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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, et al. 22q11.2 deletion syndrome. Nat Rev Dis Prim. 2015;1:15071.
Fung WL, Butcher NJ, Costain G, Andrade DM, Boot E, Chow EW, et al. Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet Med. 2015;17:599–609.
Gur RE, Bassett AS, McDonald-McGinn DM, Bearden CE, Chow E, Emanuel BS, et al. A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium. Mol Psychiatry. 2017;22:1664–72.
Insel TR. Rethinking schizophrenia. Nature. 2010;468:187–93.
Bassett AS, Lowther C, Merico D, Costain G, Chow EWC, van Amelsvoort T, et al. Rare genome-wide copy number variation and expression of Schizophrenia in 22q11.2 deletion syndrome. Am J Psychiatry. 2017;174:1054–63.
Pardinas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.
Singh T, Walters JTR, Johnstone M, Curtis D, Suvisaari J, Torniainen M, et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat Genet. 2017;49:1167–73.
Genovese G, Fromer M, Stahl EA, Ruderfer DM, Chambert K, Landen M, et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci. 2016;19:1433–41.
Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–90.
Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49:27–35.
Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2012;17:142–53.
Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–84.
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.
Johnston HR, Chopra P, Wingo TS, Patel V, International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome, Epstein MP, et al. PEMapper and PECaller provide a simplified approach to whole-genome sequencing. Proc Natl Acad Sci USA. 2017;114:E1923–E32.
Rees E, Kendall K, Pardinas AF, Legge SE, Pocklington A, Escott-Price V, et al. Analysis of intellectual disability copy number variants for association with schizophrenia. JAMA Psychiatry. 2016;73:963–9.
Guo T, Diacou A, Nomaru H, McDonald-McGinn DM, Hestand M, Demaerel W, et al. Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2. Hum Mol Genet. 2018;27:1150–63.
McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016;48:1279–83.
Loh PR, Danecek P, Palamara PF, Fuchsberger C, Reshef YA, Finucane HK, et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat Genet. 2016;48:1443–8.
Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48:1284–7.
Euesden J, Lewis CM, O’Reilly PF. PRSice: Polygenic Risk Score software. Bioinformatics. 2015;31:1466–8.
Conneely KN, Boehnke M. So many correlated tests, so little time! Rapid adjustment of P values for multiple correlated tests. Am J Hum Genet. 2007;81:1158–68.
Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X. Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet. 2011;89:82–93.
Epstein MP, Duncan R, Jiang Y, Conneely KN, Allen AS, Satten GA. A permutation procedure to correct for confounders in case-control studies, including tests of rare variation. Am J Hum Genet. 2012;91:215–23.
Mlynarski EE, Sheridan MB, Xie M, Guo T, Racedo SE, McDonald-McGinn DM, et al. Copy-number variation of the glucose transporter gene SLC2A3 and congenital heart defects in the 22q11.2 deletion syndrome. Am J Hum Genet. 2015;96:753–64.
Rees E, Carrera N, Morgan J, Hambridge K, Escott-Price V, Pocklington AJ, et al. Targeted sequencing of 10,198 samples confirms abnormalities in neuronal activity and implicates voltage-gated sodium channels in schizophrenia pathogenesis. Biol Psychiatry. 2019;85:554–62.
Bergen SE, Ploner A, Howrigan D, CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium, O’Donovan MC, Smoller JW, et al. Joint contributions of rare copy number variants and common SNPs to risk for schizophrenia. Am J Psychiatry. 2019;176:29–35.
Tansey KE, Rees E, Linden DE, Ripke S, Chambert KD, Moran JL, et al. Common alleles contribute to schizophrenia in CNV carriers. Mol Psychiatry. 2016;21:1085–9.
Niemi MEK, Martin HC, Rice DL, Gallone G, Gordon S, Kelemen M, et al. Common genetic variants contribute to risk of rare severe neurodevelopmental disorders. Nature. 2018;562:268–71.
Kirov G, Rees E, Walters JT, Escott-Price V, Georgieva L, Richards AL, et al. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75:378–85.
Hoeffding LK, Trabjerg BB, Olsen L, Mazin W, Sparso T, Vangkilde A, et al. Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication: A Danish Nationwide, Register-Based Study. JAMA Psychiatry. 2017;74:282–90.
Fung SJ, Sivagnanasundaram S, Weickert CS. Lack of change in markers of presynaptic terminal abundance alongside subtle reductions in markers of presynaptic terminal plasticity in prefrontal cortex of schizophrenia patients. Biol Psychiatry. 2011;69:71–9.
Schneider M, Debbane M, Bassett AS, Chow EW, Fung WL, van den Bree M, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry. 2014;171:627–39.
International Multiple Sclerosis Genetics Consortium. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell. 2018;175:1679–87.
Ganna A, Satterstrom FK, Zekavat SM, Das I, Kurki MI, Churchhouse C, et al. Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum. Am J Hum Genet. 2018;102:1204–11.
Coe BP, Stessman HAF, Sulovari A, Geisheker MR, Bakken TE, Lake AM, et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat Genet. 2019;51:106–16.
Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet. 2008;40:751–60.
Forstner AJ, Degenhardt F, Schratt G, Nothen MM. MicroRNAs as the cause of schizophrenia in 22q11.2 deletion carriers, and possible implications for idiopathic disease: a mini-review. Front Mol Neurosci. 2013;6:47.
Schofield CM, Hsu R, Barker AJ, Gertz CC, Blelloch R, Ullian EM. Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortex. Neural Dev. 2011;6:11.
Brzustowicz LM, Bassett AS. miRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome. Front Genet. 2012;3:291.
Merico D, Costain G, Butcher NJ, Warnica W, Ogura L, Alfred SE, et al. MicroRNA dysregulation, gene networks, and risk for schizophrenia in 22q11.2 deletion syndrome. Front Neurol. 2014;5:238.
Merico D, Zarrei M, Costain G, Ogura L, Alipanahi B, Gazzellone MJ, et al. Whole-genome sequencing suggests schizophrenia risk mechanisms in humans with 22q11.2 deletion syndrome. G3. 2015;5:2453–61.
Warnica W, Merico D, Costain G, Alfred SE, Wei J, Marshall CR, et al. Copy number variable microRNAs in schizophrenia and their neurodevelopmental gene targets. Biol Psychiatry. 2015;77:158–66.
Costain G, McDonald-McGinn DM, Bassett AS. Prenatal genetic testing with chromosomal microarray analysis identifies major risk variants for schizophrenia and other later-onset disorders. Am J Psychiatry. 2013;170:1498.
Harrison PJ. Recent genetic findings in schizophrenia and their therapeutic relevance. J Psychopharmacol. 2015;29:85–96.
Smeland OB, Bahrami S, Frei O, Shadrin A, O’Connell K, Savage J, et al. Genome-wide analysis reveals extensive genetic overlap between schizophrenia, bipolar disorder, and intelligence. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-018-0332-x. [Epub ahead of print].
Swillen A, Moss E, Duijff S. Neurodevelopmental outcome in 22q11.2 deletion syndrome and management. Am J Med Genet A. 2018;176:2160–6.
Bassett AS, Marshall CR, Lionel AC, Chow EW, Scherer SW. Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome. Hum Mol Genet. 2008;17:4045–53.
Van L, Boot E, Bassett AS. Update on the 22q11.2 deletion syndrome and its relevance to schizophrenia. Curr Opin Psychiatry. 2017;30:191–6.
Karczewski KJ, Weisburd B, Thomas B, Solomonson M, Ruderfer DM, Kavanagh D, et al. The ExAC browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Research. 2017;45(D1):D840–D845.
Smith CL, Blake JA, Kadin JA, Richardson JE, Bult CJ. Mouse Genome Database (MGD)-2018: knowledgebase for the laboratory mouse. Nucleic Acids Research. 2018;46(D1):D836–D842.
MacDonald JR, Ziman R, Yuen RKC, Feuk L, Scherer SW. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Research. 2013;42 (D1):D986–D992.
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 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.
Author information
Authors and Affiliations
Consortia
Corresponding authors
Ethics declarations
Conflict of interest
DM is a full-time employee and is entitled to a stock option of Deep Genomics Inc., a start-up developing oligonucleotide therapeutics for rare genetic disorders. FT received funding from Zynerba and Asuragen Inc. for her work on Fragile X syndrome. All other authors report no financial relationships with commercial interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Cleynen, I., Engchuan, W., Hestand, M.S. et al. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Mol Psychiatry 26, 4496–4510 (2021). https://doi.org/10.1038/s41380-020-0654-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-020-0654-3