Molecular Genetics in Mood Disorders
D. Souery, S. Linotte and J. Mendlewicz
Despite intensive search for biological underpinnings, the aetiology of major mood disorders remains unknown. More work on the neurobiology of these disorders is clearly indicated. Twin and family studies have consistently demonstrated a genetic component to the disorders. Decades of research into the genetic aetiology of mood disorders provide evidence in favour of a complex mode of inheritance unlikely to be determined by single gene dysfunction, and apparently non-Mendelian patterns of inheritance. Part of the complexity of the genetic variance lies in the heterogeneity of the disorders — the depressive patient, for example, can be characterized by a variety of different symptoms and identifying features that may represent different subtypes. Different genetic mechanisms may be involved: epistasis, locus heterogeneity, allelic heterogeneity, dynamic mutations, imprinting and mitochondrial gene mutation (these issues are reviewed in Chapter XII). In terms of phenotype, there are also a variety of non-genetic factors mat lessen our ability to detect genes in mental disorders: phenocopies, clinical heterogeneity, assessment bias, population stratification and lack of appropriate control groups.
Of the genetic mechanisms listed above, it is possible that more man one may be involved in the transmission of psychiatric disorders. In complex disorders the correspondence between gene and phenotype is not necessarily direct: a given genotype may give rise to a variety of phenotypes according to other genes present and environmental factors, or different genotypes may give rise to the same phenotype. Despite these complex characteristics, family- and population-based studies have provided substantial evidence that genetic factors contribute to the expression of me disorders. Recent molecular genetic approaches indicate that several chromosomal regions may be involved in me aetiology of mood disorders.
The initial molecular genetic studies of Bipolar disorder (BPAD), considered as the core phenotype of mood disorders, involved the parametric linkage studies of large families. Linkage examines the cosegregation of a genetic marker and disease in affected individuals within families; that is, me non-random sharing of marker alleles between affected members of each family (Smeraldi and Macciardi, 1995). Two genetic loci are linked if they are located closely together on a chromosome. In linkage analysis, the frequency of meiotic recombinations as an expression of the distance between marker locus and the gene under investigation is used for gene mapping (see Chapter XII). Given the difficulties inherent in detecting genes of small to modest effect using the linkage approach, the candidate gene association method offers an alternative strategy of studying genetic factors involved in complex diseases in which the mode of transmission is not known. Association between diseases and marker may be found if the gene itself, or a locus in linkage disequilibrium with the marker, is involved in the pamophysiology of the disease (Hodge, 1994). Thus, an association may imply a direct effect of me gene tested, or the effect of another gene close to the marker examined. The candidate gene approach is a useful method to investigate association between markers and disease. A candidate gene refers to a region of the chromosome which is potentially implicated in me aetiology of the disorder concerned. The possibility of false-positive results must be taken into account, as a very large number of candidate genes now exist. The probability that each of these genes is involved in the aetiology of the disorder is relatively low.
The candidate gene approach can be extended to phenotypes not directly linked to the diagnoses of mood disorders. The therapeutic effect of psychotropic drugs may be considered to investigate genetic polymorphisms (psychopharmacogenetics). In recent years, research in psychopharmacogenetics has focused on evaluating functional polymorphisms both in genes coding for drugmetabolizing enzymes and in genes coding for other enzymes or receptors involved in the mechanism of action of psychoactive drugs. In this context, the use of new technologies is rapidly evolving. Gene expression patterns in response to drug treatments can be investigated by new techniques such as DNA microarrays. Microarrays are powerful tools for investigating the mechanism of drug action by measuring changes in mRNA levels in brain tissues before and after exposure to treatment (Debouck and Goodfellow, 1999).
This chapter reviews the current methodologies and study tools used to search for molecular genetic factors in mood disorders and the chromosomal regions of interest already investigated for bipolar (BPAD) and unipolar (UPAD) mood disorders.
AND CANDIDATE GENES
A systematic review of the literature on linkage studies in BPAD (Turecki et al, 1996) indicated mat the proportion of positive DNA findings is higher for X markers compared to other chromosomal regions. Mendlewicz et al (1987) first reported possible genetic linkage between BPAD and coagulation Factor IX (F9) located at Xq27 in 11 pedigrees. The same genetic marker was also tested in a French pedigree where linkage was confirmed (Lucotte et al, 1992). Linkage with DNA markers on the X chromosome has been excluded, however, in other pedigrees (Berrettini et al, 1990; Bredbacka et al, 1993; Gejman et al, 1990). A study published in 1987 by Baron et al. (1987) demonstrated positive linkage for glucose 6 phosphate dehydrogenase (G6PD), but later results from the same author did not support this finding (Baron et al, 1993), although G6PD was slightly positive for linkage in one family. In a more recent study (De Bruyn et al, 1994), several DNA markers in the Xq27–28 region were tested in nine bipolar families.