GWAS of Suicidal Phenotypes in Patients with Depression of Slavonic Ancestry Point on Neurodevelopment Genes and Galactose Metabolism

Non-fatal suicidal behavior (SB, comprising suicidal ideation and attempted suicide) is a serious public health problem. It is most often associated with depression and is partly heritable. Recent GWAS studies have been searching for genomic markers of SB associated with affective disorders or independent of them, most conclusive results being produced by large-scale meta-analyses. However, associations from limited but clinically well-defined monoethnic samples may substantially augment existing knowledge by utilizing replication strategy. Here we present results of GWAS on suicidal ideation (SI) and suicide attempts (SA) among 245 patients with major depressive disorder (MDD) and 132 healthy volunteers (67.7% of the whole sample were women) of Slavic ancestry. The study revealed 53 genome-wide significant (p < 5 × 10–8) associations. The most significant markers belonged to behavioral phenotypes (life-time SA, SA count, SA lethality) in contrast to SI. We replicated rs2648369, rs17672004 and rs10208300 in several other cohorts associated with self-harm from IEU Open GWAS catalogue. Conversely, rs72740088 from other GWAS on suicidality was confirmed in our sample. Among the genes identified using POSTGAP pipeline our study replicated previously reported PGBD5 and identified 22 additional potential genes. Functionally these genes belong to the same brain and systemic pathways that have been previously implicated in SB, including genome regulation, oncogenesis, intercellular interactions, synaptogenesis, and the immune system. Of special interest are B3GALT1 and GALM that are involved in galactose metabolism. Gene-set enrichment analysis suggests a link between SB-associated genes and inflammation, oxidative stress, cognitive impairment, GABAergic neurotransmission, postsynaptic membrane organization and different types of cancer.