Florey Department of Neuroscience and Mental Health - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/269

Filters

2019 1
1
Reset filters

Settings
Statistics
Citations
Start date: 2019 × Type: Abstract × Author: Dean, Brian ×

Search Results

Now showing 1 - 1 of 1
  • Item
    No Preview Available
    METHYLOME-WIDE ASSOCIATION STUDIES FOR MAJOR DEPRESSIVE DISORDER IN BLOOD OVERLAP WITH METHYLATION RESULTS FROM BRAIN AND LARGE-SCALE GWAS
    Aberg, K ; Dean, B ; Shabalin, A ; Zhao, M ; Chan, R ; Hattab, M ; van Grootheest, G ; Han, L ; Aghajani, M ; Milaneschi, Y ; Jansen, R ; Xie, L ; Clark, S ; Penninx, B ; van den Oord, E (ELSEVIER SCIENCE BV, 2019-01-01)
    Background: Epigenetic modifications such as DNA methy- lation provide stability and diversity to the cellular phenotype and aberrant methylation has been implicated in processes underlying psychiatric disorders. Therefore, studies combining DNA methylation and genotype information provide a promis- ing approach to study disorders where genotype information alone has failed to reveal the full etiology. Methods: We applied an optimized MBD-seq protocol to assay the complete CpG methylome in cases with Major Depressive Disorder (MDD) and controls using blood samples (N=1,132) from Netherlands Study of Depression and Anxiety and brain samples (N=64) from the Victorian Brain Bank Network. Data were analyzed with RaMWAS, a novel Biocon- ductor package specifically designed for Methylome-Wide Association Studies (MWAS). To study the overlap between top MWAS findings in blood and brain, we used a permutation based enrichment test (shiftR) that accounted for the depen- dency between adjacent CpG sites. Furthermore, we utilized the methylation data in combination with existing genotype information from the same individuals in a MWAS of CpGs created or destroyed by SNPs. Next, we tested whether top results from this CpG-SNP MWAS overlapped with recent large- scale GWAS to identify robust associations with genomic loci of importance for MDD etiology Results: The MWAS in blood identified five methylome- wide significant sites (P o 5 10-8) from three distinct loci and 472 nominally significant (P o 1 10-5) CpG sites. To study the robustness of the overall MWAS signal, we used an “in-sample” replication based on k-fold cross validation. Results showed that the findings replicated (P = 4.0 10- 10). When we compared blood and brain we found that top blood MWAS findings were significantly enriched for top CpGs in the brain MWAS (P = 5.4 10-3). The MWAS of CpG-SNPs identified 32 nominally significant sites and in- sample replication showed that the signal replicated (P = 2.2 10-8). Finally, the top CpG-SNP MWAS showed a consistent trend towards enrichment in all tested large- scale GWAS, with the most significant enrichment observed for the 23andMe study (P = 4.9 10-3). This overlap involved 55 genes that were overrepresented (P o 0.01) in 12 level-5 gene ontology terms, of which a major portion was related to neuronal regulation, function and development. Discussion: This work involves the largest MWAS for MDD performed to date. Our integrated analysis with brain tissue, genotype information and GWAS results highlighted biological functions of potential value for MDD etiology. Part of the associated methylation marks in blood overlapped with MWAS finding in brain. As blood can easily be collected in a clinical setting, these loci may be of direct value as potential diagnostic biomarkers for MDD.