PhD Scientific Days 2024

Mental Health Sciences III.

Do different genetic effects shape distinct subtypes of depression? –results from a GWAS study

Text of the abstract

Introduction Several factors play a role in the heterogeneity of depression. In the present study we investigated the genetic variants associated with depressive symptoms following exposure or non-exposure to recent stressors with a GWAS approach.
Methods Genome-wide association studies were conducted in the UK Biobank database (N=332,292) in three groups corresponding to “without” (N=187,884), “minor” (N=107,088) and “major” (N=37,320) stress exposure in the past two years. Current depressive symptoms were measured in the three groups with four questions related to depressive symptoms in the last 2 weeks. SNP-level association was assessed using linear regression models, assuming additive genetic effects using PLINK2.0, with sex, age and the first ten principal components (PC) of the genetic data as covariates. Bonferroni-corrected significance threshold was p≤5.0×10-8 and the suggestive significance threshold was p≤1.0×10-5. GWAS results were interpreted using FUMA v1.3.8.
Results In the “without stress” group 68 lead SNPs were found, 4 SNPs with genome-wide and 64 SNPs with suggestive significance. rs60939828 (P= 5.91702e-11; β= 0.0213987; chr 18) within the DCC gene survived correction for genome-wide significance (p ≤ 5 x 10–8).
In the „minor stress” group 37 lead SNPs were identified, 1 SNP survived Bonferroni correction for multiple testing and 36 SNPs showed suggestive significance. rs12968428 (P= 4.63648e-7; β= -0.0222375; chr 18) is found near the DCC gene with suggestive significance. In the “Major stress group 14 lead SNPs were found, no SNPs survived the Bonferroni correction for multiple testing, but all of them showed suggestive significance. rs138310410 (P= 3.03927e-7; β= 0.146477; chr 4) is located near the CLOCK gene with suggestive significance.
Discussion In the “without stress” group we found significant association with DCC gene variants. Previous studies also implicated the DCC/Netrin 1 gene in the background of depression and depression-related traits. In the “major stress” group the SNP-level analyses identified a variant close to the CLOCK gene, which is a major activator of the downstream elements of the pathway involved in generating circadian rhythm. Our results may help in understanding the role of divergent pharmacological targets in effectively treating the different subtypes of depression.