Analysis of copy number variants (cnvs) in a brazilian high-risk cohort for psychiatric disorders

Psychiatric disorders have been neglected in the public health system, especially in low and middle-income countries such as Brazil. As they are multifactorial phenotypes, environmental and genetic risk factors contribute to their development. There is a high genetic correlation among psychiatric disorders. Rare genetic variants with high effect size and penetrance, such as copy number variations (CNVs), have a known impact on the development of these disorders. For example, the deletion in 22q11.2 includes approximately 90 genes and confers a 20-fold increased risk for schizophrenia, presenting with psychosis a quarter of the time. This proposal aims to analyze pathogenic CNVs associated with psychiatric disorders and verify their impact in the Brazilian High-Risk Cohort Study (BHRCS), a longitudinal study. 2,190 probands and 3,174 parents were genotyped using the SNP array and the CNVs were detected using the PennCNV software, which identifies the fluorescence intensity of the array probes and the frequency of the alleles. The identified CNVs underwent quality control excluding centromeric, telomeric, segmental duplications, and immunoglobulin regions. Adjacent CNVs were merged into one single call when there was a gap smaller than 50% of total CNV length and only CNVs with at least 10 consecutive SNVs and 1 kb in size were selected. Subsequently, we analyzed the phenotypes associated with CNVs and the genes affected by each in the UCSC Genome Browser database. We calculated the frequency of CNVs in the cohort, the individual burden of CNVs, and the proportion of inherited and de novo CNVs using RStudio software. The frequencies found were compared with population frequencies based on the DGV and gnomAD databases. Statistical analyses were based on Mann-Whitney's test, Spearman's correlation test, Analysis of Variance (ANOVA), and Tukey's test. A total of 14,304 CNVs were detected, of which 5,521 are duplications and 8,783 are deletions of up to 5 Mb. In the 897 trios, 24% of CNVs are de novo. Thirteen regions larger than 1 Mb found are associated with a high risk for the development of psychiatric disorders according to the literature, six of which are related to schizophrenia. Among the 24 individuals with schizophrenia-related CNVs, four of them were diagnosed with Generalized Anxiety Disorder and Attention Deficit Hyperactivity Disorder and they were parents of probands. Four duplications were found in the 22q11.2 region with a size of 2.5 Mb and one of them was inherited. The most common deletion and duplication were found in 8.7% and 5% of the cohort, respectively, and this duplication (8p21.3) has been associated with Autism Spectrum Disorder. Some CNVs have a similar frequency between the cohort and the general population. We found that probands with a higher CNV burden tend to have a psychiatric diagnosis (p-value = 0,4209), cognitive and school performance problems (p-value = 0,814), and average or below average IQ (p adj = 0.2012863) when compared to individuals with a lower CNV burden in BHRCS, although this was not statistically significant. This is one of the largest CNV studies in a Brazilian sample, BHRCS have a new fourth wave of data collection and we expect to follow the diagnosis of the CNV risk carriers to evaluate their transition to psychiatric disorders and its impact on cognitive tests.