Dosage effect of Copy Number Variation in Epilepsy and ten regions of the human brain

Dosage effect of Copy Number Variation in Epilepsy and ten regions of the human brain Tisham De1,2,3 *, Lachlan Coin3,4,§, Michael R Johnson5,§ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK Department of Genomics of Common Diseases, Imperial College London, UK Department of Infectious Diseases, Imperial College London, UK Department of Microbiology and Immunology, University of Melbourne at The Peter Doherty, Institute for Infection and Immunity, Melbourne, Australia Department of Brain Sciences, Imperial College London, UK * Email: [email protected] or [email protected] § Joint senior authors Abstract Epilepsy and seizures are one of the most common neurological conditions which often manifest with complex symptoms. Several studies including large scale GWAS and exome studies have reported a comprehensive catalog of genes related to Epilepsy. Similarly, there exists several successful studies elucidating the role of SNP QTLs in the normal human brain. Here, as one of few studies in current literature we have explored and reported the dosage effect of small to intermediate length CNVs in two Epilepsy cohorts characterized for phenotypes such as seizure counts, seizure frequency and remission to anti-epilepsy drugs. In addition, we have performed comprehensive CNV QTL analysis in ten regions of the human brain (normal) from the UKBEC study. We leveraged all analyses to decipher new genes for Epilepsy phenotypes such as seizure frequency and further uncovered genetic controls of neurotransmitters such as serotonin, dopamine and signaling molecules like GPCRs. Importantly we observed and have reported clustering of CNV QTL signals in specific regions of the genome such as the chromosome 1p36 proband containing the GNB1 gene or the chromosome 9q22 proband containing NANS. This observed phenomenon of clustering of association signals was further corroborated by our non-negative matrix factorization (NMF) analysis of UKBEC gene expression data. To conclude our results here successfully describe in detail the dosage effect of CNVs for Epilepsy seizures and further elucidates its role in the genomic architecture of gene expression in various regions of the human brain.