Genetic  studies of bipolar affective disorder in large families

Background Genetic factors are known to be important in the aetiology of bipolar disorder.

Aims To review linkage studies in extended families multiply affected with bipolar disorder.

Method Selective review of linkage studies of bipolar disorder emphasising the gains and drawbacks of studying large multiply-affected families and comparing the statistical methods used for dataanalysis.

Results Linkage of bipolar disorder to several chromosome regions including 4p, 4q, 10p, 12q, 16p, 18q, 21q and Xq has firstbeen reported in extended families. In other families chromosomalrearrangements associated with affective illnesses providesignposts to the location of disease-related genes. Statisticalanalyses using variance component methods can be applied to extended families, require no prior knowledge of the diseaseinheritance, and can test multilocus models.

Conclusion Studying single large pedigrees combined with variance component analysis is an efficient and effective strategylikely to lead to further insights into the genetic basisof bipolar disorders.

LINKAGE IN LARGE FAMILIES

TOP

LINKAGE IN LARGE FAMILIES

Linkage analysis has been highly effective when used to identifythe genes responsible for monogenic disorders, such as cysticfibrosis and Huntington's disease, but has been less consistentwhen applied to genetically complex conditions such as bipolardisorder, which are likely to be influenced by multiple geneticloci and by non-genetic environmental effects (Risch & Botstein, 1996).The lack of consistent findings from genome-widelinkage studies in bipolar disorder may be due to non-significanteffects being reported or because different genes and/or differentalleles at these genes are causing illness in different familiesand populations. Indeed, the hypothesis that different relativelyuncommon alleles are segregating in different families would predict a lack of consistent findings across linkage studiesbased on sibling pairs or small families, since the powerof the linkage approach is greatly reduced for diseases thatshow genetic heterogeneity (Terwilliger & Weiss, 1998).Bipolar disorder is likely to be genetically heterogeneous; mutations in one of several independent genes may producea similar clinical phenotype and different mutations in thesame gene may cause a variety of related symptoms. Anotherpossible model is that the clinical symptoms of the affectivedisorders can be viewed as continuous variables, called quantitative traits, that are produced by the additive or interactive effectsof mutations in two or more genes. Under this model, eachgene — termed a quantitative trait locus (QTL) —has only a small effect on the trait, and symptoms developas a result of the cumulative effects of mutations in severalgenes, probably combined with other internal and external environmentalrisk factors. In these situations there is also an advantagein studying single large pedigrees where the disease is likelyto be caused by a more limited number of interacting genesand environmental factors.

The study of multiply-affected families with sufficient poweron their own to generate significant evidence for linkageremains one of the most promising strategies to find genesimplicated in bipolar disorder and other psychiatric conditionsthat may be characterised by extreme allelic complexity. Several chromosomal regions have been initially identified by linkageanalysis in single families. These include chromosome 4p,reported in three studies of four extended pedigrees (Blackwoodet al, 1996; Asherson et al, 1998; Ewald et al, 1998a);chromosome 4q (Adams et al, 1998); chromosome 10p (Armstrong et al, 1997);chromosome 12q, where bipolar disorder, initiallyfound to associate with Darier's disease (Craddock et al,1994), was found to show linkage in large pedigrees studiedindependently (Barden et al, 1996; Ewald et al, 1998b; Morissette et al, 1999); chromosome 16p (Ewald et al, 1995);chromosome 18q (Freimer et al, 1996); chromosome 21q (Straub et al, 1994); and chromosome Xq (Pekkarinen et al, 1995).The Old Order Amish, one of the largest extended families studiedso far, has yielded several regions of suggestive linkage (Ginns et al, 1996;LaBuda et al, 1996) and the intriguing findingon chromosome 4p of an apparent ‘protective’ locusin the same region where linkage to a susceptibility locushas been identified in other families (Ginns et al, 1998). All of these studies illustrate some of the advantages ofworking with large families. The penetrance and mode of inheritancemay vary between different populations but can often be definedmore clearly within one family where information about thepresence of anticipation, imprinting and other factors isalso likely to be available. It is likely that within a singlefamily the influence of one or a small number of genes willbe paramount and hence detectable. However, there are limitationsto using large families. Disease in a family may be derivednot from one but from several founders, or the disease maybe the result of rare genetic causes that explain an insignificant fraction of the condition in a wider population. Despite theselimitations, identifying any gene contributing to bipolarillness would be a significant advance and would point toother genes related by sequence or function.

FAMILIES WITH CHROMOSOME ABNORMALITIES

TOP

FAMILIES WITH CHROMOSOME...

Karyotype abnormalities associated with the development of amedical illness can point directly to chromosomal regionsthat contain candidate disease genes and have played a keyrole in the search for genes for many genetic conditions.If the anomaly is inherited, its co-segregation with a specificillness can be tested by linkage. Moreover, if the size of available pedigree is small then the chance of true association is increasedif the chromosomal abnormality lies within a region wherelinkage or association has been previously reported in otherfamilies.

A balanced reciprocal chromosomal translocation t(1;11)(q42.1;q14.3)has been found to co-segregate with several major psychiatricdisorders, including severe recurrent major depressive disorderand schizophrenia, in a large Scottish pedigree (St Clairet al, 1990). A recent follow-up of this family has identified additional subjects with the translocation who have developedmajor psychotic illness, including bipolar disorder (Blackwood et al, 1998).Systematic physical mapping of the breakpointsof this translocation has revealed disrupted coding sequenceson chromosome 1 that represent candidate genes for the psychoseswithin this family (Muir et al, 1995; Millar et al, 2000, 2001).

A rare chromosomal abnormality, inv(18)(p11.3;q21.1), has beendescribed in separate Danish and Scottish families (Mors et al, 1997).The inversion is associated with bipolar disorderin one family and schizophrenia in the other. The breakpointslie within the linkage regions on the long and short armsof chromosome 18 and it may be hypothesised that they havedisrupted genes at one or both breakpoints (Hampson et al, 1999).

STATISTICAL ANALYSES

TOP

STATISTICAL ANALYSES

Model-based linkage analysis in single extended pedigrees requiresprior specification of the mode of inheritance, penetranceand population frequency of the trait. Since none of thesevariables in bipolar disorder is known for certain, a highrate of false positive or negative linkage findings are likely.Recently, there has been renewed interest in variance-basedmethods to detect QTLs for complex traits (Almasy & Blangero, 1998).These methods do not specify any particular genetic model but identify regions of the genome which explaina significant amount of the phenotypic variation in the trait.These regions are then the best estimates for the locationof a QTL. When data from a single large pedigree that showedsignificant linkage between bipolar disorder and markers onchromosome 4p were re-analysed using a variance component method,the results confirmed that this more robust approach can besuccessfully used for the analysis of data from a single pedigree (Visscher et al, 1999). The variance component method, unlikelinkage analysis, can distinguish between polygenic variationand single-gene effects. In addition, this model can includefactors and covariates such as cohort or gender effects andallow other random effects which cause the observations to becorrelated, such as a common environmental effect. Furthermore,variance models can be extended to multiple QTLs, making itpossible to examine for epistatic interactions between lociin a family, and can be applied also to multiple traits simultaneously.

CONCLUSION

TOP

CONCLUSION

The dramatic successes of linkage studies in identifying genesfor neuropsychiatric disorders, such as Huntington's diseaseand Alzheimer's disease, have not yet been matched in theaffective disorders. Linkage strategies based on affectedsibling pairs or many small families have limited power ifthe disease phenotype can be caused by variation in one of manygenes in a population. In diseases with marked allelic complexitymuch can be learned by examining single large families, evenwhen these show atypical clinical phenotypes. These includeinbred or geographically isolated pedigrees, families withchromosomal abnormalities co-segregating with illnesses, andfamilies with mental illness and comorbid conditions such as learning disabilities or deafness. In these families the searchfor linkage is facilitated because only one or a few locimay be responsible for the trait. To identify even a rarelocus could point the way to other causes of bipolar disorder.

Clinical Implications and Limitations

TOP

Clinical Implications and...

CLINICAL IMPLICATIONS

Understanding genetic risk factors in bipolar disorder may:
Form the basis of a biological classification of the disorder.
Guide the search for new drug therapies.
Suggest preventativemeasures.

LIMITATIONS

A single family may express an uncommon form of a disease andgive findings of limited application to the general population.An example is that of the BRCA genes which explain much ofthe variance in breast cancer in some affected families butless of the variance in the population as a whole.
The resolutionfor linkage in single families is limited bythe relativelysmall number of meioses available for study:a typical linkage region will be 5-30 centimorgans. Linkagedisequilibrium methodswhich essentially use historical meiosesmay reduce the mappingresolution to less than 1 centimorgan.
Linkage results inextended pedigrees may be confounded by inbreedingor thepresence of several founders.

REFERENCES

TOP