Genetic Linkage in Bipolar Disorder
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Genetic Linkage in Bipolar Disorder Document Transcript

  • 1. Review Article Genetic Linkage in Bipolar Disorder By Carol A. Mathews, MD, and Victor I. Reus, MD The relative risk of bipolar disorder for first-degree FOCUS POINTS relatives of individuals with bipolar I disorder is • There are various approaches to identifying genetic seven times that of the general population risk of loci conveying risk for bipolar illness. ~1%. The risk of affective disorder is also increased • Chromosomal regions have shown evidence of among relatives of individuals with bipolar II disor- positive linkage to bipolar illness. der or schizoaffective disorder.1-3 Adoption studies • Endophenotypes play an important role in ascer- show that the biological relatives of adopted indi- taining individuals for genetic studies. viduals with bipolar disorder are at greater risk for bipolar disorder than are the adoptive relatives, ABSTRACT providing further evidence for a genetic component Bipolar disorder is an etiologically complex syndrome to bipolar disorder susceptibility. 4 Twin studies, that is clearly heritable. Multiple genes, working singly or however, indicate that, although bipolar disorder is in concert, are likely to cause susceptibility to bipolar dis- highly heritable, it is not exclusively determined by order. Bipolar disorder genetics has progressed rapidly in genetics. The risk for bipolar I disorder in a the last few decades. However, specific causal genetic monozygotic twin of an individual with bipolar dis- mutations for bipolar disorder have not been identified. order is ~60 times higher than that of the general Both candidate gene studies and complete genome screens population, and concordance rates for bipolar disor- have been conducted. They have provided compelling evi- der range between 60% and 90% in monozygotic dence for several potential bipolar disorder susceptibility twins and ~8% for dizygotic twins. 1,5-8 Some, but loci in several regions of the genome. The strongest evi- not all, segregation analyses have provided support dence suggests that bipolar disorder susceptibility loci may for a locus of major effect for bipolar disorder, and lie in one or more genomic regions on chromosomes 18, have suggested a variety of inheritance patterns, 4, and 21. Other regions of interest, including those on including autosomal dominant, X-linked, and chromosomes 5 and 8, are also under investigation. New recessive inheritance. Other studies have suggested approaches, such as the use of genetically isolated popula- that a more realistic model involves several genes tions and the use of endophenotypes for bipolar disorder, acting in a multiplicative manner.9-13 hold promise for continued advancement in the search to Although epidemiologic studies have suggested identify specific bipolar disorder genes. multiple possible modes of inheritance for bipolar dis- CNS Spectr 2003;8(12):891-904 order, the most current belief is that bipolar disorder is genetically heterogeneous, with a number of genes INTRODUCTION playing at least some role in its etiology. What role Bipolar disorder, like all neuropsychiatric disor- they play and how they interact with one another has ders, is an example of an etiologically complex syn- yet to be elucidated. Phenomena, such as anticipa- drome in which multiple environmental and tion (where successive generations of affected indi- genetic factors act either jointly or independently viduals suffer from an earlier onset or a more severe to produce the trait or illness. Genetic epidemio- form of the disorder because of instability in the logic investigations, including family, adoption, and genetic mutation) and imprinting (differential mater- twin studies, suggest that there is a prominent nal and paternal inheritance), have also been genetic component in susceptibility to bipolar dis- hypothesized. Anticipation is seen in several other order, although efforts to identify specific causative neuropsychiatric disorders, such as Huntington’s dis- genetic variants have not yet been successful. ease and Fragile X syndrome, and in these disorders is Dr. Mathews is assistant professor in residence in the Department of Psychiatry at the University of California, San Diego. Dr. Reus is professor in residence in the Department of Psychiatry at the University of California, San Francisco. Disclosure: This paper was partially supported by a grant from the National Center for Research Resources (K23RR15533) and by a grant from the National Institute of Mental Health (2R01MH049499). This paper was submitted on April 8, 2003, and accepted on June 3, 2003. Please address correspondence to: Victor I. Reus, MD, Department of Psychiatry, Langley Porter Psychiatric Institute, University of California, San Francisco, 401 Parnassus Ave., San Francisco, CA 94143-0984; Tel: 415-476-7478, Fax: 415-476-7404; E-mail: Volume 8 – Number 12 891 CNS Spectrums – December 2003
  • 2. Review Article secondary to a trinucleotide (DNA) repeat sequence the highest likely lod score in a particular region, that expands as it is passed to successive generations. even when this position lies between markers. The best known example of differential parental For simple Mendelian disorders, where only one inheritance, or imprinting, is that of the Prader-Willi mode of inheritance is tested (and generally only a and Angelman syndromes, which are both due to few markers are used), a lod score of 3 is considered to deletions on chromosome 15, but diffaer in that the be significant evidence for linkage. This is because defect is inherited with Prader-Willi ona the paternal the prior probability that any two given loci are chromosome, where as for Angelman it is inherited linked due to chance is ~1:50 (based on the esti- on the maternal chromosome. mated length of the genome). In order to compensate for this, and to bring the overall probability of linkage GENETIC MAPPING APPROACHES to 1:20 (corresponding to the commonly accepted Strategies to map disease genes are based on iden- significance level of P =.05), a lod score of 3 is tifying genetic marker alleles that are inherited from required. For complex traits, such as bipolar disorder, a common ancestor along with a linked disease gene, however, where the mode of inheritance is unknown, or inherited identical-by-descent. Multiple methods many hundreds of markers and multiple genetic mod- for identifying regions that are linked or associated els are frequently tested, dramatically increasing the with a particular disorder exist, both for candidate risk of obtaining false positive results. In a standard gene studies and genome screens, including tradi- genome screen of several hundred markers, for exam- tional pedigree studies (large, multigenerational fami- ple, one can expect to find false positives (regions lies with multiple affected members), affected sibling that are significant at P<.05, corresponding to a lod pair studies (families with two or more affected sib- score of >1) by chance alone ~24 times (once per lings), affected relative pair studies, and association chromosome). For this reason, a lod score of 3.4 has studies using family trios or cases and controls. been suggested as providing sufficient evidence for The primary goal of linkage studies is to determine linkage in circumstances where multiple genetic if two or more genetic loci (ie, a genetic marker and markers and/or multiple models (modes of transmis- the disease of interest) are co-segregating within one sion) are tested. or more pedigrees. For each marker locus of interest, a Because some investigators have argued that a lod recombination fraction (θ), which corresponds to the score of 3.4 is too conservative for complex traits, number of recombinants within the pedigree com- which are subject to high degrees of heterogeneity, a pared to the number of non-recombinants within the classification system for reporting linkage based on pedigree, is estimated. The recombination fraction is dense genome scans has been proposed. 14 In this equal to the genetic distance between the two loci (a schema, lod scores or other statistical tests equivalent θ=0.01 is 1 centiMorgan [cM] in genetic distance, to P≤.001 would be considered suggestive evidence and on average, covers a physical distance of about for linkage, those equivalent to P≤.0001 would be sig- 1 megabase [Mb] of DNA). A recombination fraction nificant evidence of linkage, and those equivalent to of 0.5 indicates that the two loci are not linked, but P≤.00002 would be highly significant evidence for rather that they are segregating independently. A lod linkage. In general, P=.001 corresponds to a lod score (log of the odds ratio) score is then calculated to of ~2.5, P=.0001 to a lod score of 3, and P=.00002 to determine the likelihood that the two loci are linked a lod score of 3.7. The exact lod score corresponding at the distance suggested by θ. The lod score is calcu- to these P values varies somewhat based on the ana- lated for each pedigree by dividing the likelihood of lytic test that is used. These P values correspond to acquiring the data if the loci are linked at a given the statistical evidence that would be expected to recombination fraction by the likelihood of acquiring occur 1, 0.05, or 0.001 times at random in a genome the data if the loci are unlinked (θ=0.5) and taking screen. Linkage for complex traits, such as bipolar dis- the log10 of this odds ratio. In general, a lod score of order, would only be confirmed when significant find- 1 corresponds to a significance level of 0.05, and a lod ings from one or several studies had been score of 3 corresponds to a significance level of subsequently replicated in an independent sample.14 P=.0001. Data from multiple family pedigrees can be It is important to note, however, that failure to repli- combined to derive a cumulative lod score (desig- cate a linkage finding in another population does not nated by Z), and maximum multipoint lod scores for necessarily mean that there is not linkage at that individual families or for multiple pedigrees can be locus. Failure to replicate the finding may be due derived by extrapolating the information obtained to ethnic differences or other forms of genetic hetero- from multiple adjacent genetic markers to identify geneity, diagnostic differences between the study Volume 8 – Number 12 892 CNS Spectrums – December 2003
  • 3. Review Article populations, or stochastic (statistical) fluctuation. In Family-based studies, which control for the prob- such cases, extension studies in the original popula- lems of differential allele frequencies by using tion or a meta-analysis of all studies may help to con- parental chromosomes as controls, which, by defin- firm or refute the initial finding. ition, have the same genetic background as the cases, have been negative or equivocal for linkage CANDIDATE GENE STUDIES to the serotonin transporter.15 A candidate gene is one whose genetic location Brain-derived neurotrophic growth factor has already been determined, whose protein product (BDNF), is another gene that has excited some inter- is known, and that is hypothesized to play a role in est as a potential candidate gene for bipolar disorder. the pathophysiology of the disorder in question. Initially thought to be a strong candidate gene for A candidate gene may also be one with unknown schizophrenia, most association studies for that disor- function that is located in a particular chromosomal der were negative or equivocal. BDNF was subse- region of interest (eg, identified via a genome quently suggested as a candidate gene for bipolar screen). To date, a number of candidate genes for disorder because of its postulated role in the action of bipolar disorder have been examined, principally antidepressants. Considerable evidence suggests that involving serotonergic, dopaminergic, and adrenergic BDNF plays an important role in neuronal adapta- receptor, transporter, and enzymatic or metabolic tion to stress and to antidepressant response. 17,18 genes.15 Because the pathophysiology of bipolar disor- Intracerebral administration of BDNF to animals der is not well understood, candidate genes for bipo- causes the growth of 5-HT neurons and the sprouting lar disorder have been chosen using pharmacologic of 5-HT nerve terminals, and administration of anti- response data or cytogenetic data (chromosomal depressants to BDNF knockout mice can reverse translocations or deletions co-segregating with bipo- some of the behavioral changes (similar to those seen lar disorder in particular families or individuals) indi- in depression in humans) observed in these strains.17,18 cating a candidate region. Of the 20 or more genes As with other candidates for bipolar disorder, associa- that have been examined, none have provided con- tion studies of BDNF have been mixed. The evidence clusive evidence for a role in bipolar disorder suscep- for association between BDNF and bipolar disorder tibility. 15 The most widely studied has been the was the strongest in a recent family-based association serotonin transporter gene (5-HTT) on chromosome study conducted by Neves-Pereira and colleagues.19 17q. The promoter region of the 5-HTT gene has an In this sample, P values between .04 and .0004 were insertion/deletion polymorphism (in effect, a long obtained for both of the two single nucleotide poly- and short version of the gene) that shows differential morphisms examined within the BDNF gene. In the gene expression. The short allele of the 5-HTT gene other two studies20,21 that have been conducted to results in reduced transcription of the serotonin date, however, the evidence of association has been transporter, and reduced serotonin (5-HT) uptake in weak or negative. lymphoblasts compared with the long version, lead- For all of the other proposed candidate genes for ing to speculation that it may be a functional bipolar disorder, both positive and negative studies (causative) polymorphism for bipolar disorder. 16 have been reported. Because of the problems in inter- Although positive associations have been reported, preting such contrasting results, several investigators numerous negative studies15 also exist. These mixed have used meta-analysis as a way to assess the associa- results may mean that the 5-HTT is a risk factor for tion data for a particular candidate gene. This some individuals with bipolar disorder, and that the approach has the advantage of increased power by variation between studies is due to genetic hetero- combining data from a number of small (and presum- geneity among affected individuals. Another possibil- ably underpowered) studies, although problems lead- ity is that that these findings are false positives. Most ing to false positive results in the original studies may of the positive findings have occurred in case-control be compounded in a meta-analysis. Meta-analyses studies, which are subject to high false positive rates have been done for multiple candidate genes, includ- due to underlying differences in allele frequency ing the 5-HTT gene, the monoamine oxidase A between cases and controls for reasons unrelated to (MAOA) gene, the dopamine D 3 receptor gene disease status. This problem can occur when the cases (DRD 3 ), and the tyrosine hydroxylase gene. 22-25 and controls have different genetic backgrounds (and Neither the DRD3 gene nor the tyrosine hydroxylase hence different allele frequencies), usually because gene showed any evidence of association with bipolar they are composed of individuals of varying disorder using meta-analytic techniques. 22,23 The ethnicities and are not matched carefully enough. meta-analyses for the MAOA gene and the 5-HTT Volume 8 – Number 12 893 CNS Spectrums – December 2003
  • 4. Review Article gene, each of which examined two separate polymor- by Berettini and colleagues26 that examined 11 mark- phisms within the gene or in the promoter region, ers distributed across chromosome 18 and identified a gave positive results for one polymorphism but not region of interest near the centromere. Because this the other (MAOA: P=.02, 5-HTT: P=.049).24,25 The was a linkage analysis using pedigree data, model significance of these results is unclear, as the p values, specification (ie, mode of inheritance) was required, although nominally significant, were no longer statis- and the results were analyzed using both recessive tically significant when corrected for multiple testing. and dominant models. Of the positive lod scores These studies did not report tests for homogeneity reported (the highest was 2.38), no clear pattern of across studies, a crucial factor in the interpretation of inheritance was observed. Some of the markers were meta-analyses. In the case of the MAOA gene, the positive under a recessive model in some families, association studies were done with silent polymor- some under a dominant model in other families, and phisms (genetic variants that do not code for changes some markers gave positive lod scores in some fami- in amino acids, and, therefore, do not affect protein lies under both models. Nonparametric tests, which function). No functional variants in the MAOA do not require a mode of inheritance to be specified, gene have been identified that are associated with provided somewhat stronger evidence for linkage. bipolar disorder. Additional genotyping in the area of interest has sup- ported the original linkage finding and subsequently Genome Screens narrowed the region to about 11–15 Mb from the P The other approach to searching for linkage is to telomere, with a maximum lod score of 2.32.27 conduct a whole genome screen, where multiple Attempts to replicate this finding in other popula- genetic markers (usually hundreds) distributed tions have been mixed. Although at least one group throughout the genome are tested for evidence of has found evidence to support linkage to the pericen- linkage to the disorder of interest. This approach tromeric region of chromosome 18, others have assumes that there are no known specific areas of found no evidence for linkage to this region. In the interest within the genome and therefore involves first positive replication study, Stine and colleagues28 screening the entire genome with evenly spaced hypothesized that a parent-of-origin effect might play markers in an attempt to find an area or areas of a role in the genetics of bipolar disorder because they potential linkage. Although candidate gene studies observed that in their bipolar disorder pedigrees, continue, genome-wide screens are currently the transmitting mothers were more common than trans- approach of choice for bipolar disorder, primarily due mitting fathers. They divided their sample into those to the relative lack of information about the patho- families where the disorder appeared to be inherited physiology and the lack of success with candidate from the paternal side and those where it appeared to gene approaches. These studies have an important be inherited from the maternal side, and these sub- advantage in that they do not require a priori knowl- groups were analyzed both together and separately. edge of the biological underpinnings of bipolar disor- Evidence for excess allele sharing in the paternal der. Most of the performed genome screens support pedigrees was identified for several markers in the the idea that bipolar disorder is genetically heteroge- pericentromeric area of chromosome 18 (18p11) neous and suggest that many, if not all, of the genes using nonparametric methods and a broad diagnostic for bipolar disorder confer a modest susceptibility risk category, which included bipolar I disorder, bipolar II rather than being genes of major effect. There are at disorder, and recurrent major depression. Since this least three chromosomal areas in which multiple finding, two other groups29,30 have also reported evi- studies have shown evidence for linkage—chromo- dence of a parent-of-origin effect (although not con- some 18, chromosome 4, and chromosome 21q, as sistently paternal transmission) in this area of well as a number of other regions that have shown chromosome 18. some evidence of linkage or association in one or a Chromosome 18q and 18p few studies. In addition to analyzing the pericentromeric Chromosome 18 Pericentromeric region of chromosome 18, Stine and colleagues28 also The evidence that there is at least one susceptibil- analyzed markers distributed across the chromosome, ity gene for bipolar disorder on chromosome 18 is and found excess allele sharing in the area of 18q as mounting. The precise location remains unclear, well. Unlike the linkage finding in the pericen- however, and there may in fact be more than one tromeric region (18p11), which was obtained under a important region on this chromosome. The first broad diagnostic category, the evidence for linkage report of linkage came from a partial genome screen on 18q was found using a relatively narrow diagnostic Volume 8 – Number 12 894 CNS Spectrums – December 2003
  • 5. Review Article category, including only subjects with bipolar I disor- ciation in this study was found on chromosome 18p, in der or bipolar II disorder. As with 18p11, the linkage the area of the conserved haplotype (~330 kilobase) results for 18q were somewhat strengthened when the present in the original pedigrees. pedigrees were divided into paternal and maternal Subsequent groups have also examined chromo- samples. Although the original maximum lod score some 18 for evidence of linkage to bipolar disorder. was 1.45 in the overall sample, two-point lod scores Several of these groups30,36-39 have found some evi- in the area of 18q were between 2.6 and 3.5 in the dence for linkage, although weak, at or near 18q23, paternal-inheritance pedigrees, the maximum multi- as well as near 18q22 and 18q12. Support for linkage point lod score in this area was 3.11, and there was on 18p has been more uncertain, although many evidence of excess allele sharing for several markers studies report weak evidence of linkage in this region, in the region.28 When this group attempted to repli- primarily pericentromeric.40-42 There have also been a cate their findings in a new sample of bipolar disorder few studies43-45 to report no evidence of linkage to all pedigrees using the same diagnostic criteria as the or part of chromosome 18 in their samples. In an original study, they found evidence for excess allele attempt to consolidate the results of the various link- sharing among affected sibling pairs in two markers in age studies, Dorr and colleagues46 conducted a meta- the region of interest on 18q (18q21), but little evi- analysis of some of the chromosome 18 linkage data. dence for linkage on 18p.31 Support for the parent-of- Although the study did not include data from all of origin effect was also reduced in this new sample. the chromosome 18 studies, it did include ~700 fami- Analysis of these bipolar disorder families combined lies, and attempted to standardize the genetic data for with the original study set strengthened the evidence pooling and comparison. This study46 found evidence for linkage on 18q, although most of the linkage was of excess allele sharing at the tip of 18p, as well as in shown to come from allele sharing between sibling the pericentromeric region of chromosome 18 when pairs with bipolar II disorder and not from those with a broad phenotype was used. There was less evidence bipolar I disorder, and the investigators were unable for association on chromosome 18q, although there to significantly narrow the region of interest.31 were some isolated markers that showed evidence of In an independent study of bipolar disorder from excess allele sharing under various models. Results of the genetically isolated population of the Central the meta-analysis under a narrow phenotypic model Valley of Costa Rica, Freimer and colleagues32,33 con- were not reported. ducted a complete genome screen in two large bipolar The combined evidence of these studies, although disorder pedigrees. This study also gave evidence for somewhat contradictory and confusing, suggest that linkage on chromosome 18 in two regions, one on there may be two different susceptibility loci on chro- 18p and one on 18q. Under a narrow diagnostic mosome 18, one on 18p, and one on 18q. These loci, model that included only bipolar I disorder and if they do indeed represent true separate areas of link- schizoaffective disorder, manic type, the strongest age, are different in intriguing ways. The 18p finding evidence for linkage was found in the area of is perhaps the most difficult to explain, as for most 18q22–q23, where the maximum linkage/association- individual studies a single marker contributes the based lod score was 4.06 and a shared 30 cM haplo- majority of the positive findings, and each study type (composed of several alleles that are relatively points to a different marker at a different location. rare in the general population of Costa Rica) was These differences may reflect the imprecision in found in the majority of affected individuals in both localization that is common in genetic studies, or pedigrees. 32 Weaker evidence of linkage was also they may be false positives due to stochastic varia- found in one of the two families to chromosome 18p, tion. The meta-analytic results, however, suggest that near the telomere. Although lod scores for this region 18p cannot currently be excluded as a potential did not reach significance, a shared genetic haplotype region of linkage for bipolar disorder. was identified.33 The evidence for linkage in this area appears to be Follow-up studies33-35 using unrelated family-based strongest in individual families—in most studies, the evi- trios from the the Central Valley of Costa Rica have dence actually diminishes when families are combined, provided support for both of the areas on chromo- and in both the individual studies and in the meta-analy- some 18 that were originally identified in the pedi- sis, it is strongest under a broad phenotype definition that gree analysis, 18p-telomeric and 18q23. These studies includes not only bipolar disorder but also major depres- have also identified an additional area of association sion, suggesting that 18p may be more likely to harbor a in the middle of 18q that was not identified in susceptibility locus for affective disorders in general the pedigree analysis. The strongest evidence for asso- rather than for bipolar disorder specifically. Volume 8 – Number 12 895 CNS Spectrums – December 2003
  • 6. Review Article In contrast to 18p, the 18q finding extends over Several other studies have provided supporting several markers, and is robust to the addition of new evidence of a potential susceptibility locus at 4p, families. Although different markers were tested in although weaker than the findings in the original the different studies, they all lie within the area of the study. In a study of Danish families conducted by larger haplotype originally noted in the Costa Rican Ewald and colleagues,51 a lod score of 2.0 was found families. This finding is dependent on a narrow phe- at D4S394, the original marker of interest in the notypic definition—the evidence weakens or disap- Scottish families. A subsequent study of German pears when the phenotype is expanded to include families by Nothen and colleagues 52 also showed major depression, suggesting that this putative locus evidence of allele sharing at D4S394 in a sample of may be more specific for bipolar disorder. To date, no affected sibling pairs, with 81% of sibling pairs causative mutations have been identified, although sharing a particular allele when the analysis was several candidate genes on chromosome 18 have been restricted to families showing evidence of paternal examined,47-49 including clusterin-like 1 (retinal) gene, inheritance. Blackwood and colleagues 53 have myo-inositol monophosphatase, and the human G reportedly narrowed the area of interest on chro- protein golf alpha gene. These genes were chosen as mosome 4p to ~11 cM using haplotype analysis, potential candidates because they lie within the and has constructed a high-resolution physical map regions of strongest linkage on chromosome 18, are of the area to assist in identifying candidate genes expressed in brain, and a plausible hypothesis for their in the region. putative role in bipolar disorder susceptibility can be Analysis of chromosome 4q has also provided derived from what is currently known of their func- some evidence for linkage to bipolar disorder, tion. However, there are many other genes or putative although weaker than for the 4p region. The initial genes that lie within the broader linkage regions for report54 of linkage to 4q35 came from a complete bipolar disorder that may also be of interest. genome screen of a single, large bipolar disorder Chromosome 4 pedigree, with a maximum single point lod score of Another potential susceptibility locus (or possibly 2.39, and a maximum multipoint lod score of 3.19 more than one) for bipolar disorder is located on using a broad phenotype. Analysis of an additional chromosome 4. The first linkage finding on chromo- 10 pedigrees 54 lowered the lod score to 2.03, some 4 was reported by Blackwood and colleagues50 although when examined independently, at least one who conducted a complete genome screen of 12 of the additional families showed evidence of linkage Scottish families with bipolar I disorder, bipolar II dis- to this locus. Two other studies have also shown order, and recurrent major depression. Maximum lod some support for this locus, including a genome scores were between 2.9 and 3.3, which although screen conducted by the Dana Consortium (maxi- strongly suggestive, is not conclusive evidence for mum heterogeneity lod score of 2.11), and one con- linkage. There was evidence for locus heterogeneity ducted by the National Institute of Mental Health in the 12 families, and ~30% to 35% of the families Genetics Initiative Bipolar Disorder, which gave a were hypothesized to be linked to this locus. When maximum nonparametric lod score of 2.7, also using the apparent genetic heterogeneity was accounted for a broad phenotype. 55,56 Expanded analysis of this in the analysis, the maximum lod score for the com- region strengthened the original finding, giving bined families increased to 4.1. When the families maximum lod score of 3.19 in 55 bipolar disorder were analyzed separately, one of the 12 independently pedigrees, and haplotype analysis has tentatively nar- had a maximum lod score of 4.1 and positive lod rowed the putative susceptibility region to 2.3 Mb.57 scores in the flanking markers under an autosomal As with the chromosome 18 findings, the evi- dominant model. The peak multipoint lod score in dence for a susceptibility locus on chromosome 4 is this region was 4.8. In all cases, the lod score was compelling, although not conclusive. The region on highest under the narrow phenotypic model, which chromosome 4p (4p16) provides the strongest evi- included bipolar I disorder and bipolar II disorder dence of linkage, with relatively high lod scores only. Haplotype analysis in this family identified reported by several groups, while the evidence for a seven markers that were shared by all of the individu- susceptibility locus on 4q, while intriguing, is sub- als with bipolar I disorder or bipolar II disorder, and stantially weaker. As with all of the putative suscepti- by the majority of those with recurrent major depres- bility loci for bipolar disorder, no functional sion. Extended relative pair analysis also provided mutations in any specific genes have yet been found some evidence for linkage, although this result was to be associated with bipolar disorder in this region, not statistically significant. although the investigation continues. Volume 8 – Number 12 896 CNS Spectrums – December 2003
  • 7. Review Article Chromosome 21 lod scores between 4 and 9. 67-69 Early replication The initial report of linkage to bipolar disorder on studies70 in other populations failed to produce positive chromosome 21 came from a partial genome screen results for the X chromosome. Extension and reanalysis of 47 multigenerational bipolar disorder families of the original data also failed to support the findings. completed in 1994 by Straub and colleagues58 This The most likely explanation is that, despite the high study initially gave high lod scores for 10 markers on lod scores, the initial linkage results on the X chromo- 21q22.3 in one family (the maximum lod score was some were false positives due to a number of factors, 3.41) under an autosomal dominant model, as well including some errors in G6PD diagnosis and bipolar as significant results in this region using an affected- disorder affected status, and the use of variations in pedigree-member approach. As with many of the phenotype, such as color blindness or G6PD defi- initial genetic findings in bipolar disorder, attempts ciency, rather than DNA polymorphisms as genetic to replicate this finding have been inconsistent. markers, which are more informative and less likely to Early attempts to strengthen the finding by adding result in missed recombinations. other families to the sample significantly diminished Interest in the X chromosome as a potential region evidence for this finding rather than enhancing it. of linkage for bipolar disorder has continued, despite A replication study59 by the same group in an addi- the revision of the findings of the early studies. At tional 40 families reported a peak heterogeneity lod least two groups 71-73 have reported linkage to score of 3.35, with 50% of the families studied con- Xq24–27, with a maximum lod score of 3.9 reported tributing to the linkage results, and a subsequent fol- in one bipolar disorder family. These reports have not low-up study using additional pedigrees and a denser been replicated, despite attempts by other groups, and marker map resulted in a two-point lod score of 3.56,60 although these findings may be true linkages in the Other studies examining this region have been families reported, genetic epidemiologic studies sug- equivocal. There have been two reports61,62 of excess gest that X-linked inheritance is not a major mode of allele sharing among individuals with bipolar disor- transmission in the majority of bipolar families.74-76 der on chromosome 21, as well as studies 53-65 that have found no evidence for linkage to bipolar disor- der in this region. In a study by Smyth and col- leagues,62 a two-locus admixture model was used that 18p11.32 18p11.31 incorporated potential linkage effects from both the chromosome 21q locus and the tyrosine hydroxylase 18p11.2 gene located on chromosome 11p15. Under this admixture model, the maximum lod score for 21q was 3.87, suggesting that in some, but not all, of the 18q11.2 families studied, a gene(s) in the 21q region might 18q12.1 have an influence on bipolar disorder susceptibility. 18q12.2 The chromosome 21q findings, while interesting, are 18q12.3 clearly weaker than the findings for chromosomes 18 18q21.1 and 4. The majority of the evidence for this region 18q21.2 comes from the work of one laboratory—the evi- 18q21.3 dence for linkage to 21q in other samples has been 18q22 weak or negative, making interpretation of the link- age results in this region difficult. 18q23 Other regions of interest for bipolar disorder have included the X chromosome, chromosome 5q, and chromosome 8p, among others. In one of the first stud- ies66 ever to report positive linkage findings for bipolar FIGURE. Representative Human Chromosome disorder, investigators noted that in several families, The short segment (top) is called the p arm and the bipolar disorder and other affective disorders appeared longer segment is called the q arm. These arms are to be inherited in an X-linked fashion, and that these separated by the centromere, represented here by an disorders appeared to co-segregate with color blindness “X.” Dark and light regions represent banding regions and glucose-6-phosphate sehydrogenase (G6PD) defi- and are identified by numbers that indicate the relative physical location along the chromosome. ciency, which map to the X chromosome. Initial link- Mathews CA, Reus VI. CNS Spectr. Vol 8, No 12. 2003. age studies of the X chromosome in these families gave Volume 8 – Number 12 897 CNS Spectrums – December 2003
  • 8. Review Article Chromosome 5q has for several years been an area Rica.84-85 In the study with the strongest evidence, by of interest for schizophrenia genetics, and recently Cichon and colleagues,84 two regions on chromo- has been shown to potentially be linked to bipolar some 8 were identified, one on 8q and one on 8p. disorder as well.58,77-79 Association or linkage for bipo- The region on chromosome 8q had the highest two- lar disorder has been identified on 5q31–33 in three point lod score in the genome screen (3.62), genetically isolated populations, including in two, although two markers on chromosome 8p also had large extended families from Costa Rica and the relatively high lod scores (2.3 and 1.67). Somewhat Saguenay-Lac-St.-Jean region of Quebec, as well as in weaker evidence for linkage has also come from one bipolar disorder cases from Japan.80-83 Linkage results other study,55 where the maximum lod score in the from a genome screen of a large bipolar disorder pedi- 8q region was 2.39. In the study from the genetically gree in the Central Valley of Costa Rica population isolated population of the Central Valley of Costa identified 5q31–32 as a region of interest (in addition Rica, 109 parent-offspring trios were genotyped to the 18q region) using a nonparametric approach using a dense genome screen, and evidence for link- (Markov chain Monte Carlo analysis) that was able age tested on chromosome 8p12–21, and an overrep- to accommodate the size and complexity of the pedi- resented three-marker haplotype, or shared segment gree, which had several inbreeding loops. Initial link- was also identified in this region. Chromosome 8p age results and follow-up analysis showed significant has also been reported to be associated with schizo- identity-by-descent allele sharing on 5q31–33, with phrenia in a number of studies, including one study the majority of affected individuals sharing a single in Iceland, another genetically isolated population, 15 cM haplotype.81 Given the haplotype distribution and one in the Central Valley of Costa Rica, suggest- pattern for the 5q and the 18q regions, the authors ing that this region (8p) may be more likely to harbor conclude that the majority of the risk to bipolar dis- susceptibility loci for psychotic syndromes in general, order in this large pedigree, at least, is due to loci in or may represent a severity locus, rather than being these two regions.81 A second pedigree analysis82 that specific to bipolar disorder.86-90 took advantage of the genetic homogeneity present A number of other chromosomal regions have in a population isolate, this time using a large family been identified through complete genome screens as from Quebec, also identified the distal portion of 5q potential areas of interest for bipolar disorder. These as the site of a potential susceptibility locus for bipo- include (but are not necessarily limited to) chromo- lar disorder. In this study,82 in which 42 individuals somes 22q11-3, 6pter-p24, 13q13, and 15q11-qter.91-93 had bipolar I disorder or schizoaffective disorder- The majority of these regions have only been identi- manic type, and 5 had bipolar, a maximum paramet- fied in one study sample or genome screen,91 however, ric lod score of 2.15 was found on 5q, with a and confirmation or exclusion of these regions as maximum nonparametric lod scores of 3.41 at the potentially harboring susceptibility loci awaits the same marker. Power analyses suggested that the pedi- results of replication studies. gree had insufficient power to overcome the intra- pedigree heterogeneity that was suggested by the high THE USE OF ISOLATED POPULATIONS variability in lod scores between branches of this fam- Successful genetic mapping of complex disorders ily, making future directions for this finding unclear. requires addressing multiple complicating factors, In the third study,83 markers in the 5-HT4 receptor including incomplete penetrance, phenocopies, locus gene located at 5q32 were tested in 53 Japanese heterogeneity, polygenic inheritance, and multifacto- patients with bipolar disorder and 187 controls. Weak rial inheritance, which can act to decrease the likeli- association between these markers and bipolar disor- hood that a causative gene will be identified by der was identified, both at the individual marker level increasing sample heterogeneity. For this reason, and for a haplotype of the markers (P=.002). A fol- strategies that decrease potential heterogeneity have low-up study83 in trios from the National Institute of become very important in genetic mapping studies of Mental Health Bipolar Genetics Initiative provided bipolar disorder. Traditional approaches, such as pedi- some support for this association when a narrow bipo- gree studies, have one important limitation for the lar disorder phenotype was used (P=.009). study of complex traits. Because of smaller family sizes Interest in chromosome 8 is relatively recent, and in modern industrialized countries, the collection of a is based on the findings from two complete genome sample with sufficient power to detect linkage often screens, one in 75 bipolar disorder families of requires the collection of multiple small families, German, Israeli, and Italian origin, and one in unre- increasing the risk of including probands with differ- lated family trios from the Central Valley of Costa ent genetic backgrounds in the study. One way to Volume 8 – Number 12 898 CNS Spectrums – December 2003
  • 9. Review Article decrease genetic heterogeneity is to use population and/or association studies (either family-based or isolates, which have a potential advantage because case-control studies) can be used, both for initial they are descended from a small number of original genome screens, and for fine-mapping efforts.94 founders.94 Over time, recombination across the gen- Genetic investigations of bipolar disorder have erations will gradually diminish the length of the been carried out in several genetic isolates, includ- chromosomal regions that are shared identical-by- ing the Old Order Amish, the Central Valley of descent from a common founder, and most current- Costa Rica, the French-Canadian population of day individuals will share very little of the genome. Quebec, Finland, and the Faroe Islands, to name Individuals who share a common trait or disease in only a few.32-35,47,73,85,93,95-100 Some of these studies have such a population may have inherited the same sus- been complete genome screens (the Old Order ceptibility allele and are, therefore, more likely than Amish, the Central Valley of Costa Rica, Finland, random individuals in the population to share marker Quebec), and some have been follow-up studies of alleles that are in linkage disequilibrium with the sus- other reported findings (eg, the Faroe Islands). ceptibility allele. In recently founded isolates, such as Such studies have made important contributions to the Central Valley of Costa Rica, these affected indi- field of bipolar disorder genetics. Studies in Costa viduals may be <20 generations removed from their Rica’s Central Valley have provided much of the common ancestors, and they may demonstrate link- evidence of genetic linkage to bipolar disorder on age disequilibrium for sizable genomic segments chromosomes 18, for example, while studies in around disease susceptibility genes. In older popula- Finland provide the most recent evidence for tions, such as Finland, the size of the shared segment genetic linkage to bipolar disorder on the X chro- is expected to be significantly smaller. In genetically mosome.32-35,47,73,85 Other population isolates, such as isolated populations, traditional pedigree studies the Antioquia region of Columbia101 and the Azores TABLE. MAJOR REGIONS OF LINKAGE FOR BIPOLAR DISORDER* Chromosomal Region Research/Collaborative Groups Berrettini et al26 Stine et al28 Freimer et al32 Coon et al36 18p 2.32 1.45 1.43 (SH) 18q 3.11 4.06 (SH) 2.6 Blackwood et al50 Ewald et al51 Nothen et al52 4p 4.8 2.0 (81% sharing for ASP) NIMH Genetics Initiative Adams et al54 DANA consortium55 (Willour et al)56 4q 3.19 2.1 2.7 Straub et al58 Smyth et al62 21q 3.35 3.87 Mendlewicz et al71 Pekkarinen et al73 Xq 3.1 3.9 NIMH Genetics Initiative Hong et al80 Shink et al82 Ohtsuki83 (Shink et al)82 5q SH (P=.003–.01) 3.41 P=.002 P=.009 Cichon et al84 Ophoff et al85 Friddle et al55 8p 2.3 8q 3.6 SH (P=.00005) 2.39 * Highest reported multipoint lod scores or P values for a particular research group or consortium are reported. SH=shared haplotype; ASP=affected sibling pairs; NIMH=National Institute of Mental Health. Mathews CA, Reus VI. CNS Spectr. Vol 8, No 12. 2003. Volume 8 – Number 12 899 CNS Spectrums – December 2003
  • 10. Review Article Islands off the coast of Portugal,102 are also under ENDOPHENOTYPES investigation for their use in genetic studies of The genetic studies of bipolar disorder in the bipolar disorder. Amish illustrate many of the inherent difficulties of doing genetic analysis in complex disorders. The ANIMAL MODELS Amish10,41 appear to be a perfect population for doing Although animal models have historically been bipolar disorder genetic studies; they are an isolated used to further our understanding of the etiology population with known genealogies, clean pheno- and pathophysiology of complex disorders and to types with little comorbidity, and large extended fam- inform genetic studies, designing an appropriate ani- ilies. Linkage findings for bipolar disorder in this mal model for bipolar disorder is complicated by the group have so far been inconsistent and/or contradic- fact that the majority of symptoms are changes in tory, and even in this ideal population no evidence emotional or cognitive state. Most animal models of for linkage has withstood attempts at confirmation or bipolar disorder have focused on easily quantifiable replication. The failure to identify unequivocal sus- behavioral traits that are often associated with ceptibility loci for bipolar disorder may be due to mania, primarily hyperactivity and arousal, with the genetic heterogeneity, or it may reflect uncertainty idea that manic states are pathognomonic for bipo- about the “true” affected phenotype. There is signifi- lar disorder.103 Although not perfect, drug-induced cant symptom overlap between bipolar disorder and hyperactivity states in rodents have been shown to other affective and psychotic disorders, as well as dis- respond to treatment with lithium, neuroleptics, or agreement about the degree of relationship between cholinergic agonists. This suggests that they are rea- these disorders. One recent study106 using monozy- sonable models for mania. 103 Administration of gotic and diazygotic twins with bipolar disorder, schiz- amphetamine, which acts as a dopamine agonist, ophrenia, or schizoaffective disorder suggests that increases locomotion and aggression, and causes there is genetic overlap between these syndromes. stereotyped behaviors, such as sniffing, and an This study found that bipolar disorder and schizo- increased startle response in rats is one way of phrenia had evidence of both syndrome-specific and inducing hyperactivity. Morphine administration, 5- shared genetic components, and that all of the HT depletion using parachlorophenylalanine, and genetic contribution for schizoaffective disorder brain lesions in various anatomic structures, includ- appeared to be shared with the other two syndromes. ing the hippocampus, frontal cortex, globus pallidus, Because of the problems in identifying susceptibil- ventral tegmentum, and a number of others have ity genes for bipolar disorder, some investigators have also been used.103 Taken together, these models indi- suggested the use of endophenotypes, which may cate that activation of either the dopaminergic or have more straightforward inheritance patterns, to the serotonergic systems results in an increase in further inform the genetic studies of bipolar disor- locomotor activity and arousal, both fundamental der.107 Endophenotypes traditionally include bio- characteristics of mania. The major problem with chemical or pathologic disease changes, such as the hyperactivity-related animal models is that they all presence of neurofibrillary tangles in Alzheimer’s dis- produce chronic changes rather than cyclical ease; serum or cerebrospinal fluid levels of metabo- changes in rodents, making their relevance to bipo- lites; hormones; or trophic factors, such as insulin lar disorder somewhat limited. levels in diabetes; and biophysical markers, such as Other animal models that have been proposed abnormalities in responses to evoked potentials in for bipolar disorder focus more on the cyclic nature schizophrenia. Analyzing endophenotypes has been a of the disorder. These include changes in circadian useful strategy in identifying susceptibility genes for rhythm, including the rhythms of activity and rest other complex disorders, most notably the long QT that occur in all mammals, as well as the cyclical syndrome, where, because the inheritance patterns of rhythm of rest and hyperactivity that occurs when the syndrome itself were complex, a specific electro- an animal is placed in a novel environment or sub- cardiogram finding that appeared to have a more jected to endocrine alterations, such as thyroidec- straightforward inheritance pattern was used as the tomy. 104,105 Although animal models of these phenotype of interest.107 A variety of approaches for paradigms are scarce, the cyclicity seen when an endophenotyping bipolar disorder have been sug- animal is placed in a novel environment has been gested, including the use of abnormal biochemical, studied, and both the amplitude and the frequency neuroanatomic, neurophysiologic, or neurocognitive of the cycles have been shown to be reduced by changes associated with bipolar disorder or identified administration of lithium.103-105 from animal models of bipolar disorder. Other Volume 8 – Number 12 900 CNS Spectrums – December 2003
  • 11. Review Article 3. Andreasen NC, Rice J, Endicott J, Coryell W, Grove WM, Reich options include subgrouping by genetic epidemiology T. Familial rates of affective disorder. A report from the national (family history, maternal or paternal inheritance), Institute of Mental Health Collaborative Study. Arch Gen treatment response, symptom severity, or the pres- Psychiatry. 1987;44:461-469. ence of comorbid disorders, such as panic disor- 4. Mendlewicz J, Rainer JD. Adoption study supporting genetic trans- der. 107,108 Some of these approaches have been mission in manic-depressive illness. Nature. 1977;268:327-329. attempted, with little success to date, while others are 5. Allen MG, Cohen S, Pollin W, Greenspan SI. Affective illness in vet- still being explored. Some of the more promising eran twins: a diagnostic review. Am J Psychiatry. 1974;131:1234-1239. endophenotype studies include linkage analysis of 6. Bertelsen A, Harvald B, Hauge M. A Danish twin study of manic- depressive disorders (22 monozygotic and 27 dizygotic twin pairs). clinical response to lithium treatment, sensitivity to Br J Psychiatry. 1977;130:330-351. cholinergic activity (cholinergic agents can cause 7. Kendler KS, Pedersen N, Johnson L, Neale MC, Mathe AA. depression, while anticholinergic agents can trigger A pilot Swedish twin study of affective illness, including hospital- mania), sensitivity to psychostimulants, rapid eye and population-ascertained subsamples. Arch Gen Psychiatry. movement sleep latency, and the presence of white 1993;50:699-700. matter hyperintensities, all of which are correlated 8. Cardno AG, Marshall EJ, Coid B, et al. Heritability estimates for with bipolar disorder and are thought or known to psychotic disorders: the Maudsley twin psychosis series. Arch Gen segregate within families.105-108 Psychiatry. 1999;56:162-168. 9. Rice J, Reich T, Andreasen NC, et al. The familial transmission of bipolar illness. Arch Gen Psychiatry. 1987;44:441-447. CONCLUSION 10. Pauls DL, Bailey JN, Carter AS, Allen CR, Egeland JA. Complex Bipolar disorder genetics is in the process of enter- segregation analyses of old order Amish families ascertained ing a new phase. Multiple genome screens and follow- through bipolar I individuals. Am J Med Genet. 1995;60:290-297. up studies have identified a number of genomic 11. Spence MA, Flodman PL, Sadovnick AD, Bailey-Wilson JE, regions of interest. The difficulty in interpreting the Ameli H, Remick RA. Bipolar disorder: evidence for a major often contrasting results of the existing genetic studies locus. Am J Med Genet. 1995;60:370-376. points to the importance of replication; carefully fol- 12. Goldin LR, Gershon ES, Targum SD, Sparkes RS, McGinniss M. lowing up isolated positive results by examining flank- Segregation and linkage analyses in families of patients with bipo- lar, unipolar, and schizoaffective mood disorders. Am J Hum ing markers, adding new families or affected Genet. 1983;35:274-287. individuals, and replication of significant or near sig- 13. Bucher KD, Elston RC, Green R, et al. The transmission of manic nificant results in an independent sample are all cru- depressive illness—II. Segregation analysis of three sets of family cial. Despite the uncertainties and contradictions data. J Psychiatr Res. 1981;16:65-78. inherent in these studies, however, taken together, the 14. Lander E, Kruglyak L. Genetic dissection of complex traits: guide- genetic studies of bipolar disorder indicate significant lines for interpreting and reporting linkage results. Nat Genet. progress in identifying potential susceptibility genes 1995;11:241-247. for this disorder. It is likely that at least some of the 15. Potash JB, DePaulo JR Jr. Searching high and low: a review of the genetics of bipolar disorder. Bipolar Disord. 2000:2:8-26. susceptibility loci initially identified for bipolar disor- 16. Mundo E, Walker M, Cate T, Macciardi F, Kennedy JL. The role der will be found to overlap, acting in concert with of serotonin transporter protein gene in antidepressant-induced other genetic and/or environmental influences to pro- mania in bipolar disorder: preliminary findings. Arch Gen duce not only bipolar disorder, but other affective or Psychiatry. 2001;58:539-544. psychotic disorders, as may be the case for genes 17. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and within the chromosome 18p and 8p regions. It is also trkB mRNA in rat brain by chronic electroconvulsive seizure and possible that some of the genes thus identified will be antidepressant drug treatments. J Neurosci. 1995;15:7539-7547. involved in causing a variety of symptom patterns and 18. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and gluco- neuropsychiatric syndromes, rather than being unique corticoids affect the expression of brain-derived neurotrophic fac- tor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. to a particular disorder. Given the current pace of 1995;15:1768-1777. progress, it is reasonable to expect that in the next few 19. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, decades much of the genetic etiology of bipolar disor- Kennedy JL. The brain-derived neurotrophic factor gene confers der and related disorders will be understood. CNS susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet. 2002;71:651-655. REFERENCES 20. Sklar P, Gabriel SB, McInnis MG, et al. Family-based association 1. Craddock N, Khodel V, Van EP, Reich T. Mathematical limits of study of 76 candidate genes in bipolar disorder: BDNF is a poten- multilocus models: the genetic transmission of bipolar disorder. Am tial risk locus. Brain-derived neutrophic factor. Mol Psychiatry. J Hum Genet. 1995;57:690-702. 2002;7:579-593. 2. Gershon ES, Hamovit J, Guroff JJ, et al. A family study of schizoaf- 21. Nakata K, Ujike H, Sakai A, et al. Association study of the brain- fective, bipolar I, bipolar II, unipolar, and normal control probands. derived neurotrophic factor (BDNF) gene with bipolar disorder. Arch Gen Psychiatry. 1982;39:1157-1167. Neurosci Lett. 2003;337:17-20. Volume 8 – Number 12 901 CNS Spectrums – December 2003
  • 12. Review Article 22. Elvidge G, Jones I, McCandless F, Asherson P, Owen MJ, 39. Detera-Wadleigh SD, Badner JA, Yoshikawa T, et al. Initial Craddock N. Allelic variation of a BalI polymorphism in the genome scan of the NIMH genetics initiative bipolar pedigrees: DRD3 gene does not influence susceptibility to bipolar disorder: chromosomes 4, 7, 9, 18, 19, 20, and 21q. Am J Med Genet. results of analysis and meta-analysis. Am J Med Genet. 1997;74:254-262. 2001;105:307-311. 40. Maier W, Hallmayer J, Zill P, et al. Linkage analysis between peri- 23. Furlong RA, Rubinsztein JS, Ho L, et al. Analysis and metaanaly- centrometric markers on chromosome 18 and bipolar disorder: a sis of two polymorphisms within the tyrosine hydroxylase gene in replication test. Psychiatry Res. 1995;59:7-15. bipolar and unipolar affective disorders. Am J Med Genet. 41. Pauls DL, Ott J, Paul SM, et al. Linkage analyses of chromosome 1999;88:88-94. 18 markers do not identify a major susceptibility locus for bipolar 24. Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel, ES, affective disorder in the Old Order Amish. Am J Hum Genet. Rubinsztein JS. Analysis of the monoamine oxidase A (MAOA) 1995;57:636-643. gene in bipolar affective disorder by association studies, meta- 42. Knowles JA, Rao PA, Cox-Matise T, et al. No evidence for signif- analyses, and sequencing of the promoter. Am J Med Genet. icant linkage between bipolar affective disorder and chromosome 1999;88:398-406. 18 pericentromeric markers in a large series of multiplex extended 25. Furlong RA, Ho L, Walsh C, et al. Analysis and meta-analysis of pedigrees. Am J Hum Genet. 1998;62:916-924. two serotonin transporter gene polymorphisms in bipolar and 43. Mynett-Johnson LA, Murphy VE, Manley P, Shields DC, unipolar affective disorders. Am J Med Genet. 1998;81:58-63. McKeon P. Lack of evidence for a major locus for bipolar disorder 26. Berrettini WH, Ferraro TN, Goldin LR, et al. Chromosome 18 in the pericentromeric region of chromosome 18 in Irish pedi- DNA markers and manic-depressive illness: evidence for a suscep- grees. Biol Psychiatry. 1997;42:486-494. tibility gene. Proc Natl Acad Sci U S A. 1994;91:5918-5921. 44. Claes S, Raeymaekers P, Van den Broeck M, et al. A chromosome 27. Detera-Wadleigh SD, Badner JA, Berrettini WH, et al. A high- 18 genetic linkage study in three large Belgian pedigrees with density genome scan detects evidence for a bipolar-disorder sus- bipolar disorder. J Affect Disord. 1997;43:195-205. ceptibility locus on 13q32 and other potential loci on 1q32 and 45. Kalsi G, Smyth C, Brynjolfsson J, et al. Linkage analysis of manic 18p11.2. Proc Natl Acad Sci U S A. 1999;96:5604-5609. depression (bipolar affective disorder) in Icelandic and British 28. Stine OC, Xu J, Koskela R McMahon FJ, et al. Evidence for link- kindreds using markers on the short arm of chromosome 18. Hum age of bipolar disorder to chromosome 18 with a parent-of-origin Hered. 1997;47:268-278. effect. Am J Hum Genet. 1995;57;1384-1394. 46. Dorr DA, Rice JP, Armstrong C, Reich T, Blehar M. A meta- 29. Gershon ES, Badner JA, Detera-Wadleigh SD, Ferraro TN, analysis of chromosome 18 linkage data for bipolar illness. Genet Berrettini WH. Maternal inheritance and chromosome 18 allele Epidemiol. 1997;14:617-622. sharing in unilineal bipolar illness pedigrees. Am J Med Genet. 47. McInnes LA, Service SK, Reus VI, et al. Fine-scale mapping of a 1996;67:202-207. locus for severe bipolar mood disorder on chromosome 18p11.3 in 30. Nothen MM, Cichon S, Rohleder H, et al. Evaluation of linkage the Costa Rican population. Proc Natl Acad Sci U S A. of bipolar affective disorder to chromosome 18 in a sample of 57 2001;98:11485-11490. German families. Mol Psychiatry. 1999;4:76-84. 48. Yoshikawa T, Turner G, Esterling LE, Sanders AR, Detera- 31. McMahon FJ, Hopkins PJ, Xu J, et al. Linkage of bipolar affective Wadleigh SD. A novel human myo-inositol monophosphatase disorder to chromosome 18 markers in a new pedigree series. Am J gene, IMP.18p, maps to a susceptibility region for bipolar disorder. Hum Genet. 1997;61:1397-1404. Mol Psychiatry. 1997; 2:393-397. 32. Freimer NB, Reus VI, Escamilla MA, et al. Genetic mapping 49. Rojas K, Liang L, Johnson EI, Berrettini WH, Overhauser J. using haplotype, association and linkage methods suggests a locus Identification of candidate genes for psychiatric disorders on for severe bipolar disorder (BPI) at 18q22-q23. Nat Genet. 18p11. Mol Psychiatry. 2000;5:389-395. 1996;12:436-441. 50. Blackwood DH, He L, Morris SW, et al. A locus for bipolar affec- 33. McInnes LA, Escamilla MA, Service SK, et al. A complete genome tive disorder on chromosome 4p. Nat Genet. 1996;12:427-430. screen for genes predisposing to severe bipolar disorder in two Costa 51. Ewald H, Degn B, Mors O, Kruse TA. Support for the possible Rican pedigrees. Proc Natl Acad Sci U S A. 1996;93:13060-13065. locus on chromosome 4p16 for bipolar affective disorder. Mol 34. Escamilla MA, McInnes LA, Service SK, et al. Genome screening Psychiatry. 1998;3:442-448. for linkage disequilibrium in a Costa Rican sample of patients 52. Nothen MM, Cichon S, Franzek E, et al. Systematic search for with bipolar-I disorder: a follow-up study on chromosome 18. Am susceptibility genes for bipolar disorder [abstract]. Am J Hum J Med Genet. 2001;105:207-213. Genet. 1997;61:1679. 35. Escamilla MA, McInnes LA, Spesny M, et al. Assessing the feasi- 53. Evans KL, Le Hellard S, Morris SW, et al. A 6.9-Mb high-resolu- bility of linkage disequilibrium methods for mapping complex tion BAC/PAC contig of human 4p15.3-p16.1, a candidate region traits: an initial screen for bipolar disorder loci on chromosome 18. for bipolar affective disorder. Genomics. 2001;71:315-323. Am J Hum Genet. 1999;64:1670-1678. 54. Adams LJ, Mitchell PB, Fielder SL, et al. A susceptibility locus for 36. Coon H, Hoff M, Holik J, et al. Analysis of chromosome 18 DNA bipolar affective disorder on chromosome 4q35. Am J Hum Genet. markers in multiplex pedigrees with manic depression. Biol 1998;62:1084-1091. Psychiatry. 1996;39:689-696. 55. Friddle C, Koskela R, Ranade K, et al. Full-genome scan for link- 37. De bruyn A, Souery D, Mendelbaum K, Mendlewicz J, Van age in 50 families segregating the bipolar affective disease pheno- Broeckhoven C. Linkage analysis of families with bipolar illness type. Am J Hum Genet 2000;66:205-215. and chromosome 18 markers. Biol Psychiatry. 1996;39:679-688. 56. Willour VL, Zandi PP, Gershon ES, et al. Genome scan on fifty- 38. Ewald H, Mors O, Koed K, Eiberg H, Kruse TA. Susceptibility loci six multiplex bipolar pedigrees collected by the NIMH genetics for bipolar affective disorder on chromosome 18? A review and a initiative (bipolar disorder) [abstract]. Am J Med Genet. study of Danish families. Psychiatr Genet. 1997;7:1-12. 2001;105:608. Volume 8 – Number 12 902 CNS Spectrums – December 2003
  • 13. Review Article 57. Badenhop RF, Moses MJ, Scimone A, et al. Genetic refinement 76. Hebebrand J. A critical appraisal of X-linked bipolar illness. and physical mapping of a 2.3 Mb probable disease region associ- Evidence for the assumed mode of inheritance is lacking [see com- ated with a bipolar affective disorder susceptibility locus on chro- ments]. Br J Psychiatry. 1992;160:7-11. mosome 4q35. Am J Med Genet. 2003;117B:23-32. 77. Schwab SG, Eckstein GN, Hallmayer J, et al. Evidence suggestive 58. Straub RE, Lehner T, Luo Y, et al. A possible vulnerability locus of a locus on chromosome 5q31 contributing to susceptibility for for bipolar affective disorder on chromosome 21q22.3. Nat Genet. schizophrenia in German and Israeli families by multipoint affect- 1994;8:291-296. ed sib-pair linkage analysis. Mol Psychiatry. 1997;2:156-160. 59. Aita VM, Liu J, Knowles JA, et al. A comprehensive linkage 78. Gurling HM, Kalsi G, Brynjolfson J, et al. Genomewide genetic link- analysis of chromosome 21q22 supports prior evidence for a puta- age analysis confirms the presence of susceptibility loci for schizo- tive bipolar affective disorder locus. Am J Hum Genet. phrenia on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides 1999;64:210-217. support for linkage to schizophrenia on chromosomes 11q23.3-24 60. Liu J, Juo SH, Terwilliger JD, et al. A follow-up linkage study sup- and 20q12.1-11.23. Am J Hum Genet. 2001;68:661-673. ports evidence for a bipolar affective disorder locus on chromo- 79. Paunio T, Ekelund J, Variol T, et al. Genome-wide scan in a some 21q22. Am J Med Genet. 2001;105:189-194. nationwide study sample for schizophrenia families in Finland 61. Detera-Wadleigh SD, Badner JA, Goldin LR, et al. Affected-sib- reveals susceptibility loci on chromosomes 2q and 5q. Hum Mol pair analyses reveal support of prior evidence for a susceptibility Genet. 2001;10:3037-3048. locus for bipolar disorder on 21q. Am J Hum Genet. 80. Garner C, McInnes LA, Service SK, et al. Linkage analysis of a 1996;58:1279-1285. complex pedigree with severe bipolar disorder, using a Markov 62. Smyth C, Kalsi G, Curtis D, et al. Two-locus admixture linkage chain Monte Carlo method. Am J Hum Genet. 2001;68:1061- analysis of bipolar and unipolar affective disorder supports the 1064. presence of susceptibility loci on chromosomes 11p15 and 21q22. 81. Hong KS, McInnes LA, Service SK, et al. Genetic mapping using Genomics. 1997;39:271-278. haplotype and a model-free linkage analysis supports previous evi- 63. Kwok JB, Adams LJ, Salmon JA, Donald JA, Mitchell PB, dence for a locus predisposing to severe bipolar disorder at 5q31- Schofield PR. Nonparametric simulation-based statistical analyses 33. Am J Med Genet. In press. for bipolar affective disorder locus on chromosome 21q22.3. Am J 82. Shink E, Morissette J, Villeneuve A, et al. Support for the pres- Med Genet. 1999;88:99-102. ence of bipolar disorder susceptibility loci on chromosome 5: het- 64. Ewald H, Eiberg H, Mors O, Flint T, Kruse TA. Linkage study erogeneity in a homogeneous population in Quebec. Prog between manic-depressive illness and chromosome 21. Am J Med Neuropsychopharmacol Biol Psychiatry. 2002;26:1273-1277. Genet. 1996;67:218-224. 83. Ohtsuki T, Ishiguro H, Detera-Wadleigh SD, et al. Association 65. Byerley W, Holik J, Hoff M, Coon H. Search for a gene predispos- between serotonin 4 receptor gene polymorphisms and bipolar dis- ing to manic-depression on chromosome 21. Am J Med Genet. order in Japanese case-control samples and the NIMH Genetics 1995;60:231-233. Initiative Bipolar Pedigrees. Mol Psychiatry. 2002;7:954-961. 66. Mendlewicz J, Fleiss JL. Linkage studies with X-chromosome 84. Cichon S, Schumacher J, Muller DJ, et al. A genome screen for markers in bipolar (manic-depressives) and unipolar (depressive) genes predisposing to bipolar affective disorder detects a new sus- illnessess. Biol Psychiatry. 1974;9:261-294. ceptibility locus on 8q. Hum Mol Genet. 2001;10:2933-2944. 67. Mendlewicz J, Linkowski P, Guroff JJ, Van Praag HM. Color 85. Ophoff RA, Escamilla MA, Service SK, et al. Genomewide link- blindness linkage to bipolar manic-depressive illness. New evi- age disequilibrium mapping of severe bipolar disorder in a popula- dence. Arch Gen Psychiatry. 1979;36:1442-1447. tion isolate. Am J Hum Genet. 2002;71:565-574. 68. Mendlewicz J, Linkowski P, Wilmotte J. Linkage between glucose- 86. Blaveri E, Kalsi G, Lawrence J, et al. Genetic association studies of 6-phosphate dehydrogenase deficiency and manic-depressive psy- schizophrenia using the 8p21-22 genes: prepronociceptin chosis. Br J Psychiatry. 1980;137:337-342. (PNOC), neuronal nicotinic cholinergic receptor alpha polypep- 69. Baron M, Risch N, Hamburger R, et al. Genetic linkage between tide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1). X-chromosome markers and bipolar affective illness. Nature. Eur J Hum Genet. 2001;9:469-472. 1987;326:289-292. 87. Blouin JL, Dombroski BA, Nath SK, et al. Schizophrenia suscep- 70. Baron M, Freimer NF, Risch N, et al. Diminished support for link- tibility loci on chromosomes 13q32 and 8p21. Nat Genet. age between manic depressive illness and X-chromosome markers 1998;20:70-73. in three Israeli pedigrees. Nat Genet. 1993;3:49-55. 88. Stefansson H, Sigurdsson E, Steinthorsdottir V, et al. Neuregulin 1 71. Mendlewicz J, Simon P, Sevy S, et al. Polymorphic DNA marker on and susceptibility to schizophrenia. Am J Hum Genet. X chromosome and manic depression. Lancet 1987;1:1230-1232. 2002;71:877-892. 72. Lucotte G, Landoulsi A, Berriche S, David F, Babron MC. Manic 89. DeLisi LE, Mesen A, Rodriguez C, et al. Genome-wide scan for depressive illness is linked to factor IX in a French pedigree. Ann linkage to schizophrenia in a Spanish-origin cohort from Costa Genet. 1992;35:93-95. Rica. Am J Med Genet. 2002;114:497-508. 73. Pekkarinen P, Terwilliger J, Bredbacka PE, Lonnqvist J, Peltonen L. 90. Lachman HM, Kelsoe JR, Remick RA, et al. Linkage studies suggest a Evidence of a predisposing locus to bipolar disorder on Xq24-q27.1 possible locus for bipolar disorder near the velo-cardio-facial syn- in an extended Finnish pedigree. Genome Res. 1995;5:105-115. drome region on chromosome 22. Am J Med Genet. 1997;74:121-128. 74. Gejman PV, Detera-Wadleigh S, Martinez MM, et al. Manic 91. Kelsoe JR, Spence MA, Loetscher E, et al. A genome survey indi- depressive illness not linked to factor IX region in an independent cates a possible susceptibility locus for bipolar disorder on chromo- series of pedigrees. Genomics. 1990;8:648-655. some 22. Proc Natl Acad Sci U S A. 2001;98:585-590. 75. Vallada HP, Vasques L, Curtis D et al. Linkage analysis between 92. Ginns EI, Ott J, Egeland JA, et al. A genome-wide search for chro- bipolar affective disorder and markers on chromosome X. Psychiatr mosomal loci linked to bipolar affective disorder in the Old Order Genet. 1998;8:183-186. Amish. Nat Genet. 1996;12:431-435. Volume 8 – Number 12 903 CNS Spectrums – December 2003
  • 14. Review Article 93. Escamilla MA. Population isolates: their special value for locating 100. Ospina-Duque J, Duque C, Carvajal-Carmona L, et al. An associa- genes for bipolar disorder. Bipolar Disord. 2001:3:299-317. tion study of bipolar mood disorder (type I) with the 5-HTTLPR 94. Morissette J, Villeneuve A, Bordeleau L, et al. Genome-wide search serotonin transporter polymorphism in a human population isolate for linkage of bipolar affective disorders in a very large pedigree from Colombia. Neurosci Lett. 2000;292:199-202. derived from a homogeneous population in Quebec points to a 101. Goodwin FK, Jamison KR. Manic Depressive Illness. New York, NY: locus of major effect on chromosome 12q23-q24. Am J Med Genet. Oxford University Press; 1990:402-405. 1999;88:567-587. 102. Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A 95. Ewald H, Wang AG, Vang M, et al. A haplotype-based study of twin study of genetic relationships between psychotic symptoms. lithium responding patients with bipolar affective disorder on the Am J Psychiatry. 2002;159:539-545. Faroe Islands. Psychiatr Genet. 1999;9:23-34. 103. Lenox RH, Gould TG, Manji HK. Endophenotypes in bipolar dis- order. Am J Med Genet. 2002:114:391-406. 96. Degn B, Lundorf MD, Wang A, et al. Further evidence for a bipolar 104. Schull J, McEachron DL, Adler NT, et al. Effects of thyroidectomy, risk gene on chromosome 12q24 suggested by investigation of hap- parathyroidectomy and lithium on circadian wheelrunning in rats. lotype sharing and allelic association in patients from the Faroe Physiol Behav. 1988;42:33-39. Islands. Mol Psychiatry. 2001;6:450-455. 105. Bauer MS, Whybrow PC. The effect of changing thyroid function 97. Jorgensen TH, Borglum AD, et al. Search for common haplotypes on cyclic affective illness in a human subject. Am J Psychiatry. on chromosome 22q in patients with schizophrenia or bipolar disor- 1986;143:633-636. der from the Faroe Islands. Am J Med Genet. 2002;114:245-252. 106. MacKinnon DF, Zandi PP, Cooper J, et al. Comorbid bipolar disor- 98. Ewald H, Flint TJ, Jorgensen TH, et al. Search for a shared segment der and panic disorder in families with a high prevalence of bipolar on chromosome 10q26 in patients with bipolar affective disorder or disorder. Am J Psychiatry. 2002;159:30-35. schizophrenia from the Faroe Islands. Am J Med Genet. 107. Grof P, Duffy A, Cavazzoni P, et al. Is response to prophylactic lithi- 2002;114:196-204. um a familial trait? J Clin Psychiatry. 2002;63:942-947. 99. Pato CN, Macedo A, Ambrosio A, et al. Detection of expansion 108. Turecki G, Grof P, Grof E, et al. Mapping susceptibility genes for regions in Portuguese bipolar families. Am J Med Genet. bipolar disorder: a pharmacogenetic approach based on excellent 2000;96:854-857. response to lithium. Mol Psychiatry. 2001;6:570-578. Bipolar Disorder Roundtable Monograph Series An Expert Panel Review of Clinical Challenges in Neurology and Psychiatry Earn up to 3 hours of free CME credit by accessing the following expert panel discussions available online soon at: Part 1: Treatment of Bipolar Depression–AVAILABLE NOW Moderator: Robert M. Post, MD Discussants: Claudia F. Baldassano, MD, and Roy H. Perlis, MD Part 2: Treatment of Bipolar Mania–AVAILABLE JANUARY 1, 2004 Moderator: Robert M. Post, MD Discussants: Melissa Delbello, MD, and Philip G. Janicak, MD Part 3: Treatment of Rapid-Cycling Bipolar Disorder–AVAILABLE FEBRUARY 1, 2004 Moderator: Robert M. Post, MD Discussants: Kiki D. Chang, MD, and Trisha Suppes, MD Supported by an educational grant from AstraZeneca Volume 8 – Number 12 904 CNS Spectrums – December 2003