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Integration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11.2 CNV genes
- Source :
- Genome medicine, vol 13, iss 1, Genome Medicine, Vol 13, Iss 1, Pp 1-26 (2021), Genome Medicine
- Publication Year :
- 2021
- Publisher :
- eScholarship, University of California, 2021.
-
Abstract
- Background Deletions and duplications of the multigenic 16p11.2 and 22q11.2 copy number variant (CNV) regions are associated with brain-related disorders including schizophrenia, intellectual disability, obesity, bipolar disorder, and autism spectrum disorder (ASD). The contribution of individual CNV genes to each of these identified phenotypes is unknown, as well as the contribution of these CNV genes to other potentially subtler health implications for carriers. Hypothesizing that DNA copy number exerts most effects via impacts on RNA expression, we attempted a novel in silico fine-mapping approach in non-CNV carriers using both GWAS and biobank data. Methods We first asked whether gene expression level in any individual gene in the CNV region alters risk for a known CNV-associated behavioral phenotype(s). Using transcriptomic imputation, we performed association testing for CNV genes within large genotyped cohorts for schizophrenia, IQ, BMI, bipolar disorder, and ASD. Second, we used a biobank containing electronic health data to compare the medical phenome of CNV carriers to controls within 700,000 individuals in order to investigate the full spectrum of health effects of the CNVs. Third, we used genotypes for over 48,000 individuals within the biobank to perform phenome-wide association studies between imputed expressions of individual 16p11.2 and 22q11.2 genes and over 1500 health traits. Results Using large genotyped cohorts, we found individual genes within 16p11.2 associated with schizophrenia (TMEM219, INO80E, YPEL3), BMI (TMEM219, SPN, TAOK2, INO80E), and IQ (SPN), using conditional analysis to identify upregulation of INO80E as the driver of schizophrenia, and downregulation of SPN and INO80E as increasing BMI. We identified both novel and previously observed over-represented traits within the electronic health records of 16p11.2 and 22q11.2 CNV carriers. In the phenome-wide association study, we found seventeen significant gene-trait pairs, including psychosis (NPIPB11, SLX1B) and mood disorders (SCARF2), and overall enrichment of mental traits. Conclusions Our results demonstrate how integration of genetic and clinical data aids in understanding CNV gene function and implicates pleiotropy and multigenicity in CNV biology.
- Subjects :
- Schizophrenia Working Group of the Psychiatric Genomics Consortium^
Scavenger Receptors
Autism Spectrum Disorder
Autism
Genome-wide association study
Chromosome Disorders
QH426-470
Electronic health records
2.1 Biological and endogenous factors
Copy-number variation
Aetiology
Transcriptome imputation
Genetics (clinical)
Genetics
Scavenger Receptors, Class F
Phenotype
Mental Health
Schizophrenia
Autism spectrum disorder
Molecular Medicine
Medicine
Chromosome Deletion
Human
Biotechnology
Genotype
DNA Copy Number Variations
Intellectual and Developmental Disabilities (IDD)
Clinical Sciences
Biology
Chromosomes
Clinical Research
Intellectual Disability
medicine
DiGeorge Syndrome
Humans
Bipolar disorder
Genetic Testing
Autistic Disorder
Bipolar Disorder Working Group of the Psychiatric Genomics Consortium^
Molecular Biology
Genetic association
Psychiatric traits
Copy number variants
Pair 16
Research
Tumor Suppressor Proteins
Human Genome
medicine.disease
Human genetics
Phenome-wide association studies
Brain Disorders
Good Health and Well Being
Psychotic Disorders
Autism Working Group of the Psychiatric Genomics Consortium^
Transcriptome
Chromosomes, Human, Pair 16
Imputation (genetics)
Class F
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Genome medicine, vol 13, iss 1, Genome Medicine, Vol 13, Iss 1, Pp 1-26 (2021), Genome Medicine
- Accession number :
- edsair.doi.dedup.....90afc7174562b8102ec0b9dad289b673