Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder

Song, Jie; Bergen, Sarah E.; Florio, Arianna Di; Karlsson, Robert; Charney, Alexander; Ruderfer, Douglas M.; Stahl, Eli A.; Chambert, Kimberly; Moran, Jennifer L.; Gordon‐Smith, Katherine; Forty, Liz; Green, E. K.; Jones, Ian; Jones, Lisa; Scolnick, Edward M.; Sklar, Pamela; Smoller, Jordan W.; Lichtenstein, Paul; Hultman, Christina M.; Craddock, Nicholas; Landén, Mikael

doi:10.1038/mp.2015.165

Cited by 84 publications

(61 citation statements)

References 74 publications

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“…With regard to noncanonical Wnt signaling in BD, a recent large GWAS study identified a single locus containing a noncoding SNP with strong linkage to lithium-responsive BD: SEC14 and spectrin domain containing 1 (SESTD1) [305]. Sestd1, expressed both during neurodevelopment and in the mature CNS [306], has recently been shown to directly interact with Dvl2, Dact1, and Vangl2 in a PCP-related signaling cascade during embryonic development [307].…”

Section: Human Genomic Studiesmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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Section: Human Genomic Studiesmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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“…Another recent GWAS from Sweden and the United Kingdom was performed on over 2698 patients with subjectively defi ned (self-reported) lithium response and 1176 patients with objectively defi ned (clinically documented) lithium response and compared with a group of healthy controls (Song et al 2015 ). When comparing lithium-responsive patients with controls, two imputed markers revealed genomewide signifi cant associations, one of which was validated in confi rmatory genotyping.…”

Section: Pharmacogenetics Of Lithiummentioning

confidence: 99%

“…When comparing lithium-responsive patients with controls, two imputed markers revealed genomewide signifi cant associations, one of which was validated in confi rmatory genotyping. These two genetic markers are an intronic single nucleotide polymorphism (SNP) on chromosome 2q31.2 in gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulating phospholipids (Song et al 2015 ). Phospholipids have been strongly implicated as lithium treatment targets.…”

Section: Pharmacogenetics Of Lithiummentioning

confidence: 99%

What Is Lithium and How Does It Work?

Bauer

Gitlin

2016

The Essential Guide to Lithium Treatment

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Lithium is a chemical element symbolized by Li carrying atomic number three in the periodic table. It is a soft, silver-white metal belonging to the alkali metal group of chemical elements and has-beyond medical indications-several industrial applications, e.g., in heat-resistant glass and ceramics, and lithium-ion batteries.Because lithium is highly reactive, it is usually stored in mineral oil (paraffi n). As a medication, it is always used as one of its salts, for example, lithium carbonate, lithium sulfate, or lithium citrate. It is the lithium part of the salt, the lithium atom, that is effective, and it does not matter which salt is used; no clinically relevant differences have been found among the different lithium salts in clinical studies.As described earlier in Chap. 3 on lithium's history, lithium is an unusual and unique medication for the treatment of mood disorders because it is a chemical trace element, a small atom with unique pharmacological and chemical properties (Birch 2006 ). It is not known whether lithium plays a physiological role in humans. Since it is a simple element, one might think that lithium acts by a simple mechanism. The opposite is probably true; yet after more than 60 years of widespread clinical use, we still do not know exactly why lithium works so well for many patients suffering from mood disorders (Malhi et al. 2013 ). Table 4.1 summarizes important clinical aspects of lithium therapy that may be most relevant when investigating which molecular actions of lithium could be responsible for its clinical effects.Nevertheless, during the past decade, new evidence has expanded our understanding of how lithium might exert its mood-stabilizing properties in individuals suffering from bipolar disorder. As a result of novel insights into the mechanisms by which lithium might work, research has demonstrated that lithium induces its cellular and molecular effects, at least partially, by activating neurotrophic and neuroprotective pathways and their associated signaling mechanisms (Quiroz et al. 2010 ).

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“…In the past few years, genome-wide association studies suggested several genetic variants associated with lithium response [Chen et al, 2014;Perlis et al, 2009;Song et al, 2015;Squassina et al, 2011]. However, it must be noted that most of these studies were limited by small sample size.…”

Section: Pharmacogenetics Of Lithium Responsementioning

confidence: 99%

“…Interestingly, dysfunction of emotional processing has been observed in BPD [Rock et al, 2010] and a number of emotional processing tasks have been proposed as potential surrogate markers of response in mood disorders [Harmer et al, 2011]. Specifically, ebselen decreased reward reinforcement during the reward and punishment learning task [Song et al, 2015] and increased recognition of emotional facial expressions during the emotional processing tasks [Masaki et al, 2016;Song et al, 2015]. Similarly to lithium [Adida et al, 2015], ebselen can reduce impulsivity [Masaki et al, 2016].…”

Section: The Promise Of New Interventions: the Case Of Ebselenmentioning

confidence: 99%

Lithium Pharmacogenetics: Where Do We Stand?

Pisanu

Melis

Squassina

2016

Drug Development Research

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Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic research will ultimately lead to the identification of new molecular targets and safer treatments for BPD. Drug Dev Res 77 : 368-373, 2016. © 2016 Wiley Periodicals, Inc.

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Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder

Cited by 84 publications

References 74 publications

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

What Is Lithium and How Does It Work?

Lithium Pharmacogenetics: Where Do We Stand?

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