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

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.

Lost in translocation: the functions of the 18-kD translocator protein

“…Thus, while the evolutionary dynamics behind the preservation of the ancient TSPO is likely to be more complex than presently understood [73], an importance as a disease-modifying gene regulated in cellular stress or conditions of pathological challenge or adaptation should be considered. Current evidence in humans is sparse but intriguing, in as far as the known rs6971 polymorphism in the TSPO gene [74] may relate to complex mental health phenotypes; notably, to different metabolic responses as seen in differences in weight gain under antipsychotic treatment [75].…”

Evolving understanding of translocator protein 18kDa (TSPO)

“…Of considerable additional interest is the observation that a human single nucleotide polymorphism in TSPO is associated with anxiety-related diseases [11–13]. The polymorphism causes one amino acid substitution, A147T, in the LAF-CRAC region.…”

“…Recent studies suggest that TSPO forms part of a large complex that facilitates the import of cholesterol [4,5]; however, the precise mechanism of its involvement remains unclear [6,7]. TSPO has also received considerable attention as an important player in neurological disease, since the discovery that brain produces steroids locally [8–10] and that a human single polymorphism of TSPO is associated with anxiety disorders [11–13]. A role of TSPO in other processes, including inflammation, apoptosis, mitophagy, cancer, transport of porphyrin and stress sensing [10,14–19] has also been extensively documented.…”

Therapeutic actions of translocator protein (18 kDa) ligands in experimental models of psychiatric disorders and neurodegenerative diseases

“…For instance, a polymorphism (rs6971) in the TSPO gene has been associated with the diagnosis of bipolar disorder [95]. This polymorphism causes an amino acid substitution within the transmembrane domain, which is in the same location of the cholesterol binding pocket [4] and therefore it may affect cholesterol transport.…”