Meta Gene 27 (2021) 100823 Available online 4 November 2020 2214-5400/© 2020 Published by Elsevier B.V. The impact of BDNF variant on bipolar susceptibility, suicidal behavior, and response to lithium carbonate in bipolar patients Sara Sadat Aghabozorg Afjeh a , Jamal Shams c , Safar Hamednia b, d , Behzad Bushehri e , Amir Olfat d , Mir Davood Omrani f, * a Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran b Department of Psychiatry, Urmia University of Medical Sciences, Urmia, Iran c Behavioral Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran d Department of Statistics, Allameh Tabatabai University, Tehran, Iran e Department of Forensic Medicine and Toxicology, Urmia University of Medical Sciences, Urmia, Iran f Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran A R T I C L E INFO Keywords: Neuroplasticity BDNF Bipolar disorder Lithium carbonate ABSTRACT Synaptic plasticity is intimately involved in the pathophysiology and treatment of bipolar disorder and disrup- tions in neuroplasticity can play an important role in the process of suicide behavior in bipolar patients. One of the major neurotrophic factors with essential role in the maintenance and survival of neurons and synaptic plasticity is Brain-Derived Neurotrophic Factor (BDNF) which is encoded by BDNF gene. The impact of BDNF variant on predisposition to bipolar disorder, suicidal behavior and response of patients to lithium carbonate was investigated in this study on 201 bipolar patients compared with 201 healthy controls. The tetra primers -Amplification Refractory Mutation System-PCR method was used for genotyping. Results were confirmed by Sanger sequencing method. The obtained results showed significant association of different genotypes of rs6265 with bipolar susceptibility, suicide tendency, suicide ideation as well with various responses of patients to the treatment. Overall, it appears that BDNF variant may serve as an important biological risk factor in bipolar pathogenesis, suicidality, and various responses to lithium carbonate in bipolar patients in Iranian population. 1. Introduction Suicide is one of the leading cause of death for about one million people and the second leading cause of death among people aged 15 to 29 globally (https://www.who.int/news-room/fact-sheets/detail/suici de). Many researches focused on the brain activity patterns of people who had suicide ideation or had committed suicide compared to the brain activity patterns of people who did not have this condition and results showed that many structural, functional, and molecular changes could be thought to be associated with an increased risk of suicide (Schmaal et al., 2019). Evidences suggest the significant role of neuro- tophin systems in neurobiology of suicide behavior (De Luca et al., 2011; Deveci et al., 2007). Neurotrophins are the most important trophic factors known in the nervous system, prominent family of poly-peptide growth factors and the major factors in synaptic survival, growth, and development regulation (Huang and Reichardt, 2001). All neurotrophins have a common main structure but operate in specific areas and attach to specific receptors, thus exhibiting different functions and eventually finding their way to survival or apoptosis (Bernd, 2008). Among all neurotrophic factors with essential role in the mainte- nance and survival of neurons and synaptic plasticity Brain-Derived Neurotrophic Factor (BDNF) and its receptor ((tropomyosin-related ki- nase) receptor tyrosine kinase B-TrkB) are well known factors in relation to the suicidal behavior (Bathina and Das, 2015). It has been stablished that BDNF and TrkB both localized on the pre- synaptic and post-synaptic membranes (Cattaneo et al., n.d.). These receptors are divided into three categories, A, B and C. BDNF binds to type B receptors in the form of both monomers and homodymers, lead dimerization and auto phosphorylation, which subsequent activation of intracellular cascades to activate proteins involved in neuronal differ- entiation and growth (Huang and Reichardt, 2001). In addition to neurotrophic effects, the BDNF activity for synapses connections at brain * Corresponding author at: Human Genetics, Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail address: davood_omrani@yahoo.co.uk (M.D. Omrani). Contents lists available at ScienceDirect Meta Gene journal homepage: www.elsevier.com/locate/mgene https://doi.org/10.1016/j.mgene.2020.100823 Received 26 July 2020; Received in revised form 23 October 2020; Accepted 2 November 2020