Integration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11.2 CNV genes
Year: 2021
Type: article
Study design: Observational Study
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.
Source: Genome Medicine
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,480
Funders: Vanderbilt University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G163211900, G1680256299, G1967470738, G2043572114, Understanding the genetic risk underlying racial disparities in uterine fibroids, G2310098089, G2328519459, G25420283, G3420921512, BioVU Plasma Storage Equipment, G5760518052, Genetic Epidemiology of Multiple Sclerosis, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Vanderbilt Genome Electronic Records Project, Discovering Biology for Neuropsychiatric Diseases Through Omics Studies on Comorbidities, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), Pharmaceutical Sciences and Pharmacogenomics, Vanderbilt Institute for Clinical and Translational Research (VICTR), G949362299, G95160140
OpenAlex ID: W3208068596