Genome-wide gene-gene interaction of the 5-HTTLPR promoter polymorphism emphasizes the important role of neuroplasticity in depression

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 119; p. 110614
• Main Authors: Garvert, Linda, Kirchner, Kevin, Grabe, Hans J., Van der Auwera, Sandra
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 20.12.2022
• Subjects: 5-HTTLPR; Depression; Depression - genetics; Depressive disorder; DPF1; Genome-Wide Association Study; Genotype; Interaction analysis; Neuronal Plasticity - genetics; Polymorphism, Single Nucleotide - genetics; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin transporter; Interaction analysis; Depression; Serotonin transporter; 5-HTTLPR; DPF1; Depressive disorder
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2022.110614

Recent genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms affecting depressive disorders. GWAS results support the heterogeneity of depression as a disorder affected by a large number of genetic variants with mainly small effect sizes. However, not much is known about the interplay of different genetic risk factors. Moreover, recent studies are questioning the role of common candidate genes in the development of depressive disorders. One such candidate variant is the serotonin-transporter-promoter-polymorphism 5-HTTLPR in the SLC6A4 gene. We hypothesize that 5-HTTLPR exerts its effect on depressive disorders in interaction with other genetic variants. In the present study we test this hypothesis using a genome-wide gene-gene interaction approach on a large sample from the UK Biobank (N = 127,558). We identified a region in the DPF1 gene that displayed a genome-wide significant (p = 3.31 × 10−7) interaction effect with the biallelic version of 5-HTTLPR on lifetime depression. DPF1 has not previously been described as risk factor for depressive disorders but is exclusively expressed in the brain as a major regulator of neuronal development and neuroplasticity. This study stresses the need for further analyses that take into consideration the fact that genetic variants do operate in biological networks. •Biallelic 5-HTTLPR variant interacts with DPF1 gene on depression.•DPF1 new risk factor for depression; regulator of neurodevelopment, −plasticity.•Interaction analyses important in the quest to understand disease development.