Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD. METHOD: The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them. RESULTS: PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples. CONCLUSIONS: CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Genome-wide association analysis of copy number variation in recurrent depressive disorder.

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10(-6), odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 × 10(-4), OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.

Estimating the heritability of reporting stressful life events captured by common genetic variants.

BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

Depressive disorder moderates the effect of the FTO gene on body mass index.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.

Interaction between serotonin transporter gene variants and life events predicts response to antidepressants in the GENDEP project.

There is substantial inter-individual variation in response to antidepressants, and genetic variation may, in part, explain these differences. For example, there is evidence to suggest that variation in the serotonin transporter gene (SLC6A4) predicts response to selective serotonin reuptake inhibitors (SSRIs). Environmental factors such as the occurrence of stressful life events before treatment may also be important. One prior report suggests that both factors interact in predicting response to antidepressants. GENDEP, a prospective part-randomized pharmacogenomics trial, collected longitudinal data on the outcome of 811 patients with major depression undergoing treatment with either an SSRI (escitalopram) or a tricyclic antidepressant (nortriptyline). Life events experienced over 6 months preceding treatment were measured using a List of Threatening Experiences Questionnaire, and several polymorphisms in the serotonin transporter gene (SLC6A4) have been genotyped including the serotonin transporter-linked polymorphic region (5-HTTLPR). Stressful life events were shown to predict a significantly better response to escitalopram but had no effect on response to nortriptyline. Variation in the 5-HTTLPR and another polymorphism in the gene, STin4, significantly modified these effects. Gene-environment interactions including life events may therefore be important not only in the aetiology of depression, but also in predicting response to antidepressant medication.

A follow-up case-control association study of tractable (druggable) genes in recurrent major depression.

The High-Throughput Disease-specific target Identification Program (HiTDIP) aimed to study case-control association samples for 18 common diseases. Here we present the results of a follow-up case-control association study of HiTDIP in major depressive disorder (MDD). The HiTDIP in MDD was conducted in a sample of 974 cases of recurrent MDD of white German origin collected at the Max-Planck Institute (MP-GSK) and 968 ethnically matched controls screened for lifetime absence of depression. Six genes were identified as of interest for a follow-up, based on the strength of the association and based on the interest as potential candidate target for developing new treatment for depression: Solute Carrier Family 4 Member 10 (SLC4A10), Dipeptidyl Peptidase IV (DPP4), Dopamine Receptor D3 (DRD3), Zinc Finger Protein 80 (ZNF80), Nitric Oxide Synthase 2A (NOS2A) and Peroxisome Proliferator-Activated Receptor-Gamma, Coactivator 1, Alpha (PPARGC1A). Within the current study, we attempted to follow-up these findings in a sample from the UK, the Depression Case Control (DeCC) sample consisting of 1,196 cases and 842 screened controls, phenotyped using exactly the same methods as the MP-GSK sample. Performing Cochran-Mantel-Haenzel statistics to test for genotypic and/or allelic differences between the DeCC and MP-GSK samples, we found no significant differences, thus being able to combine the two samples for association testing. In the combined sample of 2,170 MDD cases and 1,810 controls, there were positive findings in the Nitric Oxide Synthase 2A (NOS2A) gene both using single SNP analysis and haplotype analysis.

Adverse life event reporting and worst illness episodes in unipolar and bipolar affective disorders: measuring environmental risk for genetic research.

BACKGROUND: Studies exploring gene-environment interplay in affective disorders now include very large numbers of participants. Methods for evaluating the role of adversity in such studies need to be developed that do not rely on lengthy and labour-intensive interviews. In the present study, a brief questionnaire method for measuring 11 adverse events reported before interview and before their worst illness episodes by bipolar, unipolar and healthy control participants, participating in genetic association studies, was evaluated. METHOD: Five hundred and twelve bipolar disorder (BD) participants, 1447 participants with recurrent unipolar depression (UPD) and 1346 psychiatrically healthy control participants underwent the researcher-administered version of the List of Threatening Experiences Questionnaire (LTE-Q) for the 6 months before their worst affective episodes for UPD and BD participants, and for the 6 months before interview for the UPD participants and controls. RESULTS: UPD and BD cases were significantly more likely to report at least one event, as well as more events in the 6 months before interview and before their worst illness episodes, than healthy controls. Both manic and depressive episodes were significantly associated with adverse events in the BD cases. Depressed mood at the time of interview influenced event reporting in UPD and control participants but not the BD cases. Age was negatively correlated with the number of events reported by controls. CONCLUSIONS: The researcher-administered LTE-Q provides a measure of case-control differences for adversity that is applicable in large genetic association studies. Confounding factors for event reporting include present mood and age.

Extracting a needle from a haystack: reanalysis of whole genome data reveals a readily translatable finding.

There is significant unmet need for more effective treatments for bipolar disorder. The drug discovery process is becoming prohibitively expensive. Hence, biomarker clues to assist or shortcut this process are now widely sought. Using the publicly available data from the whole genome association study conducted by the Wellcome Trust Case Control Consortium, we sought to identify groups of genetic markers (single nucleotide polymorphisms) in which each marker was independently associated with bipolar disorder, with a less stringent threshold than that set by the original investigators (p< or =1 x 10(-4)). We identified a group of markers occurring within the CACNA1C gene (encoding the alpha subunit of the calcium channel Cav1.2). We then ascertained that this locus had been previously associated with the disorder in both a smaller and a whole genome study, and that a number of drugs blocking this channel (including verapamil and diltiazem) had been trialled in the treatment of bipolar disorder. The dihydropyridine-based blockers such as nimodipine that bind specifically to Cav1.2 and are more penetrant to the central nervous system have shown some promising early results; however, further trials are indicated. In addition, migraine is commonly seen in affective disorder, and calcium channel antagonists are successfully used in the treatment of migraine. One such agent, flunarizine, is structurally related to other first-generation derivatives of antihistamines such as antipsychotics. This implies that flunarizine could be useful in the treatment of bipolar disorder, and, furthermore, that other currently licensed drugs should be investigated for antagonism of Cav1.2.

Depression, migraine with aura and migraine without aura: their familiality and interrelatedness.

Migraine is frequently comorbid with depression. There appear to be common aetiological factors for both disorders, but the aetiology of migraine within depressed patients, in particular the significance of aura, has been little studied. A large sample of concordantly depressed sibling pairs [the Depression-Network (DeNT) sample] was assessed as having migraine with aura (MA), migraine without aura (MoA), probable migraine or no migraine according to International Headache Society guidelines. Correlations between siblings' migraine status were used to assess the nature of familial liability to migraine. A multiple threshold isocorrelational model fit best, in which different syndromes are conceptualized as different severities of one underlying dimension rather than as having separate aetiologies. Thus, MA and MoA were found to be different forms of the same disorder, with MA occupying the more extreme end of the spectrum of liability. Implications for our understanding of the relationship between migraine and depression are discussed.

Twin concordance for DSM-III schizophrenia. Scrutinizing the validity of the definition.

DSM-III diagnoses were applied to 26 monozygotic (MZ) and 34 dizygotic (DZ) probands and their co-twins from the Maudsley Hospital (1948 to 1965) schizophrenic series of Gottesman and Shields. DSM-III criteria for schizophrenia were found to be highly reliable and valid, and to have a broad heritability of 0.85, which is comparable with the Research Diagnostic Criteria and Feighner criteria from which they were derived. When the full range of DSM-III diagnoses were considered, both affective disorder and schizophrenia were found in genetically identical individuals. The effect of DSM-III nosology on the twin series was also explored by adding other diagnoses to that of schizophrenia and observing the effect on the MZ/DZ concordance ratio. The addition of affective disorder with mood-incongruent delusions to the schizophrenia spectrum produced the largest increase in the ratio and, by implication, a "more genetic" combination than schizophrenia alone. The maximum MZ/DZ concordance ratio (7.68) was produced by schizophrenia, plus affective disorder with mood-incongruent delusions, plus schizotypal personality disorder, plus atypical psychosis. The effect of adding paranoid disorder (paranoia) and all other affective categories was a reduction in the ratio.

A comparison between the Present State Examination and the Composite International Diagnostic Interview.

Item-by-item interrater agreement, CATEGO syndrome and class agreement, and agreement for Index of Definition were compared for the Present State Examination (PSE) and for the PSE items included in the Composite International Diagnostic Interview. Both interviews were given to 30 subjects representing a wide range of diagnoses, including hospitalized psychotic patients and outpatients with milder neurotic symptoms. Although agreement over individual questions was disappointing, when broader issues, such as syndrome classification, diagnostic class, and severity, were considered, agreement between interviews attained statistical significance.

Twin concordance for operationally defined schizophrenia. Confirmation of familiality and heritability.

Six sets of operational criteria for diagnosing schizophrenia were applied to a systematically ascertained twin series by raters who were blind to zygosity and to the psychiatric status of the co-twin. Assuming a multifactorial/threshold model of transmission, twin correlations in liability and, where possible, approximate broad heritabilities were calculated for each criterion. All definitions resulted in significant monozygotic twin correlations. The highest heritabilities (of approximately 0.8) were given by the Research Diagnostic Criteria and by the categories "probable" plus "definite" schizophrenia according to the criteria of Feighner et al. In contrast, Schneider's first-rank symptoms defined a form of schizophrenia with a heritability of 0 and, together with the criteria of Carpenter et al and Taylor et al, proved to be excessively restrictive, identifying fewer than half of the probands as schizophrenic.

Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.

BACKGROUND: Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. METHODS: A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. RESULTS: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. CONCLUSIONS: Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.

Drug treatment of resistant schizophrenia. Limitations and recommendations.

Despite the advances achieved since the introduction of chlorpromazine, schizophrenia may respond inadequately to standard drug treatments. The reasons for this include noncompliance, poor tolerance and the development of distressing side effects or the resistance of the illness itself. Treatment-resistant schizophrenia is increasingly the focus of new research developments. The older or classic antipsychotic drugs have a broad spectrum of action on central and peripheral nervous system receptors. Their action on dopamine receptors was an early clue to the pathogenesis of schizophrenia. More recently, multiple subtypes of dopamine receptors have been identified. These, plus serotonin receptors, have been identified in brain structures thought to be implicated in schizophrenic illnesses. Atypical antipsychotic agents whose pharmacological action is either more specific, or which have novel receptor binding profiles show characteristic effects in both animal models and clinically. These drugs may improve symptoms in otherwise resistant illness or where intolerance prevents the use of standard treatments. There are a number of adjunctive somatic treatment strategies using established agents such as lithium and electroconvulsive therapy the use of which is now being explored systematically. The most exciting current development is the re-emergence of clozapine as a highly effective atypical antipsychotic drug which can be used safely if special surveillance is undertaken to monitor for its potentially severe toxic effects. These recent advances offer hope of improvement in the prognosis of people suffering from severe and intractable forms of schizophrenia.

The pathogenesis and management of schizophrenia.

Schizophrenia remains a relatively common debilitating and stigmatising disorder, whose precise aetiology is unknown. Research has consistently shown a strong genetic component, although environmental factors are also implicated. A number of biochemical aetiological theories have been proposed but the most plausible is the dopamine hypothesis. This suggests that there is excess activity at central dopaminergic pathways in the brain. Certainly, all effective antipsychotic drugs have dopamine blocking properties. Management of this disorder includes admitting new cases to hospital for careful evaluation by a multidisciplinary team. Although the mainstay of treatment is antipsychotic (neuroleptic) medication, social interventions are also required. These include close liaison with the patient's family, which can help to prevent relapse and aid compliance with drug treatment. Modern therapy aims for recovery of social and occupational skills and gradual rehabilitation back into the community.

Phenotypic definitions of psychotic illness for molecular genetic research.

New approaches to establish the molecular genetic bases of psychotic illness have recently been suggested which make different demands on diagnosticians attempting to provide reliable and valid phenotypic definitions. The diagnostic problems that have arisen to date and some solutions to these are considered. In addition, future diagnostic requirements for linkage and association studies are discussed.

Further exploration of a latent class typology of schizophrenia.

We previously derived a typology of schizophrenia from a latent class analysis of 447 first-contact non-affective functional psychotic patients from a defined catchment area. Here, using the same sample, we show that the three subtypes, 'neurodevelopmental' (Type A), 'paranoid' (Type B) and 'schizoaffective' (Type C) have different premorbid, phenomenological and treatment response characteristics. A canonical variate analysis of the three subtypes achieved partial separation between the first two subtypes, but the 'schizoaffective' type was less distinct.

Clinical genetics as clues to the "real" genetics of schizophrenia (a decade of modest gains while playing for time).

Although a decade has passed since the genetics of schizophrenia was examined for the Schizophrenia Bulletin, the epigenetic puzzle of schizophrenia has not yielded its secrets to any scientific break-through. In this article we review a sample of the highlights relevant to enlightened genetic thinking, i.e., a broad diathesis-stressor framework with multifactorial causation assumed and with provision for the epigenetic interaction of psychosocial as well as neurobiological factors. The clinical genetic epidemiologist needs to know the lifetime morbid risks generated by different definitions of schizophrenia, as well as the consequences for the familial risks generated by the various family, twin, and adoption strategies. Schizophrenia appears to occur through an interaction of a genetic susceptibility with some kind of environmental stress; the stress need not be an environment containing a person with a diagnosis in the schizophrenia spectrum; the genetic factors in schizophrenia have specificity as they do not increase the risk for major affective disorders or delusional disorder. Clearly, schizophrenia is clinically or phenotypically heterogeneous, but whether this variety is paralleled by etiological heterogeneity or to what extent is problematic. Once the existence of an important genetic predisposition to developing schizophrenia has been established, it becomes important to provide a theory (or theories) to account for its mode (modes) of transmission. Psychiatric geneticists have not yet solved the problem, in part because of the difficulty of specifying the appropriate phenotype to analyze and also because of the unknown degree of heterogeneity. Genetic markers are a special category of biological markers. In addition to conventional markers, the advent of "the new genetics" of recombinant DNA has meant that many more genetic markers (probes) are now available and that the day is not far off when the human genome will be extensively mapped. Considerable optimism exists about the future usefulness of genetic markers in detecting major gene effects and resolving problems of heterogeneity in schizophrenia.

Heterogeneity in schizophrenia: a cluster-analytic approach.

Despite agreement that chronic schizophrenia is clinically heterogeneous, no system of subclassification has received general acceptance. Most methods for defining subgroups have relied either on course or symptom type alone. Using cluster analysis on patients rated on a broad range of items derived from commonly employed explicit diagnostic criteria, we were able to define two reasonably distinct groups. The first and larger group was characterized by later onset, good premorbid adjustment, and well-organized delusions; the second by poor premorbid adjustment, early onset, family history of schizophrenia, and symptoms such as bizarre behavior, incoherent speech, and blunted effect. Two different clustering programs yielded similar profiles. Analysis of computer-simulated data indicated that such good agreement would occur by chance less than one time in a hundred. Furthermore, the groupings remained stable when extra cases were added to the sample, and affected family members showed a significant tendency to occur in the same cluster. Although an etiological distinction between the subtypes cannot be inferred, we suggest that this form of classification provides a potentially useful starting point for further biological and genetic research.