TY - JOUR
T1 - A Regional Burden of Sequence-Level Variation in the 22q11.2 Region Influences Schizophrenia Risk and Educational Attainment
AU - Breetvelt, Elemi J.
AU - Smit, Karel C.
AU - van Setten, Jessica
AU - Merico, Daniele
AU - Wang, Xiao
AU - Vaartjes, Ilonca
AU - Bassett, Anne S.
AU - Boks, Marco P.M.
AU - Szatmari, Peter
AU - Scherer, Stephen W.
AU - Kahn, René S.
AU - Vorstman, Jacob A.S.
N1 - Funding Information:
This work was supported by the Mr. Rajeeb Mukherjee B.Sc. (Hons.) (London School of Economics) Fellowship in Schizophrenia (to EJB), an academic scholarship award from the Department of Psychiatry at the University of Toronto (to EJB), the O’Brien Scholarship (to EJB), and the National Institutes of Mental Health (Grant No. 5U01MH101722-02 [to JASV]).
Funding Information:
This work was supported by the Mr. Rajeeb Mukherjee B.Sc. (Hons.) (London School of Economics) Fellowship in Schizophrenia (to EJB), an academic scholarship award from the Department of Psychiatry at the University of Toronto (to EJB), the O'Brien Scholarship (to EJB), and the National Institutes of Mental Health (Grant No. 5U01MH101722-02 [to JASV]). DM is a full-time employee of Deep Genomics Inc. and is entitled to a stock option. JASV serves as a consultant for NoBias Therapeutics Inc. SWS is on the Scientific Advisory Committees of Deep Genomics and Population Bio and is a highly cited Academic Consultant for the King Abdul Aziz University. All other authors report no biomedical financial interests or potential conflicts of interests.
Publisher Copyright:
© 2021 Society of Biological Psychiatry
PY - 2022/4/15
Y1 - 2022/4/15
N2 - 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.
AB - 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.
KW - 22q11.2 deletion syndrome
KW - Copy number variants
KW - Educational attainment
KW - Genetic epidemiology
KW - Regional burden
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85123077371&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2021.11.019
DO - 10.1016/j.biopsych.2021.11.019
M3 - Article
AN - SCOPUS:85123077371
SN - 0006-3223
VL - 91
SP - 718
EP - 726
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 8
ER -