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Meta-Analysis
. 2017 Nov 30;9(1):106.
doi: 10.1186/s13073-017-0494-1.

Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders

Joseph T Glessner  1 , Jin Li  1   2 , Dai Wang  3 , Michael March  1 , Leandro Lima  1 , Akshatha Desai  1 , Dexter Hadley  1 , Charlly Kao  1 , Raquel E Gur  4 , Nadine Cohen  3 , Patrick M A Sleiman  1   5   6 , Qingqin Li  7 , Hakon Hakonarson  8   9   10 ; Janssen-CHOP Neuropsychiatric Genomics Working Group
Collaborators, Affiliations
Meta-Analysis

Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders

Joseph T Glessner et al. Genome Med. .

Abstract

Background: Neurodevelopmental and neuropsychiatric disorders represent a wide spectrum of heterogeneous yet inter-related disease conditions. The overlapping clinical presentations of these diseases suggest a shared genetic etiology. We aim to identify shared structural variants spanning the spectrum of five neuropsychiatric disorders.

Methods: We investigated copy number variations (CNVs) in five cohorts, including schizophrenia (SCZ), bipolar disease (BD), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and depression, from 7849 cases and 10,799 controls. CNVs were called based on intensity data from genome-wide SNP arrays and CNV frequency was compared between cases and controls in each disease cohort separately. Meta-analysis was performed via a gene-based approach. Quantitative PCR (qPCR) was employed to validate novel significant loci.

Results: In our meta-analysis, two genes containing CNVs with exonic overlap reached genome-wide significance threshold of meta P value < 9.4 × 10-6 for deletions and 7.5 × 10-6 for duplications. We observed significant overlap between risk CNV loci across cohorts. In addition, we identified novel significant associations of DOCK8/KANK1 duplications (meta P value = 7.5 × 10-7) across all cohorts, and further validated the CNV region with qPCR.

Conclusions: In the first large scale meta-analysis of CNVs across multiple neurodevelopmental/psychiatric diseases, we uncovered novel significant associations of structural variants in the locus of DOCK8/KANK1 shared by five diseases, suggesting common etiology of these clinically distinct neurodevelopmental conditions.

Keywords: Copy number variation; DOCK8; Gene-based analysis; Meta-analysis; Neuropsychiatric disorders; Quantitative PCR.

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Conflict of interest statement

Ethics approval and consent to participate

All cohorts in our study were from published datasets. Study protocols used in each cohort have been approved by corresponding Institutional Review Board or equivalent committees, and written informed consent was given from each participant or parent. Our research complies with the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

Dr. Nadine Cohen is a former employee of Janssen Research & Development. Drs. Dai Wang and Qingqin Li are current employees of Janssen Research & Development. The remaining authors declare that they have no competing interests. Funding for this study included sponsored research to The Children’s Hospital of Philadelphia by Janssen Research & Development, LLC.

Publisher’s Note

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

Figures

Fig. 1
Fig. 1
Manhattan plots for gene-based CNV meta-analysis. The results for deletion CNVs are shown in a and those for duplication CNVs are shown in b. The − log10(P value) of each gene (y-axis) in the meta-analysis is plotted against the genomic position (x-axis). Significant loci are indicated on the plot. The locus of 22q11.22 is a known locus for neuropsychiatric disorders and 9p24.3 is a novel locus at which each CNV carrier has been validated by manual visual review of BAF and LRR plots and qPCR experiments
Fig. 2
Fig. 2
Contributing calls in the DOCK8/KANK1 region from each cohort. Black bars indicate the SNP coverage of each genotyping array and blue rectangles represent each individual duplication call observed among neuropsychiatric cases in each cohort
See this image and copyright information in PMC

Comment in

References

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