Molecular Neurobiological Clues to the Pathogenesis of Bipolar Disorder
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Available online at www.sciencedirect.com ScienceDirect Molecular neurobiological clues to the pathogenesis of bipolar disorder Paul J Harrison Bipolar disorder is a serious psychiatric disorder, with a high disorders common, and suicide occurs in at least 5%, heritability and unknown pathogenesis. Recent genome-wide contributing to a life expectancy that is reduced by over association studies have identified the first loci, implicating a decade. Lithium remains the gold standard for pro- genes such as CACNA1C and ANK3. The genes highlight phylaxis, with anticonvulsants, antipsychotics, and several pathways, notably calcium signalling, as being of psychological treatments, also playing a key role in importance. Molecular studies suggest that the risk variants treatment [4]. impact on gene regulation and expression. Preliminary studies using reprogrammed patient-derived cells report alterations in BD is highly heritable, with estimates of over 80% from the transcriptome and in cellular adhesion and differentiation. twin studies [5], yet understanding of its genetic basis, Mouse models show that genes involved in circadian biology, pathogenesis, and pathophysiology have remained frus- acting via dopaminergic effects, reproduce aspects of the tratingly elusive, even by the standards of other psychi- bipolar phenotype. These findings together represent atric disorders. This partly reflects its inherent complexity significant advances in identification of the genetic and and a relative dearth of research, but also difficulties in molecular basis of bipolar disorder, yet we are still far from an modelling the disorder in animals or cells. Fortunately, integrated, evidence-based understanding of its progress has recently been made in several domains. aetiopathogenesis. Those pertaining to the genetic and molecular aspects Address of BD are reviewed here. See [6] for a complementary Department of Psychiatry, University of Oxford, Warneford Hospital, review, focusing on the role of oxidative stress and cellular Oxford OX3 7JX, United Kingdom damage. Corresponding author: Harrison, Paul J ([email protected]) Genomics of bipolar disorder As with other psychiatric disorders, genome-wide associ- Current Opinion in Neurobiology 2016, 36:1–6 ation studies (GWAS) of single nucleotide polymor- This review comes from a themed issue on Neurobiology of disease phisms (SNPs) indicate that the heritability of BD is Edited by Dennis J Selkoe and Daniel R Weinberger attributable largely to multiple loci of small effect. Table 1 summarises the current genome-wide significant loci. See [5,7] for recent reviews of BD genetics. Table 1 also notes the gene(s) implicated at each locus, but it is http://dx.doi.org/10.1016/j.conb.2015.07.002 worth emphasising that the ‘causal’ gene, and true risk # 0959-4388/ 2015 The Author. Published by Elsevier Ltd. This is an SNP or haplotype, at each locus remains unknown, hin- open access article under the CC BY-NC-ND license (http:// dering the interpretation of the GWAS signals, as is the creativecommons.org/licenses/by-nc-nd/4.0/). case for all psychiatric disorders (see [8] for discussion; see below for discussion of some of the BD-implicated genes). Introduction Bipolar disorder (BD) is classically characterised by re- Other studies have begun to investigate genotype–phe- current episodes of depression and elevated mood (ma- notype relationships within BD, and between BD and nia), interspersed with periods of normal mood other disorders. Within BD, genetic loci have been relat- (euthymia) [1]. In reality, the clinical picture is more ed to variables such as presence of psychotic symptoms, complex, with mixed mood states, residual cognitive suicidality, and body mass index (e.g. [9]). Some of these dysfunction [2] and persistent mood instability during analyses have revealed genome-wide associations, but the euthymia [3] often observed. During the mood swings, samples are inevitably smaller than for the overall BD- features of psychosis (delusions and hallucinations) may control comparisons; there is also the problem that de- occur. The combination of mood and psychotic symptoms tailed phenotyping is often not available. Reflecting the has contributed to uncertainty as to where BD sits within clinical and familial overlaps between BD and other psychiatric classifications, and in particular its relationship psychiatric disorders, cross-disorder analyses have been to schizophrenia and to other mood disorders. BD affects carried out. These show substantial sharing of risk 1–2% of the population, depending on the criteria used, loci between BD and schizophrenia [10], and also signifi- and usually begins in adolescence or early adulthood. cant commonalities with major depression, but little with Morbidity is high, comorbidity with other psychiatric autism or attention-deficit hyperactivity disorder [10,11 ]. www.sciencedirect.com Current Opinion in Neurobiology 2016, 36:1–6 2 Neurobiology of disease Table 1 and pathways, and empirical studies of the expression and function of individual genes. The latter studies are also Genome-wide significant loci for bipolar disorder. addressing the molecular basis of the genetic associations. Locus Implicated gene(s) and symbol(s) Genome-wide significant in BD Pathway analyses using gene ontology and related meth- 10q21.2 Ankyrin 3 (ANK3) ods are being carried out in various ways. A prominent 12p13.3 Calcium channel, voltage-dependent, L-type, category, for which there is convergent evidence, is alpha 1C subunit (CACNA1C) 11q14.1 Teneurin transmembrane protein 4 (TENM4, calcium signalling, particularly voltage-gated calcium formerly known as ODZ4) channels, identified in several datasets and using differing 19p12 Neurocan (NCAN) approaches. It is notable that calcium signalling was 6q25.2 Spectrin repeat containing, nuclear envelope 1 (SYNE1) already hypothesised to be important in BD and its 3p22.2 Tetratricopeptide repeat and anykrin repeat treatment [18,19]; it was perhaps less expected that this containing 1 (TRANK1) enhancement of calcium channel genes applies similarly 5p15.31 Adenylate cyclase 2 (ADCY2) to schizophrenia, and also extends to other disorders [11 ]. 6q16.1 MicroRNA 2113 (MIR2113); POU class 3 A range of other pathways are also highlighted in BD by homeobox 2 (POU3F2; formerly known as OTF7) studies which have combined GWAS data with gene 10q24.33 Arsenite methyltransferase (AS3MT) expression data; these include hormonal regulation, sec- Genome-wide significant in BD + schizophrenia (combined) ond messenger systems and glutamatergic signalling 2q32.1 Zinc finger protein 804A (ZNF804A) 3p21.1 Inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3); [20 ] as well as histone and immune pathways [21]. Each inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) of these findings should be seen as provisional and in need 16p11.2 Mitogen-activated protein kinase 3 (MAPK3) of replication, not least given the inadequacies of gene Genome-wide significant in BD + unipolar depression (combined) ontology categories, and the incomplete information be- 3p21 Polybromo 1 (PBRM1) ing fed into the analyses. Nevertheless, they do provide some of the first steps to a more meaningful integrative Adapted from [5,7,49 ]. molecular classification and understanding of BD. Complementing these approaches, the leading BD risk Shedding new genetic light on an old debate, these data genes are being investigated individually, with the goal of support the view that BD and schizophrenia are on a understanding the neurobiology of the gene, the molec- continuum, rather than being discrete disorders, as they ular basis of the disease association, and the functional have conventionally been classified [12]. impact of the putative risk variant. Three examples are given here. Despite the progress, several major limitations and unknowns deserve mention, beyond the need to identify CACNA1C encodes the L-type calcium channel Cav1.2 unambiguously the affected gene(s) at each locus. First, subunit and is arguably the best supported BD gene, the causal genetic variant being tagged by the GWAS especially if the various lines of prior evidence for altered SNPs has not been identified. In the absence of known calcium signalling in the disorder are taken into account coding variants in linkage disequilibrium, the likelihood [18,19]. In addition to many studies reporting neuroim- is that the risk SNPs alter gene regulation and expression aging, cognitive and neurophysiological correlates of [13]. There is preliminary evidence for this in terms of CACNA1C genotype, molecular studies have sought to expression quantitative trait loci (eQTLs) [11 ,14 ,15] show the proximal effect of the BD-associated SNPs. The and for some of the individual genes, as discussed below. risk haplotype, including the main SNP, rs1006737, Second, the current BD GWAS signals explain only a resides within the large (300 kb) third intron, and is hence fraction of the heritability. The source of the remainder is non-coding. Any functionality is likely to be via an effect unknown, but likely includes many more independent on expression or splicing of CACNA1C – though, as with loci, as well as gene–gene interactions (epistasis), gene– all such genetic associations, other explanations are pos- environment interactions, and a role for copy number sible (e.g. effects on antisense transcripts, non-coding variants (CNVs), although at present the data suggest that RNAs, or distant genes [13]. The size and complexity the latter are less important in BD