BRITISH JOURNAL OF (2005), 186, 179^181 EDITORIAL

Current strategies for investigating the genetic and positional candidate gene G72G72 in bothinboth disorders (Elkin et aletal, 2004). Thus, the environmental risk factors for affective disorders* molecular and the quantitative genetic findings appear to be convergent in suggest- ing three sets of genes: one conferring liab- ANNE FARMER, THALIA C. ELEY and PETER McGUFFIN ility to both schizophrenia and bipolar disorder, and two that are specific for each of the two main Kraepelinian syndromes. Interestingly, in the quantitative analyses the environmental risk factors appeared to be specific to each psychotic disorder. A rather different type of analysis seeks It is probable that the genetic components schemes of subtyping are of any use (Ken- to tease out dimensions within the broad of affective disorders (bipolar affective dell, 1976; Farmer & McGuffin, 1989). category of recurrent depression. Using disorder, major depressive disorder and One typology that has stood the test of time phenotypic data from participants in cur- anxiety states) result from multiple genes and seems clinically useful is the unipolar/ rent large-scale genetic studies of depres- that confer a susceptibility or liability to bipolar subdivision. Until recently, a sion (see below), this has produced some develop the disorder when other (environ- common view (Gershon et aletal, 1982) was interesting early results. Factor analysis of mental) risk factors are also present. In that bipolar affective disorder and major psychopathology from worst and second- general, bipolar affective disorder has been depressive disorder lie on the same severity worst episodes of depression in sibling pairs found to have the highest heritability (i.e. of liability continuum contributed to by the has shown that a four-factor solution pro- the proportion of variance explained by (mainly) additive effects of genetic and vides the best fit for the data. Three of the additive genetic factors) of around 80% environmental risk factors. The theory sug- factors were found to be familial by exam- (McGuffin(McGuffin et aletal, 2003), followed by major gests that the two phenotypes differ only in ining the sib-pair correlations, and a confir- depression (between 40% and 70%, de- respect of severity of liability, with bipolar matory factor analysis of a large sample of pending on the stringency of the definition; affective disorder representing the more unrelated patients suggested that the factor KendlerKendler et aletal, 1993; McGuffin et aletal, 1996),1996) severe, less common subtype and major structure is stable, replicable and poten- and then by anxiety disorders, with herit- depressive disorder the more common, less tially useful for analyses exploring the re- abilities of around 40–50% (Eley et aletal,, severe subtype. However, this model has lationship with genetic markers (Korszun 2002).2002). been recently refuted by McGuffin and col- et aletal, 2004).,2004). For affective disorders in adult life, the leagues, who also applied structural equa- role as precipitants of certain proximal tion model-fitting methods to explore factors such as severe and threatening life further the aetiological overlap between FINDING GENES events has been well replicated (Brown & the two disorders, using a twin design AND EXPLORING Harris, 1978). There is also much evidence (McGuffin(McGuffin et aletal, 2003). These authors FUNCTION of distal factors such as childhood adversity showed that although there is a substantial contributing to vulnerability (Gilman et aletal,, genetic correlation between mania and de- Linkage studies use genetic marker allele 2003). Important developmental aspects pression, most of the genetic variance in sharing between family members (most include the continuities between childhood liability to mania is specific to the manic commonly, affected siblings) to find regions depressive symptoms and adult depression syndrome. That is, the main clinically rele- within the genome where susceptibility and the changing contributions of genes vant subtypes of affective disorder show a genes might be located. Once such regions and environment throughout the life span. large overlap in their genetic aetiology, have been found, they can then be explored For example, recent findings support and but bipolar disorder is also contributed to in greater detail using association studies extend earlier work that has shown increas- by a set of genes that are specific to the (either case–control or within-family de- ing genetic influence on depressive symp- manic state. signs). Both approaches require large data- toms as children grow into adolescence A similar model-fitting approach has sets, drawn from hundreds or thousands (Scourfield(Scourfield et aletal, 2003).,2003). been applied to the genetic and environ- of subjects, and the application of these mental overlap between schizophrenia, methods to affective disorders has some- schizoaffective disorder and bipolar dis- what lagged behind other disorders such AFFECTIVE DISORDERS: order (Cardno et aletal, 2002). Although there as schizophrenia. However, several large ONE OR MORE SET OF GENES ? was evidence of genetic overlap between affected sib-pair and case–control collec- the three disorders there was also evidence tions of DNA for recurrent major depres- The classification of affective disorders has for specific genetic components for schizo- sion and bipolar affective disorder, as well often been the subject of debate, generating phrenia and bipolar disorder (but not as depressive and anxiety symptoms that considerable controversy as to whether schizoaffective disorder). This goes some occur in the general population, have now way towards explaining the (otherwise been collected and results of genome scans puzzling) findings from linkage studies that are beginning to emerge (Nash et aletal, 2004).,2004). *This is one of a short series of editorials being published in theinthe JournalJournalto mark the10th anniversary ofthe Social, have implicated some of the same genomic Finding genetic polymorphisms asso- Genetic and Developmental Psychiatry Centre at the regions in schizophrenia and bipolar dis- ciated with affective disorders is only the Institute of Psychiatry. order and studies that have implicated a first step on the path to understanding what

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the genes do. Currently the functional DEVELOPMENTAL ASPECTS: both depression and parental disciplinary effects of common polymorphisms in genes SAD ANDANXIOUSAND ANXIOUS style (Laustyle(Lau et aletal, 2004,2004bb).). in candidate pathways such as the serotonin CHILDREN pathway are under investigation. This CONCLUSIONS includes studies of gene expression in One of the methods for disentangling the post-mortem human brain tissue (Sugden changes in the relationship between adver- With the completion of the sequencing of et aletal, 2004) and in animal models sity and mood states throughout childhood all the base pairs in the human genome (Fernandes(Fernandes et aletal, 2004).,2004). into adult life is to carry out longitudinal earlier in the decade, we are now entering cohort studies. The Twins Early Develop- a ‘post-genomic’ era, although identifying ment Study (TEDS) (Trouton et aletal, 2002),2002) the genes involved in the aetiology of affec- the largest-ever twin study of its kind, has tive disorders remains a major research pre- undertaken regular assessments of twins occupation. However, many geneticists as GENE ^ ENVIRONMENT born in the UK between 1994 and 1995. well as researchers from other disciplines INTERPLAY Several ‘spin-off’ studies have been per- are now turning their attention to environ- formed, one of which examined the pheno- mental risk factors and how these interact Although the relationship between adverse typic and genetic structure of anxiety in and co-act with genes to lead to the expres- life events and the onset of depression is young children (Eley et aletal, 2003). Another sion of pathological phenotypes such as well established, the nature of the relation- study currently being undertaken will ex- depression. Although genetic variation in ship between this and genetic vulnerability amine mother–twin and twin–twin social humans can now be determined relatively to depression is not yet understood. Do interactions during slightly stressful or easily from a single DNA sample derived genes predispose some individuals to mildly anxiety-provoking tasks. Emotional from blood or even scrapings from the encounter adversity or do genes make some responses and measures of anxious cogni- inside of the cheek, experimental manipula- individuals more susceptible to the effects tive style in both twins as well as the quality tion of the environment of human subjects of adversity when it occurs? Several studies of the interactions are being identified. As is clearly not possible. Consequently, alter- have shown that life events aggregate in the study design crosses two time points native methods are required to measure the families (e.g. McGuffin et aletal, 1988; Rijsdijk in middle childhood, a developmental ‘environome’. One is to examine the geno- et aletal, 2001). In a nearest-aged sib-pair study hypotheses regarding aspects of cognitive types of individuals who have all been ex- of depression, Farmer et aletal (2000) found no style and anxiety symptoms can be tested posed to a specific risk factor, such as significant difference between the number (Eley(Eley et aletal, 2003).,2003). childhood adversity or severe threatening of threatening life events experienced by Another ‘spin-off’ study from a large life events, comparing those who have ex- the siblings of individuals with depression sib-pair study of depression and anxiety in pressed the phenotype, for example by be- and the siblings of healthy controls. How- a general population adult sample (The coming depressed, and those who have ever, the siblings of probands with depres- GENESiS study) (Sham et aletal, 2000) re- not (resilient individuals). Some of the long- sion who had experienced a threatening cruited the study participants’ adolescent itudinal and twin studies described above, event were significantly more likely to de- offspring (around 1900 children, of whom as well as others currently being conducted velop depression than the siblings of con- half are sibling pairs), who have been by various research groups around the trols. These findings suggest that genes examined at three time points in adoles- world, will lend themselves to this type of make individuals susceptible to adversity cence. The sib-pair sample was combined analysis.analysis. rather than influence their exposure to it. with a sample of adolescent twins identified Nevertheless, many individuals exposed to by the Office for National Statistics, and a DECLARATIONOF INTEREST adversity do not develop depression. Ex- comprehensive series of assessments have amination of resilience, whatever protects investigated socio-economic factors, edu- A.F. and P.M. have received remuneration individuals from developing psycho- cation, employment, parenting style and for presentations and chairing symposia, pathology in the presence of environmental friendships. As this age group is at increas- travel and subsistence costs from Eli Lilly, risk factors, can also be informative ing risk of developing depression, the evolu- GlaxoSmithKline and Bristol-Myers Squibb. (Farmer & McGuffin, 2003). tion of affective symptoms and disorder has Both have received consultancy fees from These findings also suggest that inter- been evaluated along with cognitive risks GlaxoSmithKline. action effects (not just simple additive associated with these disorders. The study effects) between genes and environment team has shown that regarding risk of REFERENCES are probably more common than pre- depression, there is an interaction between viously thought. Caspi et aletal (2003) demon- familial vulnerability to adolescent depres- Brown, G. W. & Harris, T.(1978) Social Origins of Depression: A Study of Psychiatric Disorder in Women. strated that a functional polymorphism in sion and parental lack of education (Eley :London:Tavistock. Tavistock. the promoter region of the 5-hydroxytryp- et aletal, 2004,2004aa). They also found an interac- tamine transporter gene (5HTTLPR5HTTLPR)) tion between negative life events, parental Cardno, A. 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