Mood stabilizer
Neurobiology area
Positive findings
Authors
Lithium
Neurotransmission
5–HTT gene
TPH gene
DRD1 gene
FYN gene
Serretti et al. [69]
Rybakowski et al. [61]
Szczepankiewicz et al. [83]
Intracellular second messengers
INPP1 gene
CREB1 gene
Steen et al. [81]
Mamdani et al. [32]
Neuroprotection
BDNF gene
NTRK2 gene
GSK3β gene
miRNA Let–7 gene
Rybakowski et al. [58]
Dmitrzak-Weglarz et al. [10]
Leckband et al. [30]
Benedetti et al. [2]
Hunsberger et al. [22]
Circadian rhythms
Rev–Erbα gene
ARNTL gene
TIM gene
DPB gene
Rybakowski et al. [64]
Rybakowski et al. [64]
Kittel-Schneider et al. [28]
Pathogenesis of bipolar disorder
NR3C1 gene
DISC–1 gene
mDNA
Szczepankiewicz et al. [86]
Czerski et al. [7]
Washizuka et al. [91]
Chromosome 22q11–13
BCR gene
XBP1 gene
CACNG2 gene
Masui et al. [39]
Silberberg et al. [77]
Valproate
Chromosome 22q11–13
XBP1 gene
Kim et al. [27]
6.2 Linkage Studies of Lithium Response
Prior to candidate gene studies, there had been some linkage studies of susceptibility loci specifically analyzing those connected with lithium response. Danish investigators [12] performed a haplotype-based study in lithium-responding patients with bipolar disorder on the Faroe Islands and found chromosomal region 18q23 to possibly be connected with lithium response. Canadian researchers [89] after having performed a genome scan of 31 families ascertained, through probands with an excellent lithium response, that the locus on chromosome 7q11 may be implicated. However, in spite of the susceptibility regions found in these studies, no specific genes have been identified (Table 6.2).
6.3 Candidate Gene Studies of Lithium Response
6.3.1 Neurotransmitters
The serotonergic system has long been implicated in the neurobiology of bipolar disorder and the mechanism of lithium action [44]. For pharmacogenetic studies, a subject of special interest has been a functional promoter polymorphism of the serotonin transporter gene (5-HTTLPR) located on chromosome 17q12 where a short (s) allele is connected with lower activity of the gene. A short allele of 5-HTTLPR has been associated with a predisposition to affective disorder, both bipolar and unipolar [19] and with a poor response to antidepressants in a Caucasian population [50]. That the s allele may be connected with prophylactic lithium nonresponse was demonstrated in several studies, including ours [59, 72, 74] but was not confirmed in two subsequent papers [34, 43]. Recently, Tharoor et al. [87] studied the serotonin transporter triallelic 5-HTTLPR and intron 2 (STin2) polymorphisms in relation to lithium response in Indian population and found a possible association with STin2 and a combined effect with 5-HTTLPR variants suggesting better efficacy of lithium in patients carrying 5-HTT polymorphisms associated with reduced transcriptional activity.
Studies on an association between lithium response and the genes of the serotonergic receptors 5-HT1, 5-HT2A, and 5-HT2C yielded negative results [9, 71]. On the other hand, one study on a polymorphism on the gene for tryptophan hydroxylase, the enzyme of serotonin synthesis, found a marginal association [69].
Severino et al. [75] showed an association between bipolar illness and A48G polymorphism of the dopaminergic receptor D1 (DRD1) gene located on chromosome 5q35, and we have demonstrated an association of this polymorphism with lithium response [61]. Earlier studies on other dopaminergic system genes (DRD2, DRD3, DRD4) brought negative results [68, 70]. Also negative were the results of studies on an association between lithium response and polymorphisms of genes coding enzymes of catecholamine metabolism such as monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) [73, 88].
The glutamatergic system has been recently implicated in the pathogenesis of bipolar illness and the mechanisms of lithium action, with special emphasis on such glutamate receptors as NMDA (N-methyl-D-aspartate) and AMPA (alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionate). In our study we did not demonstrate any association between three polymorphisms in the NMDA receptor 2B subunit (GRIN2B) gene and lithium response [83]. On the other hand, our group showed an association between two polymorphisms of the FYN gene and bipolar disorder [84] and a marginal association between T/C polymorphism of this gene and lithium response [85]. The Src family, tyrosine kinase FYN, plays a key role in the interaction between the glutamatergic receptor NMDA and the brain-derived neurotrophic factor (BDNF), and the FYN gene is located on chromosome 6q21, the susceptibility region for bipolar disorder.
6.3.2 Intracellular Second Messengers
The effect on the phosphatidylinositol (PI) pathway has long been considered the most important mechanism of lithium therapeutic action in bipolar disorder. A significant association with lithium response was obtained with polymorphism of the inositol polyphosphate 1-phosphatase (INPP1) gene located on chromosome 2q32 [81]. Such an association with lithium response was also obtained in bipolar patients with comorbid post-traumatic stress disorder [3], but this was not replicated in a study by Brazilian investigators [43]. Studies on the polymorphisms of other genes connected with the PI system, such as inositol monophosphatase2 (IMPA2) and diacylglycerol kinase eta (DGKH) genes, did not find any associations with lithium response [8, 35].
Lithium also exerts an effect on the cyclic adenosine monophosphate (cAMP) pathway. Mamdani et al. [32] performed an association study with genes for cAMP response element-binding protein (CREB) and found an association between bipolar disorder and lithium response and two polymorphisms of CREB1 gene located at chromosome 2q32–34.
Lithium interacts with the protein kinase C (PKC) pathway, a mediator of intracellular responses to neurotransmitter signaling, and PDLIM5 is an adaptor protein that selectively binds the isozyme PKC epsilon to N-type calcium channels in neurons. Squassina et al. [78] did not find an association between the PDLIM5 gene polymorphisms and lithium response.
6.3.3 Substances Involved in Neuroprotection
BDNF is a neurotrophic factor involved in neuronal proliferation and synaptic plasticity. Lithium has been shown to stimulate the BDNF system both in experimental and clinical conditions that makes one of the main mechanisms of lithium’s neuroprotective activity [52]. An association of Val66Met functional polymorphism of the BDNF gene, located on chromosome 11p13, with bipolar disorder has been suggested [67], and our group was the first to demonstrate an association of this polymorphism with lithium response [10, 58]. Furthermore, we have found a significant interaction of this polymorphism with that of the serotonin transporter where, in subjects with the s allele of 5-HTTLPR having a Val/Val genotype of BDNF, there is a 70 % probability of lithium nonresponse [60]. However, an association of lithium response with Val66Met polymorphism of the BDNF gene was not confirmed in populations other than Caucasian [37, 43]. The neurotrophin BDNF binds to the TrkB receptor, transcribed from the NTRK2 gene. The San Diego group of investigators has suggested an association of this polymorphism with lithium response in bipolar patients with higher suicidality and euphoric mania [30]; however, we were not able to find such an association in our sample of bipolar patients [10].
Lithium inhibits glycogen synthase kinase 3 beta (GSK3β), the enzyme involved in synaptic plasticity, apoptosis, and the circadian cycle. Italian investigators demonstrated an association between functional −50 T/C polymorphism of the GSK3β gene located on chromosome 3q13 and lithium response [2], but this was not confirmed in two other studies, including ours [43, 82].
Recently, a novel integrative genomic tool called GRANITE (Genetic Regulatory Analysis of Networks Investigational Tool Environment) for analyzing large complex genetic data has been developed. In an in vitro study comparing vehicle versus chronic lithium treatment in lymphoblastoid cells derived from either lithium responders or nonresponders, it was found that the microRNAs (miRNAs) of Let-7 family were downregulated in both lithium groups. This miRNA family has been implicated in neurodegeneration, cell survival, and synaptic development [22].
6.3.4 The Circadian Signaling System
Lithium has been shown to influence circadian processes. As mentioned above, GSK3β, the enzyme inhibited by lithium, is also involved in regulation of circadian cycle. In a network coordinating circadian rhythms, GSK3β interacts with a number of proteins including nuclear receptor rev-erb alpha (Rev- Erb-α). A variant of Rev–Erb–α gene has been shown, in two studies, to be associated with prophylactic lithium response [4, 40].
In our study of lithium-treated bipolar patients, we genotyped single nucleotide polymorphisms (SNPs) and haplotypes of four circadian clock genes in relation to prophylactic lithium response. The genes included CLOCK (circadian locomotor output cycle kaput), ARNTL (aryl hydrocarbon receptor nuclear translocator-like), TIM (timeless circadian clock), and PER 3 (period circadian clock-3). An association with the degree of lithium prophylaxis was found for six SNPs and three haplotype blocks of the ARNTL gene and two SNPs and on haplotype block of the TIM gene, while no association with SNPs or haplotypes of the CLOCK and PER–3 genes was observed [64].
Recently, Kittel-Schneider et al. [28] in a study of lymphoblastoid cells generated from bipolar patients and control subjects demonstrated that these two groups differed in the length period regarding expression of another clock gene, namely, DBP (albumin D-box binding protein) gene, and that chronic lithium treatment leads to decreased expression of this gene.
6.3.5 Genes Associated with Pathogenesis of BD
Our group found an association of prophylactic lithium response in bipolar patients with polymorphism of two genes implicated in the pathogenesis of bipolar disorder, namely, the glucocorticoid receptor (NR3C1) gene located on chromosome 5q31–32 [86] and the Disrupted-in-Schizophrenia (DISC–1) gene located on chromosome 1q42 [7]. Also, Japanese researchers in considering postulated abnormalities of mitochondrial DNA (mDNA) in bipolar disorder [25] demonstrated an association between 10398A mDNA polymorphism and the quality of lithium prophylaxis [91].
Matrix metalloproteinase-9 (MMP-9) is an extracellularly acting endopeptidase implicated in a number of pathological conditions including cancer, cardiovascular, and neuropsychiatric diseases. Our group demonstrated an association between functional polymorphism of the MMP–9 gene, located on chromosome 20q11–13, and bipolar disorder [62]. However, we were unable to find such an association with lithium response [63]. Also, Canadian investigators studied the prolyl endopeptidase (PREP) gene, located on chromosome 6q22, the region that has been linked to bipolar disorder in several studies, but did not find an association with lithium response [33].
6.3.6 Genes Located on 22q11–13
Positive results with lithium response have been obtained concerning associations of three genes located on chromosome 22q11–13, a possible susceptibility region for major psychoses. Japanese authors found a significant association between lithium response and genetic variations in the breakpoint cluster region (BCR) gene located on chromosome 22q11 [39] and with the X-box binding protein 1 (XBP1) gene located on chromosome 22q12 [38]. An association of both these genes with a predisposition to bipolar disorder had been previously reported [18, 24]. Silberberg et al. [77] described an association with lithium response and the calcium channel gamma-2 subunit (CACNG2) gene, also known as stargazin, located on chromosome 22q13.
6.4 Studies on Candidate Genes of Response to Other Mood Stabilizers
Only few studies have focused on the candidate genes of response to other mood stabilizers, mostly to valproate. Korean researchers studied functional −116C/G polymorphism of the XBP1 gene in relation to valproate efficacy [27]. Interestingly, they found an association with a positive prophylactic effect for valproate with the C allele of this polymorphism, while with lithium it was with the G allele [37, 38]. This may suggest that the response to different mood stabilizers may be connected with a different genetic makeup.
There are other studies which are of short duration and do not differentiate between individual mood stabilizers (lithium, valproate, or carbamazepine). In one of them, Yun et al. [92] did not find an association between antimanic efficacy of mood stabilizers and the dysbindin (DTNBP1) gene variants. In another, a significant association was found between polymorphism of the NTRK2 gene and treatment response to lithium or valproate [90]. Finally, in Lee et al. [31] study, an association was observed between the polymorphism of dopaminergic D2 receptor (DRD2/ANKK1 TaqIA) gene and treatment response in mania when dextromethorphan was added to valproate compared to adding placebo [31].
Perlis et al. [49] evaluated common genetic variations for association with symptomatic improvement in bipolar I depression following 7-week treatment with olanzapine/fluoxetine combination (OFC) or lamotrigine. They found that SNPs within the dopamine D(3) receptor and histamine H(1) receptor (HRH1) genes were significantly associated with response to OFC, while SNPs within the dopamine D(2) receptor, HRH1, dopamine beta-hydroxylase, glucocorticoid receptor, and melanocortin 2 receptor genes were significantly associated with response to lamotrigine.
6.5 Limitations of Candidate Gene Studies
Candidate gene studies have yielded a number of associations between the polymorphisms of several dozen genes and a prophylactic response to mood stabilizers, mostly lithium. However, only a minority of them has been consistently replicated in subsequent studies. Concerning lithium, each of the single nucleotide polymorphisms of a given gene accounts for a small portion of the total variance in lithium response (1–2 % at best). Therefore, lithium response is apparently polygenic and only by simultaneously examining multiple genes and multiple variants within these genes would it be possible to provide some guidelines for predicting the response. This may also apply to other mood stabilizers.
6.6 Genome-Wide Association Studies (GWAS) Focusing on Lithium Response
Perlis et al. [47] carried out a family-based association study of lithium-related and other candidate genes in bipolar disorders. Lithium genes were selected as related primarily to inositol 1,4,5-triphosphate (17 genes), to GSK3beta/Wnt signaling (39 genes), and to those implicated by messenger RNA expression data and related approaches (35 genes). Although some promising genes thought to be connected with bipolar disorder were postulated, no association with bipolar disorder was found in relation to genes specifically connected with lithium mechanisms. However, about the same time a paper appeared describing the results of GWAS in bipolar disorder, where the highest signal was obtained with the DGKH gene, which encodes a key protein in the lithium-sensitive phosphatidylinositol pathway [1].
In another study, Perlis et al. [48] utilized GWAS data, obtained from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, to examine association with risk for recurrence among patients treated with lithium and subsequently examined the regions that showed the greatest evidence of association in a second cohort of bipolar patients drawn from a clinical population at University College London. A phenotype definition was that of achieving euthymia for at least 8 weeks during prospective follow-up. It turned out that of the regions with a p value of <5 × 10−4 in the STEP-BD cohort, five (8q22, 3p22, 11q14, 4q32, 15q26) showed consistent evidence of association in a second cohort. The authors found a region of special interest on chromosome 4q32 spanning a GRIA2 gene, coding for the glutamate AMPA receptor [48].
Squassina et al. [79] performed a GWAS study on lithium-treated Sardinian patients with bipolar disorder. A phenotypic assessment of lithium response was made, using the retrospective criteria of a long-term treatment response scale. The strongest association, also supported by the quantitative trait analysis, was shown for a SNP of the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene, located on chromosome 17q12, encoding a cation channel with high affinity for sodium, and permeable to lithium. In another study, Squassina et al. [80] carried out a genome-wide expression analysis on lymphoblastoid cell lines from bipolar patients, responders, and nonresponders to lithium. It was observed that only insulin-like growth factor 1 (IGF–1) gene was significantly overexpressed in lithium responders compared to lithium nonresponders or healthy control subjects.
McCarthy et al. [41] analyzed GWAS studies performed in bipolar disorder, comparing the rates of genetic associations of circadian clock genes in bipolar disorder and control subjects in relation to possible lithium responsive genes, using a multi-level approach. They suggest that, despite the negative data obtained so far in GWAS, further studies on possible associations between clock genes, bipolar disorder, and lithium response are warranted.
Recently, the results of the GWAS performed by the Taiwan Bipolar Consortium, including a sample of 1761 patients of Han Chinese descent, were published. The strongest association with lithium response was obtained for two SNPs of glutamate decarboxylase-like protein 1 (GADL1) gene located at chromosome 3p24.1 [5]. However, subsequent studies performed by other groups failed to replicate these findings in either Asian or European ancestry samples [6, 20, 23].
It should be also mentioned that another prospective, multicenter trial named Pharmacogenomics of Mood Stabilizer Response in Bipolar Disorder (PGBD) with John Kelsoe as a principal investigator is underway where lithium is an important part. An abstract describing the study is available on the web: http://pgrn.org/display/pgrnwevsite/PGBD+Profile
6.7 Consortium on Lithium Genetics (ConLiGen)
Following an initiative by the International Group for the Study of Lithium-Treated Patient and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health, lithium researchers from around the world have formed the Consortium on Lithium Genetics (ConLiGen) in order to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder [66].
The first results of the ConLiGen initiative were presented during a CINP meeting in Stockholm in 2012. The GWAS top hit (p = 1.52 × 10−6) was found for the SLC4A10 gene coding solute carrier family 4, sodium bicarbonate transporter, member 10, which belongs to a family of sodium-coupled bicarbonate transporters [65]. This gene is located on chromosome 2q24 and is highly expressed in the hippocampus and cerebral cortex. It has been implicated in complex partial epilepsy and mental retardation [16]. The bicarbonate sensitive pathway is the most important mechanism for active lithium influx into the cell [11]. However, these results have not been replicated in a different sample.
Recently, the results of the ConLiGen GWAS, including 2563 patients collected by 22 participating sites, were reported. Data from over 6 million common SNPs were tested for association with both categorical and continuous rating of lithium response. The response-associated region on chromosome 21, containing two long noncoding RNAs (lncRNAs), was identified [21]. Although noncoding, the lcnRNA have been increasingly appreciated as important regulators of gene expression, particularly in the central nervous system. However, the biological context of these findings and their clinical utility remains to be further elucidated.
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