A Regional Burden of Sequence-Level Variation in the 22q11.2 Region Influences Schizophrenia Risk and Educational Attainment

Elemi J Breetvelt; Karel C Smit; Jessica van Setten; Daniele Merico; Xiao Wang; Ilonca Vaartjes; Anne S Bassett; Marco P M Boks; Peter Szatmari; Stephen W Scherer; René S Kahn; Jacob A S Vorstman

doi:10.1016/j.biopsych.2021.11.019

A Regional Burden of Sequence-Level Variation in the 22q11.2 Region Influences Schizophrenia Risk and Educational Attainment

Biol Psychiatry. 2022 Apr 15;91(8):718-726. doi: 10.1016/j.biopsych.2021.11.019. Epub 2021 Dec 4.

Authors

Affiliations

¹ Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address: Elemi.Breetvelt@sickkids.ca.
² Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands; Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
³ Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
⁴ Center for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Deep Genomics Inc., Toronto, Ontario, Canada.
⁵ Center for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
⁷ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Dalglish Family 22q Clinic for Adults with 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada; Medical Genetics and Genomics Residency Training Program, University of Toronto, Toronto, Ontario, Canada; Toronto General Research Institute, Toronto, Ontario, Canada; Campbell Family Mental Health Research Institute, Toronto, Ontario, Canada.
⁸ Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands.
⁹ Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Center for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹¹ Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NewYork, New York.
¹² Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands.

PMID: 35063188
DOI: 10.1016/j.biopsych.2021.11.019

Abstract

Background: Genomic loci where recurrent pathogenic copy number variants are associated with psychiatric phenotypes in the population may also be sensitive to the collective impact of multiple functional low-frequency single nucleotide variants (SNVs).

Methods: We examined the cumulative impact of low-frequency, functional SNVs within the 22q11.2 region on schizophrenia risk in a discovery cohort and an independent replication cohort (N = 1933 and N = 11,128, respectively), as well as the impact on educational attainment (EA) in a third, independent, general population cohort (N = 2081). In the discovery and EA cohorts, SNVs were identified using genotyping arrays; in the replication cohort, whole-exome sequencing was available. For verification, we compared the regional SNV count for schizophrenia cases in the discovery cohort with a normative count distribution derived from a large population dataset (N = 26,500) using bootstrap procedures.

Results: In both schizophrenia cohorts, an increased regional SNV burden (≥4 low-frequency SNVs) in the 22q11.2 region was associated with schizophrenia (discovery cohort: odds ratio = 7.48, p = .039; replication cohort: odds ratio = 1.92, p = .004). In the EA cohort, an increased regional SNV burden at 22q11.2 was associated with decreased EA (odds ratio = 4.65, p = .049). Comparing the SNV count for schizophrenia cases with a normative distribution confirmed the unique nature of the distribution for schizophrenia cases (p = .002).

Conclusions: In the general population, an increased burden of low-frequency, functional SNVs in the 22q11.2 region is associated with schizophrenia risk and a decrease in EA. These findings suggest that in addition to structural variation, a cumulative regional burden of low-frequency, functional SNVs in the 22q11.2 region can also have a relevant phenotypic impact.

Keywords: 22q11.2 deletion syndrome; Copy number variants; Educational attainment; Genetic epidemiology; Regional burden; Schizophrenia.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
DNA Copy Number Variations / genetics
Humans
Phenotype
Schizophrenia* / genetics