies, and are grateful to support charities including Max Appeal, The 22Crew and Unique. This work included participants of the NCMH study, a collaboration between Cardiff, Swansea and Bangor Universities. We thank the following members of the Division of Psychological Medicine and Clinical Neurosciences at the Cardiff School of Medicine for technical assistance: S. Chawner, A. Cunningham, C. Eaton, A. Evans, S. Morrison, H. Moulding, P. Birch, M. Tong, S. Bowen, L. Benger, M. Thomas, L. Reed, C.T. Carmichael, L. Bates, B. Lugonja, J. Morgan, N. Vinh, A. Evans, L. Hopkins, L. Tram, S. Jacques, S. Lewis.

Funding Information:
Acknowledgements The IBBC is supported by the National Institute of Mental Health grants U01MH101719, U01MH0101720, U01MH0101723, U01MH101722, and U01MH101724. Other grant support includes: Brain and Behavior Foundation Young Researcher grant (formerly NARSAD, grant no. 21278) to MA, Fondecyt-Chile Grant 1171014 to RF, CO, and GMR, grant FWO G.0E11.17N to JRV, MRC Centre grant MR/L010305/1, National Institute of Mental Health grant U01MH101724, and Welsh Government funded Research Centre 514032 to MJO, NARSAD (Brain and Behavior Research Foundation) to OYO, National Institute of Mental Health grant MH064824 to KMA, WF, WRK, and TJS, NIH grant R01GM117946 to MPE, RD and AJV, NIH grant U54NS091859 to PC, PE, HRJ, and STW, NIH grant R01MH100917 to DJC, PE, AVK, JGM, and MEZ, NIMH K01 MH112774 to MJ, NIMH R01 MH085953 and NIH U54 EB020403 to CEB and LK, NIMH U01MH101724 to MvdB, P01HD070454 to TBC, AD, BSE, TG, AJ, BL, DMM-M, DEM, EMM, BEM, HIS, RJS, OT, MU, EHZ, and YZ, P50MH09689 and R01-MH-1072351 to REG, P50MH096891 to MEC and RCG, National Institute of Mental Health R01 MH085953 to CMM and DGM, R01-MH-107235 to RCG, Canadian Institutes of Health Research grant MOP-74631 to EWCC, Swiss National Science Foundation (Grant number 324730_144260) and National Center of Competence in Research (NCCR) “Synapsy-The Synaptic Bases of Mental Diseases” (Grant number 51NF40-185897) to SE, T32 MH019112 to SXT, the Binational Science Foundation, grant 2017370

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Keywords

Adult
Case-Control Studies
Cohort Studies
DiGeorge Syndrome
Humans
Psychotic Disorders
Schizophrenia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41380-020-0654-3

Cite this

@article{0e3406dc71ee4247b6500d23669083f7,

title = "Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion",

abstract = "Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.",

keywords = "Adult, Case-Control Studies, Cohort Studies, DiGeorge Syndrome, Humans, Psychotic Disorders, Schizophrenia, schizophrenia",

author = "{International 22q11.2DS Brain and Behavior Consortium} and Isabelle Cleynen and Worrawat Engchuan and Hestand, {Matthew S.} and Tracy Heung and Holleman, {Aaron M.} and Johnston, {H. Richard} and Thomas Monfeuga and McDonald-McGinn, {Donna M.} and Gur, {Raquel E.} and Morrow, {Bernice E.} and Ann Swillen and Vorstman, {Jacob A.S.} and Bearden, {Carrie E.} and Chow, {Eva W.C.} and {van den Bree}, Marianne and Emanuel, {Beverly S.} and Vermeesch, {Joris R.} and Warren, {Stephen T.} and Owen, {Michael J.} and Pankaj Chopra and Cutler, {David J.} and Richard Duncan and Kotlar, {Alex V.} and Mulle, {Jennifer G.} and Voss, {Anna J.} and Zwick, {Michael E.} and Alexander Diacou and Aaron Golden and Tingwei Guo and Lin, {Jhih Rong} and Tao Wang and Zhengdong Zhang and Yingjie Zhao and Christian Marshall and Daniele Merico and Andrea Jin and Brenna Lilley and Salmons, {Harold I.} and Oanh Tran and Peter Holmans and Antonio Pardinas and Walters, {James T.R.} and Wolfram Demaerel and Erik Boot and Butcher, {Nancy J.} and Costain, {Gregory A.} and Chelsea Lowther and Rens Evers and {van Amelsvoort}, {Therese A.M.J.} and {van Duin}, Esther and Rosemarie Fritsch",

note = "Funding Information: to DG, U01 MH087626 to MEC, RSG, RCG, and REG, U54HD090260 to AD, TG, BEM, and YZ, UO1-MH191719 and R01 MH087636-01A1 to TBC, BSE, AJ, BL, DMM-M, DEM, EMM, HIS, RJS, OT, MU, and EHZ, Van de Werf fund for cardiovascular research to JB, IWT 131625 to WD, Wellcome Trust grant 102428/Z/13/Z to TM and NMW, and Canadian Institutes of Health Research grants MOP-79518, MOP-89066, MOP-97800 and MOP-111238, a McLaughlin Centre Accelerator grant, the Canada Research Chairs program, and Dalglish Chair to ASB. The authors thank all individuals with 22q11.2 deletion syndrome and their families for their generous contributions to this and related research studies, and are grateful to support charities including Max Appeal, The 22Crew and Unique. This work included participants of the NCMH study, a collaboration between Cardiff, Swansea and Bangor Universities. We thank the following members of the Division of Psychological Medicine and Clinical Neurosciences at the Cardiff School of Medicine for technical assistance: S. Chawner, A. Cunningham, C. Eaton, A. Evans, S. Morrison, H. Moulding, P. Birch, M. Tong, S. Bowen, L. Benger, M. Thomas, L. Reed, C.T. Carmichael, L. Bates, B. Lugonja, J. Morgan, N. Vinh, A. Evans, L. Hopkins, L. Tram, S. Jacques, S. Lewis. Funding Information: Acknowledgements The IBBC is supported by the National Institute of Mental Health grants U01MH101719, U01MH0101720, U01MH0101723, U01MH101722, and U01MH101724. Other grant support includes: Brain and Behavior Foundation Young Researcher grant (formerly NARSAD, grant no. 21278) to MA, Fondecyt-Chile Grant 1171014 to RF, CO, and GMR, grant FWO G.0E11.17N to JRV, MRC Centre grant MR/L010305/1, National Institute of Mental Health grant U01MH101724, and Welsh Government funded Research Centre 514032 to MJO, NARSAD (Brain and Behavior Research Foundation) to OYO, National Institute of Mental Health grant MH064824 to KMA, WF, WRK, and TJS, NIH grant R01GM117946 to MPE, RD and AJV, NIH grant U54NS091859 to PC, PE, HRJ, and STW, NIH grant R01MH100917 to DJC, PE, AVK, JGM, and MEZ, NIMH K01 MH112774 to MJ, NIMH R01 MH085953 and NIH U54 EB020403 to CEB and LK, NIMH U01MH101724 to MvdB, P01HD070454 to TBC, AD, BSE, TG, AJ, BL, DMM-M, DEM, EMM, BEM, HIS, RJS, OT, MU, EHZ, and YZ, P50MH09689 and R01-MH-1072351 to REG, P50MH096891 to MEC and RCG, National Institute of Mental Health R01 MH085953 to CMM and DGM, R01-MH-107235 to RCG, Canadian Institutes of Health Research grant MOP-74631 to EWCC, Swiss National Science Foundation (Grant number 324730_144260) and National Center of Competence in Research (NCCR) “Synapsy-The Synaptic Bases of Mental Diseases” (Grant number 51NF40-185897) to SE, T32 MH019112 to SXT, the Binational Science Foundation, grant 2017370 Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = aug,

doi = "10.1038/s41380-020-0654-3",

language = "English",

volume = "26",

pages = "4496--4510",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "8",

}

TY - JOUR

T1 - Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

AU - International 22q11.2DS Brain and Behavior Consortium

AU - Cleynen, Isabelle

AU - Engchuan, Worrawat

AU - Hestand, Matthew S.

AU - Heung, Tracy

AU - Holleman, Aaron M.

AU - Johnston, H. Richard

AU - Monfeuga, Thomas

AU - McDonald-McGinn, Donna M.

AU - Gur, Raquel E.

AU - Morrow, Bernice E.

AU - Swillen, Ann

AU - Vorstman, Jacob A.S.

AU - Bearden, Carrie E.

AU - Chow, Eva W.C.

AU - van den Bree, Marianne

AU - Emanuel, Beverly S.

AU - Vermeesch, Joris R.

AU - Warren, Stephen T.

AU - Owen, Michael J.

AU - Chopra, Pankaj

AU - Cutler, David J.

AU - Duncan, Richard

AU - Kotlar, Alex V.

AU - Mulle, Jennifer G.

AU - Voss, Anna J.

AU - Zwick, Michael E.

AU - Diacou, Alexander

AU - Golden, Aaron

AU - Guo, Tingwei

AU - Lin, Jhih Rong

AU - Wang, Tao

AU - Zhang, Zhengdong

AU - Zhao, Yingjie

AU - Marshall, Christian

AU - Merico, Daniele

AU - Jin, Andrea

AU - Lilley, Brenna

AU - Salmons, Harold I.

AU - Tran, Oanh

AU - Holmans, Peter

AU - Pardinas, Antonio

AU - Walters, James T.R.

AU - Demaerel, Wolfram

AU - Boot, Erik

AU - Butcher, Nancy J.

AU - Costain, Gregory A.

AU - Lowther, Chelsea

AU - Evers, Rens

AU - van Amelsvoort, Therese A.M.J.

AU - van Duin, Esther

AU - Fritsch, Rosemarie

N1 - Funding Information: to DG, U01 MH087626 to MEC, RSG, RCG, and REG, U54HD090260 to AD, TG, BEM, and YZ, UO1-MH191719 and R01 MH087636-01A1 to TBC, BSE, AJ, BL, DMM-M, DEM, EMM, HIS, RJS, OT, MU, and EHZ, Van de Werf fund for cardiovascular research to JB, IWT 131625 to WD, Wellcome Trust grant 102428/Z/13/Z to TM and NMW, and Canadian Institutes of Health Research grants MOP-79518, MOP-89066, MOP-97800 and MOP-111238, a McLaughlin Centre Accelerator grant, the Canada Research Chairs program, and Dalglish Chair to ASB. The authors thank all individuals with 22q11.2 deletion syndrome and their families for their generous contributions to this and related research studies, and are grateful to support charities including Max Appeal, The 22Crew and Unique. This work included participants of the NCMH study, a collaboration between Cardiff, Swansea and Bangor Universities. We thank the following members of the Division of Psychological Medicine and Clinical Neurosciences at the Cardiff School of Medicine for technical assistance: S. Chawner, A. Cunningham, C. Eaton, A. Evans, S. Morrison, H. Moulding, P. Birch, M. Tong, S. Bowen, L. Benger, M. Thomas, L. Reed, C.T. Carmichael, L. Bates, B. Lugonja, J. Morgan, N. Vinh, A. Evans, L. Hopkins, L. Tram, S. Jacques, S. Lewis. Funding Information: Acknowledgements The IBBC is supported by the National Institute of Mental Health grants U01MH101719, U01MH0101720, U01MH0101723, U01MH101722, and U01MH101724. Other grant support includes: Brain and Behavior Foundation Young Researcher grant (formerly NARSAD, grant no. 21278) to MA, Fondecyt-Chile Grant 1171014 to RF, CO, and GMR, grant FWO G.0E11.17N to JRV, MRC Centre grant MR/L010305/1, National Institute of Mental Health grant U01MH101724, and Welsh Government funded Research Centre 514032 to MJO, NARSAD (Brain and Behavior Research Foundation) to OYO, National Institute of Mental Health grant MH064824 to KMA, WF, WRK, and TJS, NIH grant R01GM117946 to MPE, RD and AJV, NIH grant U54NS091859 to PC, PE, HRJ, and STW, NIH grant R01MH100917 to DJC, PE, AVK, JGM, and MEZ, NIMH K01 MH112774 to MJ, NIMH R01 MH085953 and NIH U54 EB020403 to CEB and LK, NIMH U01MH101724 to MvdB, P01HD070454 to TBC, AD, BSE, TG, AJ, BL, DMM-M, DEM, EMM, BEM, HIS, RJS, OT, MU, EHZ, and YZ, P50MH09689 and R01-MH-1072351 to REG, P50MH096891 to MEC and RCG, National Institute of Mental Health R01 MH085953 to CMM and DGM, R01-MH-107235 to RCG, Canadian Institutes of Health Research grant MOP-74631 to EWCC, Swiss National Science Foundation (Grant number 324730_144260) and National Center of Competence in Research (NCCR) “Synapsy-The Synaptic Bases of Mental Diseases” (Grant number 51NF40-185897) to SE, T32 MH019112 to SXT, the Binational Science Foundation, grant 2017370 Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/8

Y1 - 2021/8

N2 - Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

AB - Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

KW - Adult

KW - Case-Control Studies

KW - Cohort Studies

KW - DiGeorge Syndrome

KW - Humans

KW - Psychotic Disorders

KW - Schizophrenia

KW - schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=85079175539&partnerID=8YFLogxK

U2 - 10.1038/s41380-020-0654-3

DO - 10.1038/s41380-020-0654-3

M3 - Article

C2 - 32015465

AN - SCOPUS:85079175539

SN - 1359-4184

VL - 26

SP - 4496

EP - 4510

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 8

ER -

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this