Whole genome sequencing and transcriptome profiling in neuropsychiatric diseases

Aims Recent studies have provided evidence of a substantial genetic contribution to risk for neuropsychiatric diseases. Here we combined whole-genome sequencing (WGS) and RNAseq data to identify differentially expressed genes showing genomic variations in either coding or associated non-coding regions for a specific neuropsychiatric disorder. Methods WGS data on peripheral blood samples from a cohort of 95 individuals were analyzed, spanning both healthy controls (HCs, 29 subjects) and the following DSM-IV-defined disorders: bipolar disorder (BP, 25 subjects), major depressive disorder (MDD, 14 subjects), schizoaffective disorder (SAD, 6 subjects), schizophrenia (SCZ, 21 subjects). Single nucleotide variants (SNVs) were called using HaplotypeCaller, filtering out variants with minor allele frequency above 5% in three cohorts (1000G, ESP6500, ExAC) and those identified in HCs. Recurrent mutations in a specific disorder were identified (p<1%, Fisher’s Exact Test). Differential expression analysis was applied to RNAseq data from iPSC-derived neural progenitor cells of 34 subjects, including 11 HCs, 3 BPs, 3 MDDs and 8 SCZs before and after treatment with Clozapine. Results After filtering common and non-causal variants, on average 55,780 SNVs were identified per individual. The enrichment analysis associated 2,225 SNVs to BP, 3,648 SNVs to MDD, 178 SNVs to SAD and 6,893 to SCZ subjects. RNAseq analysis revealed 143 genes differentially expressed only in SCZ with respect to controls, including the voltage-gated calcium channels CACNA1C, CACNA2D and CACNA1S. Interestingly, 22 mutations were uniquely associated to SCZ subjects in non-coding regions associated to CACNA1A, CACNA1B, CACNA1C, CACNA2D3, CACNA1H. Investigations of structural variants at genomic level and chromosomal rearrangements leading to the formation of fusion transcripts, with particular focus on these genes, are in process.