DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

Abstract

Background: Depression is a disabling and highly prevalent condition where genetic and epigenetic differences, such as DNA methylation (DNAm), contribute to prediction of disease liability. Method: We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N=8,898, mean age=49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined=2,049, mean age=79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N=423, mean age=17.1 years). Result: Wide-spread associations were found between PRS constructed using genetic risk variants for depression and DNAm in cytosine- guanine dinucleotide (CpG) probes that localised to genes involved in immune responses and neural development (NCpG=599, pBonferroni<0.05, p<6.5e-8). The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r=0.83) and in adolescents (r=0.76). Additional analysis on the methylome-wide associations was conducted for each lead genetic risk variant. Over 40% of the independent genetic risk variants showed associations with CpG probe DNAm located in both the same (cis) and distal probes (trans) to the genetic loci (pBonferroni<0.045). Subsequent Mendelian randomisation analysis showed that DNAm and depression are mutually causal (pFDR<0.039), and there is a greater number of causal effects found from DNAm to depression (DNAm to depression: pFDR ranged from 0.045 to 2.06e-120; depression to DNAm: pFDR ranged from 0.046 to 2.1e-23). Conclusion: Polygenic risk scores for depression, especially those constructed from genome-wide significant genetic risk variants, showed epigenome-wide methylation association differences in the methylome associated with immune responses and brain development. We also found evidence from Mendelian randomisation evidence that DNAm may be causal to depression, as well as a causal consequence of depression.

Methylation in MAD1L1 is associated with the severity of suicide attempt and phenotypes of depression

“…Furthermore, in two other open-access cohorts, this locus demonstrated a clear statistical tendency toward an association with similar phenotypes. We also confirm the association between cg19624444 and depression that has been identified previously [41]. Additionally, we investigated if the discovered CpG sites could be related to the expression of MAD1L1 and stress response.…”

“…However, a recent study by Shen et al identified cg19624444 as a depression-related methylation site that was associated with a depression polygenic risk score. This CpG has also shown casual associations based on Mendelian randomization analysis conducted in the same study [41]. Our SNP-CpG analysis with limma identified cg19624444 as a top hit based on adolescent cohorts at screening and recall using a dominant genetic model.…”

Cohort profile: BioMD-Y (biopsychosocial factors of major depression in youth) – a biobank study on the molecular genetics and environmental factors of depression in children and adolescents in Munich

“…Our principal investigator, Gerd Schulte-Körne, can be approached by interested parties for further discussion and can be reached at Gerd.Schulte-Koerne(at)med.uni-muenchen.de; the corresponding author is available at Aline.Scherff(at)med.uni-muenchen.de. The BioMD-Y sample has most recently been used as part of a large MD MWAS study (Shen et al 92, in preparation) and is open to contributing to further large consortium studies addressing particularly those aspects mentioned above requiring larger data sets. It is hoped that through explicitly testing novel gene–environment hypotheses as well as replicating findings known from adult literature, BioMD-Y will inform clinical practice, prevention and treatment of depression in children and adolescents by providing a factual basis for more tailored approaches to hitherto assumed commonalities and differences.…”

DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood

“…Detailed information related to sample processing, methylation data generation and quality control for MMNP 18 , PMMST 18 , ENID 71 , and ALSPAC [75][76][77] have been previously published. We provide some further brief details below.…”