Genetics of bipolar disorder s

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588 Craddock, JonesTable 2 Approximate lifetime rates of mood disorder in various classes of relative of bipolarprobandsDegree of relationship to bipolar probandRisk of bipolar disorder(%)Monozygotic co-twin 40–70 15–25First degree relative 5–10 10–20General population (ie, unrelated) 0.5–1.5 5–10(Additional) risk ofunipolar depression (%)The lifetime risk of major mood disorder in a relative is obtained by adding the risk of bipolar disorderand the risk of unipolar depression. General population lifetime risk of unipolar depressionis notoriously diYcult to quantify but the figures in the table are based on a definition of clinicallysignificant depression comparable to that used in the genetic studies.all show an increased probandwise concordancerate in monozygotic (MZ) twins whencompared with dizygotic (DZ) twins 41–46 (table1). Pooling the data from these studies providesan estimate of probandwise MZ concordancefor narrowly defined bipolar disorder of 50%(95% confidence intervals 40%-60%). However,three of the studies almost certainlyunderestimate the concordance so the true MZconcordance is likely to be >50%, probablyclose to the 60% found in the study ofBertelsen et al. 43 Longitudinal study of the oVspringof the unaVected members of discordantMZ twin pairs ascertained through a bipolarproband has shown an increase in risk of bipolarillness indistinguishable from that in theoVspring of subjects aVected by bipolardisorder. 47Studies of genetically identical subjects illustratethe phenotypic spectrum that may beassociated with bipolar susceptibility genes. Inaddition to bipolar disorder, unipolar disorder,or absence of illness, MZ co-twins or cotripletsof a bipolar proband have beendescribed who have a diagnosis of schizoaVectivedisorder 43 or (very rarely) schizophrenia. 48It should also be recognised that the incompletephenotypic concordance in MZ twins hasprovided the most robust evidence that nongeneticfactors play an important role in determiningsusceptibility to bipolar disorder.Adoption studiesOnly two adoption studies have used a modernconcept of bipolar disorder. Mendlewicz andRainer 49 investigated the biological and adoptiveparents of 29 bipolar and 22 normal adopteesand the biological parents of 31 bipolarnon-adoptees and found significantly (p<0.05)Table 3Some regions of interest from molecular genetic linkage studies of bipolar disordergreater risk of aVective disorder (bipolar,schizoaVective, and unipolar) in the biologicalparents of bipolar adoptees (18% risk) comparedwith the adoptive parents (7% risk). Thisrisk in biological relatives of bipolar adopteeswas similar to that in the biological relatives ofbipolar non-adoptees. The study of Wender etal 50 included only 10 bipolar probands butshowed a similar (but non-significant) trend forbiological relatives of probands to be atincreased risk compared with adoptive relatives.Summary of epidemiological, family,twin, and adoption studiesFamily, twin, and adoption studies provide animpressive and consistent body of evidencesupporting the existence of genes determiningpredisposition to bipolar disorder and show agradation in risk of mood disorder in relativesof bipolar probands in the order (highest tolowest risk) of: monozygotic co-twin, firstdegree relative, unrelated member of thegeneral population. Although there are manymethodological impediments to producing aconsistent quantification of risk, the figuresgiven in table 2 may be taken as an “order ofmagnitude” guide to risk in diVerent classes ofrelative 51 and, provided appropriate caveats aremade, are suitable for providing information topatients and their relatives.Chromosome studiesBipolar disorder is not consistently associatedwith chromosome abnormalities although anumber of such published reports haveappeared. 52 Perhaps the most interesting observationis that subjects with trisomy 21 appear tobe less susceptible to mania than are membersof the general population. 53 This is consistentwith the existence of a bipolar susceptibilitygene on chromosome 21, a possibility thatfinds support from recent molecular geneticstudies (see table 3).Mode of inheritanceEarly linkage studies were predicated on theassumption of single gene inheritance andattempts were made to recruit large unilinealapparently autosomal dominant pedigrees.Chromosomallocation Study reference Comment4p16 117 Single large UK pedigree with max lod = 4.8118 Single moderate size UK pedigree (schizoaVective disorder) with max lod =1.912q23-q24 119 Single UK pedigree in which Darier’s disease 120 121 and bipolar disorder cosegregate. Max lod = 2.1122 29 small-moderate UK pedigrees. Max lod = 2.0. No evidence in 16 German families123 Single very large pedigree from an isolated French Canadian community. Max lod = 4.9124 2 moderate size Danish pedigrees. Max lod = 3.418 centromeric 125 22 moderate size US pedigrees. Max non-parametric evidence p<0.0001126 28 moderate size US pedigrees (particularly those showing paternal transmission). Maxnon-parametric evidence p<0.00118q22 126 28 moderate size US pedigrees (particularly those showing paternal transmission). Max sib pairevidence p<0.00118q22-q23 127 2 large Costa Rican pedigrees. Max lod for combined linkage association = 4.0621q22 128 Single large US pedigree. Max lod = 3.4129 22 moderate size US pedigrees (particularly those showing maternal transmission). Max sib pairevidence p<0.001130 97 moderate size US pedigrees. Max sib pair evidence p<0.001131 23 UK & Icelandic pedigrees. Max lod = 2.2J Med Genet: first published as 10.1136/jmg.36.8.585 on 1 August 1999. Downloaded from http://jmg.bmj.com/ on May 17, 2021 by guest. Protected by copyright.This table illustrates some current regions of interest. Readers seeking a systematic overview of findings including both negative andpositive reports should consult Chromosome Workshop reports (see text).
Genetics of bipolar disorder 589Table 4 Complex genetic mechanisms that have beensuggested in bipolar disorderGenetic mechanismAuthorsLocus heterogeneity Hodgkinson et al 132Allelic heterogeneity Sandkuyl and Ott 133Epistasis Craddock et al 60Dynamic mutation McInnis et al 134Imprinting McMahon et al 135Mitochondrial inheritance McMahon et al 135Genetic mechanisms causing complex patterns of inheritanceand authors who have invoked the mechanisms to explain theinheritance of bipolar disorder.Although rare, a number of such pedigreeshave been identified and it seems likely that inat least some of these a single gene may play amajor role in determining disease susceptibility.Some segregation analyses on systematicallyascertained pedigree sets have producedresults consistent with single genemodels, 27 30 54 55 while others have been unableto show major locus transmission. 56–58 However,caution is required in interpreting theseresults because of the limited power of thestudies to distinguish between single gene andoligogenic models and because of the failure totake account of an important parameter, therecurrence risk in MZ cotwins of a bipolarproband. 59 The observed very rapid decrease inrecurrence risk from identical co-twins to firstdegree relatives and back to the general population(as shown in table 2) is not consistentwith single gene modes of inheritance. 60 Therecurrence risk data are consistent with epistaticinteraction of multiple genes or withmore complex genetic mechanisms. Severalgenetic mechanisms that are known to producecomplex patterns of inheritance and whichhave been suggested as possible explanationsfor bipolar disorder are shown in table 4.X LINKAGEThe idea that X linkage may explain someforms of aVective disorder goes back over half acentury 61 and has been debated vigorously overthe last 25 years because of several reports offamilies showing cosegregation between Xlinked markers (such as colour blindness orglucose-6-phosphate dehydrogenase deficiency)and bipolar disorder, suggesting thepossibility of an X linked dominant susceptibilitygene. 62–64 However, these reports have beencriticised on methodological grounds, 65particularproblems being ascertainment bias andnon-blinding to marker status. If X linkagedoes occur, analyses suggest that it can account56 66for only a minority of cases.In summary, as clinical psychiatrists are wellaware, although bipolar disorder tends toaggregate in families, the pattern of inheritancein most pedigrees is not simple. Although itseems likely that occasional families exist inwhich a single gene plays a major role in determiningsusceptibility to illness, the evidenceindicates that single gene transmission does notoccur in most cases. This observation isconsistent with the failure to identify genes ofmajor eVect in linkage studies predicated onsingle gene models.Molecular genetic studiesLinkage and association studies using DNAmarkers are, of course, the cutting edge ofmodern approaches to complex genetic diseases.Conceptually, molecular genetic studiescan be divided into positional and candidategene approaches. In positional approaches,chromosomal locations of susceptibility genesare determined, usually by linkage studies. Thisrequires no knowledge of disease pathophysiologyand can be considered a purely geneticapproach. In contrast, the candidate geneapproach presupposes that the researcher hassuYcient understanding of disease biology tobe able to recognise genes that may be involvedin bipolar disorder. These are then examined inlinkage or, more usually, association studies. Inpractice both positional and candidate approachesare often combined. 67 The principlesbehind, and applications of, these approachesare discussed in detail elsewhere. 68LINKAGE STUDIESEarly linkage studies of bipolar disorder usedvery large families and were based on theimplausible assumption that all illness wascaused by a single major gene. In the late 1980sthere were two high profile claims of linkagepublished in the journal Nature: Baron et al 64reported linkage to X chromosome markers inseveral Israeli pedigrees and Egeland et al 69reported linkage to markers on chromosome11p in a large pedigree of the Old Order Amishcommunity in Pennsylvania. Other workerswere unable to replicate these findings andeventually in both cases the original groupspublished updated and extended analyses oftheir own data in which the significant evidenceof linkage all but vanished. 70 71 The reasons forthese dramatic reversals in findings included:(1) family members originally diagnosed asunaVected became ill for the first time duringfollow up; (2) new family members were examinedwho did not show evidence for linkage;and (3) additional DNA markers were examinedwhich reduced the evidence for linkage.After initial pessimism following these disappointments,the field has moved forward withthe development and use of research methodologiesmore appropriate for the investigationof complex genetic traits. There has been atrend towards use of smaller families (particularlyaVected sib pairs) and of analytic methodsthat are less sensitive to diagnostic changes orerrors (reviewed by Craddock and Owen 68 ).Several groups around the world are undertakinglarge scale molecular genetic linkagestudies of bipolar disorder and promising findingsare beginning to emerge. A variety of differenttypes of sample set are being used rangingfrom single large densely aVected pedigreesin genetic isolates 69 to large numbers of affectedsib pairs 72 and systematic genome screens arebeing undertaken in many of these samples.The pattern of results emerging from theselinkage studies supports the view that no singlemajor gene exists that explains the majority ofcases of bipolar disorder. Several features areemerging that are to be expected in the searchfor genes involved in a complex geneticJ Med Genet: first published as 10.1136/jmg.36.8.585 on 1 August 1999. Downloaded from http://jmg.bmj.com/ on May 17, 2021 by guest. Protected by copyright.
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