Dosage effect of copy number variation in epilepsy and ten regions of the human brain

Epilepsy and seizures are common neurological conditions which often manifest with complex symptoms. Several studies including large scale genome-wide association studies (GWASs) and exome studies have reported several catalogues of genes related to epilepsies and seizure generation. Similarly, there exists several successful studies elucidating the role of single-nucleotide polymorphisms (SNPs) in expression quantitative trait loci (eQTLs) for the human brain. Here, as one of few studies in the current literature we have analysed and reported the dosage effect of small-to-intermediate length copy-number variants (CNVs) in two epilepsy cohorts characterised for phenotypes such as seizure counts, seizure frequency and remission to anti-epileptic drugs (AEDs). In addition, we have performed comprehensive CNV based eQTL analysis in different regions of the normal human brain from the United Kingdom Brain Expression Consortium (UKBEC) study. We leveraged all analyses to decipher new genes for epilepsy phenotypes such as seizure frequency and further uncovered genetic controls of neurotransmitters like serotonin, dopamine and signalling molecules like G protein-coupled receptors (GPCRs). Importantly, we observed and have reported clustering of cis CNV-QTL signals in specific regions of the human genome such as the chromosome 1p36 proband containing the GNB1 gene or the chromosome 9q22 proband containing NANS. This observed phenomenon of clustering or co-localisation of association signals was further corroborated by our non-negative matrix factorization (NMF) analysis of the UKBEC gene expression data. To conclude, our results here successfully describe in detail the dosage effect of CNVs for epileptic seizures and further elucidates its role in the genomic architecture of gene expression in various regions of the human brain.