Genome-wide association and whole-genome methylation studies of suicidal behaviour

Background: Suicidal behaviour, now recognised as a clinical entity per se, is one of the most significant psychiatric public health problems. Suicidal behaviour is likely to be a product of interactions between several common gene variants and both distal and proximal environmental factors. Epigenetic factors most likely underlie these gene-environment interactions. Only a few number of susceptibility genes have been consistently associated to suicidal behaviour, and an even lower number of epigenetic variations have been associated to suicidal behaviour. Aims of the project: The first aim of this project is to search for new genetic variants involved in the vulnerability to suicide attempt (SA) and suicide completion (SC) by using a genome-wide association study (GWAS). The second aim is to compare the global methylation status of the genome between SC and controls. The third aim is to explore how associated SNPs in step 1 affect the variation of the methylation levels found in step 2.Methods: 1) In a precedent GWAS we identified, in a sample of 1’567 cases and controls, association which almost reaches the genome-wide significance level (p=9.97*10-8), with rs10779481 located near PLXNA2, a gene encoding a member of the plexin-A family of semaphoring co-receptors. We have collected new DNAs from 3’884 subjects. Diagnoses were made according to DSM-IV criteria, using the Diagnostic Interview for Genetic Studies and the Mini International Neuropsychiatric Interview. Suicidal behaviour characteristics were defined using the Suicide Intent Scale and the Risk-Rescue Rating in Suicide assessment. DNAs will be genotyped with Illumina HumanOmni2.5-8 Beadchip. After quality control procedure and stratification analyses, a GWAS will firstly be performed on these new samples. Then a meta-analysis will be performed between these newly generated data and that of our first GWAS. 2) Using the Illumina Infinium® HumanMethylation450 BeadChip, global methylation status of DNA extracted from ventral prefrontal cortex will be compared between 324 suicide completers and 331 controls. A functional analysis of the genes identified will be conducted by looking at the enrichment of GO terms they are associated with as well as pathways they are involved in. We will finally query protein-protein interaction databases in order to build an interaction network of identified genes and determine core genes. 3) Finally we will explore how the SNPs identified in the first step modulate DNA methylation identified in step 2 in ventral PFC from suicide victims and controls. Linear regression of DNA methylation levels with number of the minor allele for each SNPs will be performed.Significance of the proposed project: This project is based on two unique SA and SC databases. Therefore they will offer a unique opportunity for identifying common vulnerability genes with small effect by GWAS and methylation differences between SC and for further exploring the functional effects of associated SNPs by testing how they may modulate methylation marks associated to suicide. This project could be therefore a major breakthrough in suicidology.