Convergence of evidence from a methylome-wide CpG-SNP association study and GWAS of major depressive disorder

Karolina A Aberg,Min Zhao,Gerard Van Grootheest,Gaurav Kumar,Andrey A Shabalin,Lin Y Xie,Shaunna L Clark,Edwin J C G Van Den Oord,Robin F Chan,Brenda W J H Penninx,Yuri Milaneschi

doi:10.1038/s41398-018-0205-8

Abstract

DNA methylation is an epigenetic modification that provides stability and diversity to the cellular phenotype. It is influenced by both genetic sequence variation and environmental factors, and can therefore potentially account for variation of heritable phenotypes and disorders. Therefore, methylome-wide association studies (MWAS) are promising complements to genome-wide association studies (GWAS) of genetic variants. Of particular interest are methylation sites (CpGs) that are created or destroyed by the alleles of single-nucleotide polymorphisms (SNPs), as these so-called CpG-SNPs may show variation in methylation levels on top of what can be explained by the sequence variation. Using sequencing-based data from 1132 major depressive disorder (MDD) cases and controls, we performed a MWAS of 970,414 common CpG-SNPs. The analysis identified 27 suggestively significant (P < 1.00 × 10−5) CpG-SNPs associations. Furthermore, the MWAS results were over-represented (odds ratios ranging 1.36–5.00; P ranging 4.9 × 10−3–8.1 × 10−2) among findings from three recent GWAS for MDD-related phenotypes. Overlapping loci included, e.g., ROBO2, ASIC2, and DCC. As the CpG-SNP analysis accounts for the number of alleles that creates CpGs, the methylation differences could not be explained by differences in allele frequencies. Thus, the results show that the MWAS and GWASs provide independent lines of evidence for the involvement of these loci in MDD. In conclusion, our methylation study of MDD contributes novel information about loci of relevance that complements previous findings and generates new hypothesis about MDD etiology, such as that the functional effects of genetic association may be partly mediated and/or enhanced by the methylation status in these loci.

Highlights

Major depressive disorder (MDD) is a complex disorder that is characterized by persistent dysphoria and is often accompanied by considerable morbidity[1,2,3] and mortality[2,4]
As shown in the Q-Q plot (Fig. 2a), the slightly inflated lambda observed for the MDD CpG-single-nucleotide polymorphisms (SNPs) methylome-wide association studies (MWAS) is likely caused by a combination of true associations and by that the test statistic distribution did not follow the theoretical null distribution
Consistent with a general function of DNA methylation that protects the integrity of the genome by inactivating DNA elements[39,40], this pattern would be in agreement with that a portion of potentially damaging mutations might not be properly silenced in MDD cases

Summary

Introduction

Major depressive disorder (MDD) is a complex disorder that is characterized by persistent dysphoria and is often accompanied by considerable morbidity[1,2,3] and mortality[2,4]. Because methylation is dynamic in nature and can be altered by environmental factors, it can potentially account for key clinical features of MDD such as its episodic nature or mediate the effects of environmental risk. Methylome-wide association studies (MWAS), which test a genome-wide set of methylation sites for association with an outcome of interest, are promising complements to genome-wide association studies (GWAS) of genetic variants. Of particular interest are methylation sites (CpGs) that are created or destroyed by single-nucleotide polymorphisms (SNPs). These sites, commonly referred to as CpG-SNPs, may show variation in both methylation and sequence, and may convey information beyond either of the two data types alone. Methylationdependent association signals in CpG-SNPs are not captured by GWAS and are very poorly captured by a regular MWAS. A specific CpG-SNP analysis is needed to detect these signals

Methods

Results

Discussion

Conclusion