Genetics of Bipolar Disorder

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1 Genetics of Bipolar Disorder Jordan W. Smoller, MD, ScD, and Erica Gardner-Schuster, BA Corresponding author Jordan W. Smoller, MD, ScD Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA. Current Psychiatry Reports 2007, 9: Current Medicine Group LLC ISSN Copyright 2007 by Current Medicine Group LLC Family and twin studies have consistently documented that bipolar disorder (BPD) is familial and heritable, but efforts to identify specific susceptibility genes have been complicated by the disorder s genetic and phenotypic complexity. Genetic linkage studies have implicated numerous chromosomal regions, but findings have been inconsistent. As with other complex disorders, it has become clear that linkage analysis lacks the power and precision to identify susceptibility loci for BPD. Candidate gene association studies have implicated several specific genes, but these studies have been limited by our incomplete understanding of the disorder s biology, and there have been few robustly replicated results. Within the past 2 years, a major advance in the genetics of complex disease has become feasible in the form of genome-wide association studies. Such studies, which require large sample sizes, have already proven successful in identifying susceptibility variants for a range of common medical disorders. Genome-wide association studies have begun to appear for BPD, and more are in progress. By providing an unbiased approach, this technology may reveal novel biological mechanisms underlying BPD. Introduction Bipolar disorder (BPD) is a common, chronic, and often disabling disorder affecting up to 4% of the US population [1]. In addition to the tremendous burden of suffering and economic costs that it carries, BPD can be a lethal disorder, with a lifetime suicide rate as high as 20% [2]. Despite the availability of effective treatments for mania and depression, the recurrence rate and disability associated with BPD remain substantial even among adequately treated patients [3]. Thus, intense interest exists in determining BPD s etiology, with the goal of developing more effective treatment and prevention strategies. To date, the strongest known risk factor for BPD is family history, and a large body of evidence now has established that genes play an important role in the disorder s development. In the following sections, we review the current state of knowledge regarding the genetic basis of BPD, focusing on recent progress in identifying specific susceptibility genes. Genetic Epidemiology of BPD Recent research on the molecular genetic determinants of BPD has been motivated by a substantial body of evidence demonstrating that the disorder is familial and heritable. Since 1960, approximately 20 studies have examined BPD risk among first-degree relatives of affected individuals [4]. Despite methodological differences, these studies consistently reported excess risks of BPD among first-degree relatives of bipolar probands. Overall, the recurrence risk for first-degree relatives is approximately 8% to 10%, substantially higher than the risk in the general population (1% 4%) [4]. Because genetic and environmental factors can contribute to familiality, further evidence is needed to establish that genes influence familial aggregation. This evidence can come from adoption and twin studies, which can parse the contributions of heritable and environmental factors. Adoption studies of BPD have been small and inconclusive [4]. However, twin studies have clearly established that the familiality of BPD is predominantly due to genetic influences. Twin studies have shown that the concordance rate for BPD is significantly greater among monozygotic (MZ) twin pairs (who are genetically identical) than among dizygotic (DZ) twin pairs (who share, on average, half their genes). The three largest recent twin studies have reported a concordance rate of 38.5% to 43.0% for MZ twins, compared with 4.5% to 5.6% for DZ twins [5 7]. These studies estimated the heritability (proportion of disorder risk in the population attributable to genes) of BPD to be 79% to 93%. Thus, BPD heritability exceeds that of many common medical and psychiatric disorders, and it is clear that there are genes to be found. However, it is important to understand that although a nonzero heritability implies that genes are involved, the magnitude of heritability says nothing about a disorder s genetic architecture. Genetic architecture refers to the number, magnitude of effect, and mode of inheritance of the genes contributing to a phenotype. A phenotype that is highly heritable, such as BPD, may reflect the action of many genes of small individual effect, whereas a less heritable disorder may reflect fewer but less common genetic

2 Genetics of Bipolar Disorder Smoller and Gardner-Schuster 505 variants that have a large individual effect. The importance of this concept is that the more complex the genetic architecture, the more difficult in general it is to identify specific susceptibility genes. The weight of the evidence to date suggests that BPD is highly complex and reflects the additive or interactive action of many genes and perhaps gene environment interactions. Phenotypic Complexity In addition to BPD s genetic complexity, there is substantial phenotypic complexity that presents a further challenge to identifying the disorder s genetic basis. Defining BPD s genetic boundaries is important for molecular genetic studies that require that cases, controls, or family members be designated as affected or unaffected. The diagnosis of BPD has evolved from Kraepelin s description as manic depressive insanity more than 100 years ago. In the late 1950s and early 1960s, Leonhard and others proposed the division of affective disorders into bipolar and unipolar disorders (UPDs). Family studies including probands with each of these disorders have documented a familial relationship between BPD and UPD. In controlled family studies (reviewed in [4]), overall BPD risk among first-degree relatives of BPD probands is approximately 7% (compared with a 0.7% risk among relatives of controls); at the same time, UPD risk is approximately 15% in relatives of BPD probands (compared with a risk of ~ 5% among relatives of controls). BPD risk is also significantly elevated among relatives of UPD probands compared with relatives of control probands (2.2% vs 0.7%). Data from twin studies suggest that the familial coaggregation of BPD and UPD is due at least in part to shared genetic liability [6]. In the 1970s, a further distinction was made between bipolar I disorder (characterized by manic episodes) and bipolar II disorder (characterized by hypomania and recurrent depression). Family studies have provided some evidence that bipolar II disorder is a distinct entity [4]. Bipolar II disorder risks have tended to be highest among relatives of bipolar II probands as opposed to those with bipolar I or UPD. However, UPD familial risks are similar across these proband groups, and in some studies, bipolar I risk is also elevated in relatives of bipolar II probands, suggesting that these mood disorders are not completely etiologically distinct [4]. Taken together, available data suggest that bipolar II is a heterogeneous entity in which some cases are more closely related to bipolar I and some to UPD; others may represent a genetically distinct disorder that breeds true [4]. In addition to the delineation between bipolar I and II subtypes, additional phenotypic distinctions within the BPD diagnosis have been examined in family studies. The effort to define subtypes may facilitate gene identification studies by identifying more genetically homogenous phenotypic groups. Earlier-onset bipolar disorder has been associated with greater familial risk of mood disorder in numerous studies [4]. Also, there is evidence that pediatric bipolar disorder may represent a distinct form of the disorder and that it may be genetically related to disruptive behavior disorders, particularly attention-deficit/hyperactivity disorder (ADHD) [8]. Prepubertal-onset BPD has been associated with increased familial risk of BPD and poorer response to lithium treatment [9]. In a controlled family study, Geller et al. [10] found that BPD prevalence among first-degree relatives of probands with prepubertal or early-adolescent onset was substantially higher (28.2%) than among relatives of probands with ADHD (11.2%) or healthy control probands (3.8%). The prevalence of bipolar I disorder or recurrent major depressive disorder was as high as 46.5% among first-degree relatives of prepubertal-/early-adolescent onset BPD probands. Also, relatives with ADHD were at increased risk of BPD; this is consistent with other studies suggesting that comorbid BPD and ADHD is a familial phenotype [11]. Age of first major mood episode (depression or mania) has been identified as a familial and heritable trait [12 14]. Other subphenotypic features of BPD that have been reported to aggregate in families include polarity of illness onset (mania vs depression) [15], mood episode frequency [16], psychosis [17,18], and lithium responsiveness [19]. In the largest and most recent analysis, Saunders et al. [18] examined familiality of subphenotypes in 589 sibships from the National Institute of Mental Health (NIMH) Bipolar Genetics Initiative. In multivariate models (controlling for relevant covariates), they found evidence for familial aggregation of multiple phenotypes within bipolar families, including rapid cycling, suicidality, psychosis, and comorbid alcohol use disorders and panic disorder. Linkage Studies of BPD Linkage analysis aims to identify the genomic location of susceptibility genes (ie, in which chromosomal regions they reside); it is often a prelude to association studies and other efforts to implicate specific genes. Genomescan linkage studies involve examining whether alleles of DNA markers (whose chromosomal location is known) are coinherited with the disorder within affected families. Significant linkage between a marker and the phenotype of interest implies that a gene influencing the phenotype is physically close to the linked marker. The logarithm of the odds (LOD) score is a common statistical index of evidence favoring linkage, and an LOD score greater than 3.3 (corresponding to odds of ~ 2000 to 1 in favor of linkage) often is used as a threshold for declaring significant linkage. More than 40 BPD linkage studies have been reported, implicating a broad range of chromosomal regions, although little consistency has been found. Three meta-analyses of BPD genome scans have appeared, with conflicting results [20,21,22]. The most recent and comprehensive combined original genotype data rather than summary statistics from the 11 largest linkage studies and

3 506 Bipolar Disorders identified genome-wide significant evidence for linkage on chromosomes 6q (for bipolar I disorder) and 8q (for bipolar I + bipolar II disorder) [21 ]. A number of recent studies have examined subphenotypes in an effort to reduce heterogeneity. Studies examining age of onset have supported linkage to chromosomes 3q28, 18p, and 21q [13,23]. Other analyses incorporating subtypes have found suggestive evidence for linkage to chromosome 2p12 (for BPD with suicide attempts) [24] and chromosomes 2p11-q144 and 13q21-33 (for BPD with mood-incongruent psychotic features) [25]. It has become increasingly clear that linkage studies, which were successfully applied to identify genes underlying single-gene Mendelian disorders (eg, Huntington s disease, cystic fibrosis), lack the power and precision to reliably map genes for common complex disorders such as BPD. These studies largely have given way to association analysis (candidate gene studies and, more recently, genome-wide association studies [GWAS]), which can provide substantially greater power for identifying susceptibility genes for complex traits. Cytogenetic Studies Cytogenetic studies provide another strategy for identifying genomic regions and genes influencing a disorder. These studies examine the co-occurrence of chromosomal abnormalities (translocations, duplications, deletions) and the phenotype of interest. For example, if individuals carrying a deletion of a chromosomal segment frequently exhibit a specific psychiatric phenotype, this suggests that a gene or genes in the deleted region may influence the disorder. Many cytogenetic abnormalities are relatively rare and are unlikely to underlie common forms of psychopathology. However, these observations can implicate genes in which more common variations affect disorder risk in the population. Among the most widely studied examples of cytogenetic abnormalities relevant to psychiatry is velocardiofacial/ DiGeorge syndrome (VCFS), a deletion of 1.5 to 3.0 million base pairs of DNA on chromosome 22q11. VCFS incidence is approximately one in 4000 live births, but as many as 25% to 30% of affected individuals develop schizophrenialike syndromes by adulthood [26]. An excess risk of bipolar spectrum disorders also has been reported among individuals with VCFS [27]. The deleted region contains approximately 30 genes, some of which (eg, catechol-o-methyltransferase, COMT) are plausible candidates for involvement in BPD. The hypothesis that genes in the 22q11 deleted region are involved in BPD is also consistent with studies reporting this region s linkage to BPD (and schizophrenia) [20]. A balanced translocation involving chromosomes 1q and 11q (1:11) (q42.1; q14.3) was observed to segregate with schizophrenia and mood disorders in a large Scottish kindred [28]. The translocation was found to disrupt two genes at chromosome 1q42, DISC1 and DISC2 (ie, disrupted in schizophrenia). This area s relevance is supported by linkage studies implicating 1q42 in schizophrenia and BPD [29] and by molecular studies suggesting that DISC1 is involved in neural development and neuronal signaling [30] and that its expression is reduced in a subset of bipolar patients [31]. A recent important development in genomic science is the observation that many genes and DNA sequences vary in copy number among individuals. [32] A familiar example of copy number variation (CNV) is duplication of the gene encoding the cytochrome P450 2D6, which results in interindividual differences in the pharmacokinetics of drugs metabolized by this enzyme [33]. More recently, it has become evident that CNVs may account for some forms of common, complex disorders, as has recently been demonstrated in autism [34]. Few studies have examined CNV s role in BPD, although several are underway. In one study [35], CNVs in three genes related to glutamatergic function (GLUR7, CACNG2, AKAP5) were detected in postmortem brain samples of patients with schizophrenia and BPD but not in controls. In another small study, CNVs in the gene encoding GSK-3-, a key intermediary in the signaling cascades activated by lithium, were observed in several BPD cases [36]. A more comprehensive examination of CNVs role in BPD is likely to emerge from whole-genome association studies that are underway. At this point, no convincing evidence exists to suggest that CNV contributes to common forms of BPD. Candidate Gene Studies A large, growing body of association studies examining specific candidate genes has been reported for BPD. To date, most of these studies fall into two sometimes-overlapping categories based on the nature of the candidates examined: biological candidates and positional candidates. The former is comprised of genes thought to play a role in BPD based on prior knowledge of the biological basis or mechanism of action of drug treatments for BPD. The latter includes genes whose candidacy rests on prior gene mapping (linkage and cytogenetic) studies that have implicated specific genomic regions. Genes within these regions, which may or may not have been previously implicated in the disorder s biology, are examined in genetic association analyses. Candidate gene studies in psychiatry suffer from many limitations. First, the identification of biological candidates is constrained by the state of knowledge about the disorder s biology. In BPD, progress in understanding the disorder s neurobiology and the molecular basis of drug targets has been accelerating, but our understanding remains limited. The dearth of valid animal models that could facilitate detailed molecular studies has been an important impediment. A recent advance in this area capitalized on the evidence that BPD symptoms and mood cycling reflect dysregulation of circadian rhythms.

4 Genetics of Bipolar Disorder Smoller and Gardner-Schuster 507 Roybal et al. [37 ] demonstrated that mice carrying a loss-of-function mutation in the Clock gene, a key regulator of circadian rhythms, exhibit phenotypic features of mania, including hyperactivity, increased hedonic drive, decreased sleep, and altered circadian rhythms; they further found that lithium reversed many of these behavioral changes. Such studies can identify and characterize molecular pathways that suggest candidates for genetic association studies. Using an approach they refer to as convergent functional genomics, Le-Niculescu et al. [38] have integrated gene mapping and gene expression studies to prioritize candidates for genetic association studies. Genes whose expression is altered in response to methamphetamine (whose effects in rodents recapitulate aspects of manic psychosis) or valproate (an antimanic agent) and whose involvement is supported by linkage and/or association studies may be particularly appealing. Another approach has been to identify candidates based on the cellular pathways affected by lithium and other mood stabilizers. Nevertheless, the basis for identifying compelling candidate genes for BPD remains limited. This reflects another limitation of candidate gene studies: the likelihood of a false-positive result is inversely related to the prior probability of association. That is, although a large number of plausible candidates (eg, any brain-expressed gene) exist, we have limited evidence to suggest that any one of them is clearly involved in the disorder. The result is that any statistically significant association with one of these genes has a low prior probability of being a true positive. The well-known difficulty in replicating gene associations in complex disorders is likely to be due in part to this phenomenon. Empirical investigations suggest that most reported associations are due to chance [39]. This problem is exacerbated by multiple testing of genes and phenotypes (analyses that may or may not be fully reported), which can seriously inflate spurious association risk [40]. A related problem is the risk of false-negative findings. Given evidence that individual allelic effects on complex phenotypes such as BPD are likely to be extremely small (with odds ratios [ORs] of < 1.5), most studies to date have been underpowered to robustly detect association. Also, many negative studies have examined one or a small number of variants within candidate genes, leaving open the possibility that other variants at a given locus could be associated with the phenotype. One important strategy for identifying true positive and true negative associations is the use of meta-analysis or pooled analysis of association studies [41]. To date, meta-analysis of several biological and positional candidates for BPD has been reported (results from studies since 2005 are summarized in Table 1). One of the most widely studied biological candidates is the gene-encoding brain-derived neurotrophic factor (BDNF), which has been implicated in the biology of BPD, UPD, and anxiety symptoms. However, a recent meta-analysis of 11 casecontrol studies of the common Val66Met variant (rs6265) did not support a role for this BDNF polymorphism in BPD, although this analysis did not include family-based studies that have supported association [42]. In addition, evidence exists that BDNF may play a role in rapid-cycling BPD [43,44]. Meta-analyses of another extensively studied biological candidate, the serotonin transporter gene (SLC6A4), support the possibility that it is associated with BPD, although with very modest effects [45,46]. For example, the short allele of the 5-HTTLPR promoter polymorphism has been associated with BPD, but the overall OR is less than 1.15 (Table 1). The gene known as G72 (also called DAOA for d- amino acid oxidase activator) is a positional candidate identified from linkage studies implicating the 13q32-34 region in schizophrenia and BPD [47]. This gene s function is not fully understood, but evidence initially suggested that it may facilitate the action of d-amino acid oxidase, an enzyme involved in the oxidation of d- serine (an agonist at glutamatergic N-methyl-d-aspartate [NMDA] receptors) [47]. More recently, Kvajo et al. [48 ] reported that an isoform of the G72 mrna encodes a mitochondrial protein and that G72 level increases in immature neurons are associated with increased dendritic arborization. A meta-analysis of association studies supported a role for G72 in schizophrenia, but results for BPD were modest and inconsistent [49]. As shown in Table 1, a nominally significant association was seen for one intronic marker (rs ). The gene encoding 5,10 methylenetetrahydrofolate reductase (MTHFR) also has been implicated in BPD in a meta-analysis [50], and several other genes have been associated in more than one sample, including DISC1, the dopamine transporter (SLC6A3), tryptophan hydroxylase 2 (TPH2), the NMDA glutamate receptor, subunit 2B (GRIN2B), and COMT [51 56]. GWAS: The Next Wave Over the past 2 years, advances in genotyping technologies, statistical genetics, and genomic science (especially the construction of genome-wide linkage disequilibrium maps through the International HapMap Project), have made GWAS possible. Using hundreds of thousands of single-nucleotide polymorphism markers (SNPs) selected to capture genetic variation across the whole genome, these studies can identify evidence of association without having to specify candidate genes. As such, this approach is referred to as an unbiased strategy that avoids many of the limitations of candidate gene studies previously described. At the same time, the large number of marker tests confers a high risk of spurious findings without rigorous statistical control of false-positive rates. Nevertheless, this approach s value for identifying susceptibility variants has been unequivocally demonstrated by successful GWAS studies of cardiovascular disease, diabetes, inflammatory

5 508 Bipolar Disorders Table 1. Meta-analyses of bipolar disorder genetic association studies from 2005 present Gene and polymorphism Reference Studies, n Patients, n* Method BDNF OR (95% CI) or P value Val66Met Kanazawa et al. [42] /6347 CC 0.95 ( ) G72 (DAOA) rs Detera-Wadleigh and 3 439/413; 22 families CC/FB P = McMahon [49] rs Detera-Wadleigh and 3 439/413; 22 families CC/FB P = McMahon [49] MTHFR MTHFRC677T Gilbody et al. [50] 4 550/1098 CC 1.82 ( ) SLC6A4 5-HTTLPR Cho et al. [46] families FB 1.12 ( ) /2583 CC 5-HTTLPR Lasky-Su et al. [45] /3652 CC 1.13 ( ) Intron 2 VNTR Cho et al. [46] families FB 1.12 ( ) /2703 CC Intron 2 VNTR Lasky-Su et al. [45] /2292 CC 1.05 ( ) *Cases/controls or families, as indicated. OR comparing TT and CC genotypes. OR for short allele combining CC and FB studies. OR for 12 allele combining CC and FB studies. CC case-control; FB family-based; OR odds ratio. bowel disease, and a growing list of other complex diseases. An increasing number of GWAS for psychiatric disorders is appearing, including two BPD studies that appeared in the first half of Baum et al. [57 ] performed a GWAS of 550,000 SNPs in samples of European origin. They initially screened the genome using pooled DNA samples from cases and controls in a test US sample of 461 unrelated BPD cases drawn from an NIMH affected sibling pair sample and 563 matched, unrelated controls. Using criteria for identifying SNPs in the test sample that warranted replication (P < 0.05, OR > 1.4, relative allele frequency in pooled case/control samples of > 5%, and mapping in or near known genes), they identified 1877 SNPs for testing in a replication case-control sample of German BPD cases (n = 772) and matched controls (n = 876). Of these, 88 SNPs (in 80 genes) showed evidence of association (P < 0.05) for the same allele in the replication sample. The most significant result was observed for an SNP (rs ) in the first intron of DGKH, the gene encoding diacylglycerol kinase eta, on chromosome 13q14. The P value for this SNP in the combined test and replication samples was , with an allelic OR of The DKGH gene is of interest because its product is involved in the phosphatidyl inositol pathway through which lithium may exert some of its mood-stabilizing effects. The effect sizes of all variants that demonstrated some degree of association in this study were modest (with most ORs < 1.4), suggesting that BPD s genetic basis is likely to reflect polygenic effects of many loci of small effect. Another larger GWAS for BPD was conducted as part of the Wellcome Trust Case Control Consortium [58 ] in a report on seven major diseases. A sample of 1868 cases and 3000 UK controls were genotyped at 500,000 SNPs. The strongest result in the primary analysis was for an SNP (rs420259) on chromosome 16p12, which gave a genotypic P value of , exceeding the prespecified significance threshold of and an OR of approximately 2.1 for heterozygotes and homozygotes. This SNP falls in a region near several genes that may be plausible candidates for BPD, including PALB2 (involved in the stability of key nuclear structures, including chromatin), NDUFAB1 (which encodes a component of the mitochondrial respiratory chain), and DCTN5 (which interacts with DISC1). In a second analysis that included cases from the other six diseases as controls for BPD, the 16p12 finding was no longer significant, but four other regions exhibited P values of less than These included a region on chromosome 12q21 near the KCNC2 gene (which encodes a potassium channel), and SNPs at 1p31, 2q31, and 22q12. No significant evidence existed to support association with leading candidate genes, including BDNF, DAOA, DTNBP1, DISC1, or neuregulin (NRG1).

6 Genetics of Bipolar Disorder Smoller and Gardner-Schuster 509 These studies represent only the first efforts at genomewide association analyses for BPD, and several others will be published soon. By combining these studies results (through pooled or meta-analyses), it should be possible to validate true susceptibility genes for BPD in the next several years. Genetics and the Boundaries of BPD The advent of GWAS for psychiatric disorders may help to advance another frontier in BPD genetics: defining the disorder s boundaries and its etiologic relationships to other disorders. As previously noted, psychosis appears to be a familial trait in BPD-affected families [17,18], and evidence exists that psychosis itself, a symptom that occurs in mood disorders (BPD and UPD) and psychotic disorders, is heritable [59]. Several linkage and association studies have implicated specific chromosomal regions and genes in psychotic BPD [25,60 64]. Furthermore, twin data suggest that genetic influences on BPD overlap with those on schizophrenia and schizoaffective disorder [65]. Linkage, cytogenetic, and association data have provided support for this finding. Several of the regions most commonly linked to schizophrenia also have been strongly linked to BPD, including 6q21-q25, 13q32-q34, and 22q. Cytogenetic syndromes (the translocation disrupting DISC1, and the 22q11 deletion causing VCFS) are associated with schizophrenia and bipolar spectrum phenotypes. Similarly, several genes strongly implicated in schizophrenia have been associated with BPD, including DISC1, COMT, neuregulin (NRG1), dysbindin (DTBPN1), and G72/DAOA [62,63,66 71]. These overlapping findings have challenged the classic Kraepelinian distinction between schizophrenia and BPD, although several caveats must be considered in this regard. First, no specific variants in these genes have been unequivocally established as risk factors for either disorder. Second, the alleles and haplotypes associated with schizophrenia and BPD are often inconsistent across studies. Third, the phenotypic associations are in some cases inconsistent across studies. For example, one study of G72 [63] reported association for the subset of BPD cases with persecutory delusions, whereas another study [66] found association between G72 and mood episodes (but not psychotic symptoms) in schizophrenia and BPD. Finally, as Kendler [72 ] has noted, even if some genes influence both disorders, this does not necessarily imply that the nosologic distinction between them should be overturned. Many genes are known to have pleiotropic effects, and the definition of a disease entity does not rest on its risk factors being unique to that entity. For example, GWAS analyses have convincingly shown that the same specific genetic variants confer susceptibility to rheumatoid arthritis and to type I diabetes [58 ], but no one would claim that this undermines the distinction between these disorders. Nevertheless, genetic studies may inform psychiatric nosology and provide a basis for defining disorders based on pathogenesis rather than descriptive symptom clusters. At a minimum, such genetic studies can reveal underlying pathogenetic mechanisms and pathways that cross diagnostic boundaries. Conclusions The evidence from genetic epidemiologic and molecular genetic studies of BPD has established that the disorder is heritable but that its underlying genetic architecture is quite complex. Research on BPD genetics has advanced beyond linkage studies that are better suited to map genes for single-gene disorders to association analyses that have, until recently, been limited to candidate genes studies that have often been underpowered and constrained by our incomplete understanding of the disorder s biology. Taken together, the evidence from BPD studies suggests that BPD s genetic basis involves many genes of small individual effect. Even candidate genes supported by meta-analyses appear to explain a small proportion of the disorder s heritability (with ORs for individual susceptibility variants typically < 1.5). The advent of unbiased GWAS offers new hope for identifying such susceptibility loci. However, it is clear that very large samples (on the order of many thousands of cases and controls) will be needed, along with independent replication, to establish a role for any individual genetic risk factor. The successful discovery of susceptibility genes for a growing number of complex medical disorders through genome-wide studies bodes well for genetic research on BPD. Ultimately, the identification and characterization of BPD susceptibility genes should clarify underlying biological mechanisms of the disorder and lead to novel treatment strategies for this often devastating disorder. Acknowledgments Neither author has a possible conflict of interest, financial or otherwise. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Kessler RC, Berglund P, Demler O, et al.: Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005, 62: Goldberg JF, Harrow M: Consistency of remission and outcome in bipolar and unipolar mood disorders: a 10-year prospective follow-up. 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