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. 2020 Jun;25(6):1344-1354.
doi: 10.1038/s41380-018-0247-6. Epub 2018 Sep 21.

Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples

Karolina A Aberg  1 , Brian Dean  2   3 , Andrey A Shabalin  4 , Robin F Chan  4 , Laura K M Han  5 , Min Zhao  4 , Gerard van Grootheest  5 , Lin Y Xie  4 , Yuri Milaneschi  5 , Shaunna L Clark  4 , Gustavo Turecki  6 , Brenda W J H Penninx  5 , Edwin J C G van den Oord  4
Affiliations

Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples

Karolina A Aberg et al. Mol Psychiatry. 2020 Jun.

Abstract

We present the first large-scale methylome-wide association studies (MWAS) for major depressive disorder (MDD) to identify sites of potential importance for MDD etiology. Using a sequencing-based approach that provides near-complete coverage of all 28 million common CpGs in the human genome, we assay methylation in MDD cases and controls from both blood (N = 1132) and postmortem brain tissues (N = 61 samples from Brodmann Area 10, BA10). The MWAS for blood identified several loci with P ranging from 1.91 × 10-8 to 4.39 × 10-8 and a resampling approach showed that the cumulative association was significant (P = 4.03 × 10-10) with the signal coming from the top 25,000 MWAS markers. Furthermore, a permutation-based analysis showed significant overlap (P = 5.4 × 10-3) between the MWAS findings in blood and brain (BA10). This overlap was significantly enriched for a number of features including being in eQTLs in blood and the frontal cortex, CpG islands and shores, and exons. The overlapping sites were also enriched for active chromatin states in brain including genic enhancers and active transcription start sites. Furthermore, three loci located in GABBR2, RUFY3, and in an intergenic region on chromosome 2 replicated with the same direction of effect in the second brain tissue (BA25, N = 60) from the same individuals and in two independent brain collections (BA10, N = 81 and 64). GABBR2 inhibits neuronal activity through G protein-coupled second-messenger systems and RUFY3 is implicated in the establishment of neuronal polarity and axon elongation. In conclusion, we identified and replicated methylated loci associated with MDD that are involved in biological functions of likely importance to MDD etiology.

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Conflict of interest statement

Conflict of Interest

B.W.J.H.P. has received research funding (non-related) from Jansen Research and Boehringer Ingelheim. Other authors declare no competing financial interests.

Figures

Figure 1:
Figure 1:
In this study we present a three-phase, multi-tissue design: Top) a Discovery Phase involving a MWAS in a large set of blood samples as well as a number of exploratory analysis; Middle) an Overlap Phase where we test for enrichment of MWAS overlap between blood and brain; Bottom) a Replication Phase where all sites in the significant overlap are followed up with “look-up replication” in two independent brain collections from BA10 and in the second brain tissue (BA25) from the original brain MWAS sample.
Figure 2:
Figure 2:
Left. Quantile-Quantile plot of the MWAS in blood. The observed P values, on a –log10 scale, are plotted against their expected values (grey main diagonal line) under the null hypothesis assuming none of the CpGs have an effect. Yellow lines indicate the 95% confidence intervals (CI). The deviation of P values from the main diagonal indicates that there are potentially many markers associated with MDD. The lambda (λ) is close to one, indicating that markers that are not associated behave as expected under the null hypothesis. Right. Manhattan plot of the MWAS in blood. The plot shows the MWAS P values on a –log10 scale (y-axis) by their chromosomal location (x-axis). The dashed line marks the threshold for suggestive significance (P = 1×10−5).
Figure 3:
Figure 3:
Top. Plot showing level-5 Gene Ontology (GO) terms significantly (P < 0.0001) enriched for genes present in top MWAS results that overlap between blood and brain. Solid rectangles (grey or colored) indicate overlapping genes present in the significant GO terms. GO terms were grouped in color-coded clusters based on the similarity in gene content. Bottom. For each cluster, information (name, odds ratio (OR) and enrichment P value) of the most significant GO term is given. An extended list of all level-5 GO terms with P <0.01 are given in Table S8.
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