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

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.

A Prospective Analysis of Genetic Variants Associated with Human Lifespan

“…The GWAS literature from another commercial entity with legal obligations to the members of its study population consistently reports the 10,000 most-significant SNPs (Jansen et al 2019; Shaffer et al 2017; Hu et al 2016; Jones et al . 2017; Aberg et al 2018; Huusko et al 2018; Lee et al 2018; Jones et al 2019). For our complete study, 10,171 unique SNPs provided a level of disclosure that permits scientific scrutiny while comfortably maintaining the anonymity of our users.…”

Harnessing peripheral DNA methylation differences in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease

“…In addition, BIN1, BDNF, and APOC1 while not the top most differentially methylated hits, were among the significant DMP hits ( Figure S4A-C). Several studies have found an association of genetic variants with the DNA methylation signals at specific probes [22,23]. To further evaluate the likelihood of DMPs correlating with AD, we also queried all the DMPassociated genes within the GWAS catalog for AD, (https://ebi.ac.uk/gwas/) which includes 72 individual GWAS studies and found overlaps between the GWAS hits and the DMPs from AD vs. CN, AD vs. MCI, and MCI vs. CN comparisons ( Figure S5A).…”

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood

“…10,11,[13][14][15][16][17][18] In humans, an autosomal-dominant DCC mutation results in structural and functional alterations in the connectivity of mesocortical pathways, with an associated decrease in novelty-seeking behaviour and cigarette use. 19,20 An increasing number of meta-analyses of genome-wide association studies and postmortem human studies have shown that altered levels of DCC expression and the presence of specific genetic polymorphisms in the DCC gene are associated with psychiatric conditions, 21 most notably major depressive disorder, 15,17,[22][23][24][25][26][27][28][29][30][31][32][33][34][35] schizophrenia 34,[36][37][38] and drug abuse. 19,[39][40][41][42] A study by the Cross-Disorder Group of the Psychiatric Genomics Consortium 3 revealed that a PFC-enriched network of genes prominently affected 8 psychiatric disorders, and a DCC single nucleotide polymorphism (SNP) showed the highest pleiotropic association with all 8 disorders.…”