Bipolar Disorder is associated with the rs6971 polymorphism in the gene encoding 18kDa Translocator Protein (TSPO)

Alessandro Colasanti,Eugenii A. Rabiner,Detelina Grozeva,David R. Owen,Paul M. Matthews,Allan H. Young,Nick Craddock

doi:10.1016/j.psyneuen.2013.07.007

Alessandro Colasanti, Eugenii A. Rabiner + Show 5 more

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https://doi.org/10.1016/j.psyneuen.2013.07.007

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Journal: Psychoneuroendocrinology	Publication Date: Aug 12, 2013
Citations: 59	License type: cc-by

Abstract

SummaryTSPO mediated transport of cholesterol into the mitochondrion is a necessary step in steroid synthesis. The rs6971 polymorphism in the TSPO gene causes an amino acid substitution (Ala147Thr) within the transmembrane domain where the cholesterol-binding pocket is located, and has been shown to affect the steroidogenic pathway. We report a nominal association between this TSPO polymorphism and the diagnosis of Bipolar Disorder in both the genome-wide dataset of the Wellcome Trust Case–Control Consortium and the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder group (OR = 1.11, p = 0.007; OR = 1.10, p = 0.011, respectively). We propose that the amino acid substitution affects hypothalamic–pituitary–adrenal (HPA) regulation, and hence may predispose to Bipolar Disorder. This supports the hypothesis that HPA dysregulation has a causal role in Bipolar Disorder, and is not just a consequence of the disease.

Highlights

The aetiopathogenesis of Bipolar Disorder (BD) involves both environmental and genetic factors
A common single nucleotide polymorphism in the Translocator Protein (TSPO) gene leads to an amino-acid substitution, Ala147Thr, which dramatically alters the affinity with which TSPO binds drug ligands (Owen et al, 2012)
The hypothesis that HPA dysfunction plays a causal role in BD pathophysiology would be supported by a finding that a genetic variant, which leads to a dysregulated HPA function, is associated with diagnosis of BD. To test this we investigated the association between rs6971 and a diagnosis of BD in the datasets of the Wellcome Trust Case—Control Consortium (WTCCC) and the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder group (PGC-BD)

Summary

Introduction

The aetiopathogenesis of Bipolar Disorder (BD) involves both environmental and genetic factors. Increased daytime cortisol secretion, which reflects HPA axis dysfunction, has been observed in the adolescent offspring of parents with BD and persists into young adulthood (Ellenbogen et al, 2006). The rate-limiting step in the synthesis of all steroids, including those involved in the HPA axis, is the delivery of cholesterol from the outer (OMM) to the inner mitochondrial membrane (IMM). The delivery of cholesterol to the IMM is dependent upon the function of the 18 kDa Translocator Protein (TSPO), located on the OMM, which binds cholesterol with high affinity and imports it across the membrane. As cholesterol binds TSPO in the same transmembrane domain, we hypothesised that this substitution may impair the ability of TSPO to bind or import cholesterol, and may affect steroid synthesis and HPA function

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