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Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Nature Medicine volume 26, pages 1912–1918 (2020)Cite this article

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Abstract

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

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Fig. 1: PS_SZs among phenotypic subgroups.
Fig. 2: Relationship between polygenic scores and novel phenotypes.
Fig. 3: Individual risk prediction.

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Data availability

The data sets (raw data) generated and/or analyzed during the current study are available through the National Institute of Mental Health Data Archive repository at https://nda.nih.gov/study.html?id=938, accession number 10.15154/1519190.

To construct the polygenic score for schizophrenia, we used results from the Schizophrenia Working Group of the Psychiatric Genomics Consortium24, specifically the ‘Full SNP Results’ file ckqny.scz2snpres.gz with md5 af7b9b521a196ce711d99060426fe01e, which is available after filling out an application as described at https://www.med.unc.edu/pgc/download-results/scz/.

To construct the polygenic score for fluid intelligence, we used results from the Neale lab, which are available at http://www.nealelab.is/blog/2017/7/19/rapid-gwas-of-thousands-of-phenotypes-for-337000-samples-in-the-uk-biobank, specifically the file fluid_intelligence.20016.assoc.tsv.gz with md5 685d4b5e2f35c82fe29d9d9ac6e35db4, which is available through their website, http://www.nealelab.is/uk-biobank, and is additionally mirrored at https://figshare.com/articles/dataset/fluid_intelligence_20016_assoc_tsv_gz_from_2017_Neale_lab_analysis/12746570.

Code availability

Bespoke analysis code for analyses downstream of genotype generation is available.

https://github.com/rwdavies/IBBC_Aim2_22Q11DS.

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Acknowledgements

This study was supported by the National Institute of Mental Health (NIMH) International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome (U01MH101719, U01MH0101720, U01MH0101723, U01MH101722 and EU01MH101724); the Lap-Chee Tsui Fellowship for Research Excellence and the CIHR STAGE Fellowship (to R.W.D.); the Brain and Behavior Research Foundation (to J.A.S.V.; Young Investigator Award); NIMH R01MH085953 and 1U01MH119736-01 (to C.E.B.); NIH RO1 MH064824 (to W.K.); Wellcome Trust grant 102428/Z/13/Z (to N.W. and T.M.); 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 A.S.B); the Academic Scholars Award from the Department of Psychiatry, University of Toronto and the O’Brien Scholars Fund (to E.B.); Fondecyt 1171014 and ACT 192064 (ANID-Chile) (to G.R.); Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program (FP7-HEALTH-2013-2.2.1-2-603196 Project PSYSCAN) and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 115916, Project PRISM, and grant agreement 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz (to C.A); Innovative Medicines Initiative 2 Joint Undertaking (#777394 for the project AIMS-2-TRIALS), the NIHR Maudsley BRC (to D.M.); and Binational Science Foundation grant 2017369 (to R.E.G. and D.G.).

Author information

Author notes

  1. These authors contributed equally: Robert W. Davies, Ania M. Fiksinski.

  2. Deceased: Clodagh M. Murphy.

Authors and Affiliations

  1. Program in Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada

    Robert W. Davies

  2. Department of Statistics, University of Oxford, Oxford, UK

    Robert W. Davies

  3. Department of Psychiatry, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands

    Ania M. Fiksinski, René S. Kahn & Jacob A. S. Vorstman

  4. Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Ania M. Fiksinski, Anne S. Bassett, Eva W. C. Chow & Tracy Heung

  5. Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada

    Elemi J. Breetvelt

  6. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK

    Nigel M. Williams, Thomas Monfeuga, Michael J. Owen, Marianne van den Bree, Sinead Morrison & Samuel Chawner

  7. Department of Allied Health Sciences, School of Medicine, University of North Carolina–Chapel Hill, Chapel Hill, NC, USA

    Stephen R. Hooper

  8. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Anne S. Bassett, Eva W. C. Chow & Erik Boot

  9. The Dalglish Family 22q Clinic, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

    Anne S. Bassett

  10. Department of Psychiatry and Lifespan Brain Institute, Penn Medicine–CHOP, University of Pennsylvania, Philadelphia, PA, USA

    Raquel E. Gur, Monica E. Calkins & Ruben C. Gur

  11. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

    Bernice E. Morrow

  12. Division of Human Genetics, 22q and You Center, Clinical Genetics Center, and Section of Genetic Counseling, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Donna M. McDonald-McGinn, Beverly S. Emanuel, T. Blaine Crowley & Elaine H. Zackai

  13. Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA

    Donna M. McDonald-McGinn & Elaine H. Zackai

  14. Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium

    Ann Swillen, Joris R. Vermeesch, Jeroen Breckpot, Elfi Vergaelen & Annick Vogels

  15. Department of Human Genetics KU Leuven, Leuven, Belgium

    Ann Swillen

  16. Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands

    Therese van Amelsvoort, Claudia Vingerhoets & Rens Evers

  17. Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense, Madrid, Spain

    Celso Arango & David Fraguas

  18. Developmental Imaging and Psychopathology, Department of Psychiatry, University of Geneva, Geneva, Switzerland

    Marco Armando, Stephan Eliez, Corrado Sandini, Maude Schneider & Johanna Maeder

  19. School of Psychology, University of Newcastle, Newcastle, Australia

    Linda E. Campbell

  20. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    Joseph F. Cubells, Michael P. Epstein & Stephen T. Warren

  21. Emory Autism Center, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Joseph F. Cubells

  22. Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain

    Sixto Garcia-Minaur

  23. The Child Psychiatry Division, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel

    Doron Gothelf, Ehud Mekori-Domachevsky & Ronnie Weinberger

  24. Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Doron Gothelf, Miri Carmel, Ehud Mekori-Domachevsky & Elena Michaelovsky

  25. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA

    Wendy R. Kates & Wanda Fremont

  26. Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland

    Kieran C. Murphy, Stephen Monks & Sarah E. Prasad

  27. Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, London, UK

    Clodagh M. Murphy, Declan G. Murphy & Eileen M. Daly

  28. Département de Génétique Médicale, APHM, CHU Timone Enfants, Marseille, France

    Nicole Philip & Tiffany Busa

  29. Aix Marseille Université, MMG, INSERM, Marseille, France

    Nicole Philip

  30. Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile

    Gabriela M. Repetto

  31. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Vandana Shashi & Kelly Schoch

  32. MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, CA, USA

    Tony J. Simon & Kathryn L. McCabe

  33. Genomics of Health Group and Molecular Diagnostics and Clinical Genetics Unit (UDMGC), Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, Palma de Mallorca, Spain

    Damiàn Heine Suñer

  34. Department of Life Sciences and Public Health, Catholic University; Child and Adolescent Psychiatry Unit, Bambino Gesù Children’s Hospital, IRCSS, Rome, Italy

    Stefano Vicari & Maria Pontillo

  35. Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada

    Stephen W. Scherer & Jacob A. S. Vorstman

  36. Departments of Psychiatry and Biobehavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA

    Leila Kushan & Carrie E. Bearden

  37. Department of Psychiatry, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Jacob A. S. Vorstman

  38. Department of Microbiology and Molecular Medicine, University of California Davis, Davis, CA, USA

    Flora Tassone

  39. Hospital Universitari Son Espases, Mallorca, Spain

    Jaume Morey-Canyelles

  40. Department of Psychiatry, Emory University School of Medicine, Atlanta, GA, USA

    Opal Y. Ousley

  41. Department of Psychology, Syracuse University, Syracuse, NY, USA

    Kevin M. Antshel

  42. Department of Psychiatry, Hospital Clinico Universidad de Chile, Santiago, Chile

    Rosemarie Fritsch & Claudia Ornstein

  43. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada

    Gregory A. Costain

  44. Department of Pediatrics University Medical Center Utrecht, Utrecht, the Netherlands

    Sasja N. Duijff & Michiel Houben

  45. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    René S. Kahn

  46. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Maria Jalbrzikowski

  47. Felsenstein Medical Research Center, Petach Tikva, Israel

    Miri Carmel & Elena Michaelovsky

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  1. Robert W. Davies
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  2. Ania M. Fiksinski
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  3. Elemi J. Breetvelt
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  4. Nigel M. Williams
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  5. Stephen R. Hooper
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  6. Thomas Monfeuga
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  11. Donna M. McDonald-McGinn
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  17. Therese van Amelsvoort
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  18. Celso Arango
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  19. Marco Armando
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  20. Linda E. Campbell
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  21. Joseph F. Cubells
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  22. Stephan Eliez
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  23. Sixto Garcia-Minaur
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  24. Doron Gothelf
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  26. Kieran C. Murphy
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  27. Clodagh M. Murphy
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  28. Declan G. Murphy
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  30. Gabriela M. Repetto
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Consortia

International 22q11.2 Brain and Behavior Consortium

  • Michael P. Epstein
  • , Stephen T. Warren
  • , Sinead Morrison
  • , Samuel Chawner
  • , Claudia Vingerhoets
  • , Jeroen Breckpot
  • , Elfi Vergaelen
  • , Annick Vogels
  • , Stephen Monks
  • , Sarah E. Prasad
  • , Corrado Sandini
  • , Maude Schneider
  • , Johanna Maeder
  • , David Fraguas
  • , Rens Evers
  • , Flora Tassone
  • , Jaume Morey-Canyelles
  • , Opal Y. Ousley
  • , Kevin M. Antshel
  • , Wanda Fremont
  • , Rosemarie Fritsch
  • , Claudia Ornstein
  • , Eileen M. Daly
  • , Gregory A. Costain
  • , Erik Boot
  • , Tracy Heung
  • , T. Blaine Crowley
  • , Elaine H. Zackai
  • , Monica E. Calkins
  • , Ruben C. Gur
  • , Kathryn L. McCabe
  • , Tiffany Busa
  • , Kelly Schoch
  • , Maria Pontillo
  • , Sasja N. Duijff
  • , René S. Kahn
  • , Michiel Houben
  • , Leila Kushan
  • , Maria Jalbrzikowski
  • , Miri Carmel
  • , Ehud Mekori-Domachevsky
  • , Elena Michaelovsky
  •  & Ronnie Weinberger

Contributions

J.A.S.V., R.W.D., A.M.F. and C.E.B. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. R.W.D. and A.M.F. contributed equally to the study. Study concept and design: AIM II writing group: R.W.D., A.M.F., E.J.B., T.M., N.M.W., S.R.H., C.E.B. and J.A.S.V. Acquisition of data: M.J.O., M.v.d.B., D.G.M., C.A., J.A.S.V., A.M.F., S.N.D., S.E., M.S., M.J., M.A., S.V., V.S., S.R.H., E.W.C.C., D.M.M.-M., A.V., D.G., R.W., T.v.A., W.K., K.M.A., T.S., O.Y.O., A.S., R.E.G., C.E.B. and A.S.B. Analysis and interpretation of data: AIM II writing group: R.W.D., A.M.F., E.J.B., T.M., N.M.W., S.R.H., C.E.B. and J.A.S.V. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: R.W.D., E.J.B., T.M., N.M.W. and J.A.S.V.

Corresponding author

Correspondence to Jacob A. S. Vorstman.

Ethics declarations

Competing interests

M.J.O. and M.v.d.B. report grants from Takeda Pharmaceuticals outside of the submitted work. C.A. has been a consultant to or has received honoraria or grants from Acadia, Ambrosseti, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. D.G.M. has provided consultation to Roche. S.R.H. has provided consultation to Novartis. O.Y.O. is a collaborator in a Biomarin Pharmaceutical study. None of the other authors has financial disclosures.

Additional information

Peer review information Kate Gao and Joao Monteiro were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Relationship between polygenic scores and previously studied phenotypes.

Results for the binary SSD phenotype show per-individual values as well as summaries per group, where minimum and maximum values are directly observable from the plot, the box-plot centre is the median, the boxplot edges represent the 25th and 75th percentiles, and the whiskers represent the lesser of the distance to the minimum or maximum value, or 1.5 times the inter-quartile range. Results are shown for logistic regression of SSD on controls (N = 802) and linear regression for FSIQ (N = 720), for both PS_SZ (left panel) and PS_IQ (right panel). P-values are reported from regression analyses and are two sided and are not corrected for multiple testing.

Extended Data Fig. 2 Inferred contribution of controls and future SSD cases given PS SZ.

Shown on the y-axis are group means of PS_SZ, on the x-axis the fraction of controls. For SDD and controls the fractions of controls were taken as 0 and 1, respectively (open circles). For subthreshold psychosis and putative controls they were inferred through the observed PS-SZ values for each group, using linear interpolation based on fitting a straight line between SSD and control values (red circles). Confidence intervals are shown for the group mean values for subthreshold psychosis and putative controls, as the mean plus or minus 1.96 times the standard error, and above and below these confidence intervals are the inferred fraction of controls this would represent. The observed PS_SZ in the subthreshold group is consistent with a scenario in which 86% (95% CI 56 - 100%) of individuals who had subthreshold psychotic symptoms at the time of the assessment for this study would subsequently transition to SSD, a proportion inconsistent with known rates of SSD in 22q11DS.

Supplementary information

Supplementary Information

Supplementary Tables 1–6 and Supplementary Figs. 1–8.

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Davies, R.W., Fiksinski, A.M., Breetvelt, E.J. et al. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome. Nat Med 26, 1912–1918 (2020). https://doi.org/10.1038/s41591-020-1103-1

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