Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

Genome-wide association study of recurrent early-onset major depressive disorder.

A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻7), SP4 (P=7.68 x 10⁻7) and GRM7 (P=1.11 x 10⁻6). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.

Genome-wide association study of bipolar disorder in European American and African American individuals.

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

Assessing anhedonia in psychiatric patients.

In two studies of depressed, manic, schizophrenic, and normal subjects, a scale for measuring the intensity of subjects' pleasureable responses to normally emjoyable situations (the Pleasure Scale) evidenced good internal reliability and moderate agreement with the Chapman Anhedonia Scale and Indexes of depressive symptom severity. Only the depressed patients showed extremely anhedonic responses. Although more than half the depressed patients evidenced pleasure scores in the normal range, about 185 of them seemed more anhedonic than any norma subject. A mixture analysis resolved depressed patient scores into two distinct distributions: a normal-range distribution (88% of depressives) and an extremely anhedonic distribution (12%). The findings provide some support for the existence of a qualitatively distinct subtype of major depression that has been variously defined an "endogenomorphic" or "melancholic."

The validation of the concept of endogenous depression. A family study approach.

Depressive illnesses are subdivided into endogenous and nonendogenous types in psychiatry throughout the world. We used one method of validating this nosologic subdivision: the determination of the extent to which the disorder is familial. Rates of depression were examined in 2,942 first-degree relatives of 566 individuals diagnosed as having unipolar major depressive disorder. Because no single definition of endogenous depression is universally accepted, four different methods for defining endogenous depression were compared: the Newcastle Scale, the Research Diagnostic Criteria, DSM-III, and the definition of "autonomous depression" proposed by investigators at Yale University (New Haven, Conn). In general, no matter which definition was used, the relatives of the patients with endogenous illness did not have higher rates of depressive illness than those of the nonendogenous group. The Newcastle Scale was the most sensitive in picking up familial transmission of recurrent unipolar depression. The results of this investigation suggest that longitudinal approaches should be added to cross-sectional approaches for the best definition of endogenous depression.

Differences between anhedonic and normally hedonic depressive states.

In this study of 101 patients who met DSM-III criteria for major depression, those with extreme anhedonia (N = 23) were younger, more depressed, and less neurotic than the patients with a normal-range capacity for pleasurable experiences (N = 78). The anhedonic depressed patients recovered more rapidly; at discharge they consequently had levels of symptom severity equal to those of the hedonic patients, yet they remained significantly more anhedonic. The anhedonic patients exhibited loss of pleasure in appetite, sex, social contacts, and work, which suggests a global dulling of the capacity for pleasure.

A field test of Motto's risk estimator for suicide.

The authors undertook a field test of Motto and colleagues' Risk Estimator for Suicide by selecting a subset (N = 593) of psychiatric patients with major or chronic affective disorder that corresponded to Motto's sample. They rated each subject on Motto's scale, using standardized data collected at hospital admission. Fourteen patients (2.4%) in their sample and 136 (4.9%) in Motto's sample died by suicide within 2 years. The authors tested the null hypothesis of a uniform suicide risk across all 10 deciles of risk scores by comparing observed and expected frequencies of suicide using the variance test for homogeneity of the binomial distribution. Their findings raise questions about Motto's risk scale but do not definitively invalidate it.

Interactions of risk factors in predicting suicide.

The authors examined interactions among risk factors for suicide, a strategy not typically followed in suicide research. Their results suggest an explanation for gender differences in suicide rates and qualifications in the relationship between hopelessness and suicide based on history of drug and alcohol abuse.

Bipolar affective disorder and high achievement: a familial association.

The authors studied 442 probands with nonbipolar major depression, 64 with bipolar II disorder, and 88 with bipolar I disorder. Although the proband groups did not differ in occupational or educational achievement, the first-degree relatives of probands with bipolar disorders had significantly higher mean levels of achievement than did those of probands with nonbipolar disorder. This pattern applied whether or not the relatives themselves had bipolar illness. The authors conclude that the socioeconomic advantage previously associated with affective disorder in general may be limited to the bipolar forms.

The enduring psychosocial consequences of mania and depression.

OBJECTIVE: The authors sought to determine the scope, severity, and persistence of psychosocial impairment arising from bipolar and unipolar affective disorder. METHOD: Patients with bipolar (N = 148) or unipolar (N = 240) major affective disorder were assessed as they sought treatment and again after a 5-year follow-up. Concurrently, parents, siblings, and adult children underwent similar assessments and were followed for 6 years. To quantify the impact of affective disorder, probands were individually matched to relatives who had no lifetime history of affective disorder. Sixty-nine relatives who were depressed at intake constituted a separate, nonclinical study group and were also matched to relatives who were well. RESULTS: Both unipolar and bipolar patients began follow-up with deficits in annual income. Relative to comparison subjects, affective disorder groups were significantly more likely to report declines in job status and income at the end of follow-up and significantly less likely to report improvements. Similarly, both bipolar and unipolar patients showed significant deficits in nearly all other areas of psychosocial functioning measured at follow-up. Except for relationships with spouses, deficits did not differ significantly by polarity. Surprisingly, probands with recovery sustained throughout the final 2 years of follow-up also showed severe and widespread impairment. Relatives with major depression exhibited substantial deficits on follow-up, but job status and income were not significantly affected. CONCLUSIONS: The psychosocial impairment associated with mania and major depression extends to essentially all areas of functioning and persists for years, even among individuals who experience sustained resolution of clinical symptoms.

Clinical predictors of suicide in patients with major affective disorders: a controlled prospective study.

The authors report prospective uniform clinical data differentiating 25 patients who committed suicide from 929 patients who did not in a group of 954 patients with major affective disorder followed for an average of 4 years in the Collaborative Program on the Psychobiology of Depression. Eight (32%) of the suicides occurred within 6 months and 13 (52%) within 1 year of entry into the study. Hopelessness, loss of pleasure or interest, and mood cycling during the index episode differentiated the suicide group. Diagnostic subcategories, suicidal ideation at entry to the study, suicide attempts during current or past episodes, and medical severity of prior attempts did not differentiate the suicide group.

Time-related predictors of suicide in major affective disorder.

The authors studied 954 psychiatric patients with major affective disorders and found that nine clinical features were associated with suicide. Six of these--panic attacks, severe psychic anxiety, diminished concentration, global insomnia, moderate alcohol abuse, and severe loss of interest or pleasure (anhedonia)--were associated with suicide within 1 year, and three others--severe hopelessness, suicidal ideation, and history of previous suicide attempts--were associated with suicide occurring after 1 year. These findings draw attention to the importance of 1) standardized prospective data for studies of suicide, 2) assessment of short-term suicide risk factors, and 3) anxiety symptoms as modifiable suicide risk factors within a clinically relevant period.

Depression and panic attacks: the significance of overlap as reflected in follow-up and family study data.

Ninety-one patients with panic attacks limited historically to depressive episodes had more severe depressive symptoms and were less likely to recover during a 2-year follow-up than 417 depressed patients who did not have panic attacks. Family study data clearly distinguished another 15 patients with panic disorder and secondary depression; interviewed relatives of panic disorder patients were significantly less likely to have primary depression and significantly more likely to have various anxiety disorders. These data support the hierarchical system by which many of the contemporary diagnostic systems separate panic disorder and major depression.

Lithium discontinuation and subsequent effectiveness.

OBJECTIVE: Several reports have raised concern that the discontinuation of lithium may result in treatment resistance following recurrence of affective disorder. This report explores this possibility. METHOD: The data derive from a large, naturalistic follow-up of patients with major depressive disorder or mania. Twenty-eight of the patients in the study were free of lithium and experiencing an episode of mania or schizoaffective mania diagnosed according to Research Diagnostic Criteria when they entered the study, recovered while taking lithium, later experienced a recurrence while not taking lithium, and then resumed lithium treatment. Survival analyses of time to recovery and, subsequently, time to recurrence, used continued lithium treatment as an additional censoring variable. RESULTS: Patients given lithium recovered no more quickly from their index episode than they did from their first prospectively observed episode. Moreover, lithium prophylaxis appeared no less effective after the first prospectively observed episode than after the index episode. CONCLUSIONS: These findings provide no evidence that lithium discontinuation results in treatment resistance when lithium is resumed.

Test-retest reliability of assessing psychiatrically ill patients in a multi-center design.

In a test-retest reliability study involving 25 psychiatric patients and 5 professional raters we demonstrate that research clinicians from collaborating institutions are able to achieve good reliability for most areas of the SADS and RDC when assessing psychiatrically ill patients under interview conditions that provide even less data than ideally obtained in the practice of clinical research. We expect greater reliability in the actual use of the SADS/RDC on most items and diagnoses since the SADS is intended to be used in conjunction with information obtained from relatives, friends, and treatment staff to confirm and clarify the judgements made by the raters on the patient interviews. Moreover, we are reassured that the diagnosis of schizo-affective disorders and schizophrenia is protected from the item unreliability found with specific delusions and hallucinations. Similarly, the difficulties in determining the episodic and chronic nature of the present episode does not substantially interfere with making an RDC diagnosis of the current condition. A complex diagnostic interview system such as the SADS and RDC requires multiple complementary techniques to determine reliability. We find that establishing explicit procedures for raters to discuss and categorize the reasons for their disagreements on individual items and diagnoses provides valuable data for understanding reliability problems. This has helped us to identify specific areas of the interview and criteria that require further clarification and more intensive rater training to improve ratings made by interviewers.

Reliability of lifetime diagnoses and symptoms in patients with a current psychiatric disorder.

In this study we assess the reliability of rating past psychiatric symptoms and lifetime diagnoses in a currently ill population using the SADS and RDC. Five raters from different centers interviewed 25 subjects in a short-interval test-retest design. Subjects had a wide diversity of affective and non-affective diagnoses and high levels of manifest psychopathology. Our results demonstrate that it is possible for raters from different research centers to reliably rate lifetime diagnoses and previous symptoms. Two important exceptions to the high reliability are the lifetime diagnoses of hypomania and the recurrent unipolar subtype of major depressive disorder, and we alert clinicians and researchers to be cautious when diagnosing these conditions. We conclude that the next step in measuring reliability should be a long-interval test-retest design with separate interviews conducted at the later assessment, one by the original rater and the other by a blind rater.

What is the mechanism by which suicide attempts predispose to later suicide attempts? A mathematical model.

A state dependence model of serial behavior suggests that each occurrence increases the subsequent likelihood of that behavior being repeated. A heterogeneity model, by contrast, suggests that the likelihood of a behavior occurring is predetermined, and uninfluenced by intervening occurrences. We have applied the random-effects probit model of Gibbons and Bock (1987) to examine the fit of the state dependence and heterogeneity models to longitudinal data on suicide attempts by 928 patients with affective disorder. Heterogeneity but not state dependence was required to model these data. The findings suggest that when considering patients with moderate to severe major affective disorder, the clinician should not interpret the absence of any recent suicide attempts to mean that the patient is at relatively low risk for attempting suicide in the future. An implication of the heterogeneity model is that suicide attempts made many years ago may have equal value to recent attempts when estimating an individual's "predisposition" to nonlethal attempts in the future.

Stable trait components of hopelessness: baseline and sensitivity to depression.

Hopelessness (H) plays an important theoretical and practical role in depression. The authors hypothesized that a patient's H is comprised of (a) a baseline level of H when not depressed and (b) an increment in H related to the severity of depression at the time and the person's rate of increase in H as a function of severity of depression (sensitivity). Baseline and sensitivity are explanatory stable traits; H and depression are observed, time-varying states. The corresponding statistical model described well the longitudinal data of 316 participants. Baseline and sensitivity were uncorrelated and correlated with different clinical and demographic variables. Baseline predicted a future suicide attempt; sensitivity and H when depressed did not. It may be useful to ask "How hopeless is this person when not depressed and how much more hopeless is he or she when depressed?", rather than simply "How hopeless is this depressed person?"

Alcoholism and primary major depression: a family study approach to co-existing disorders.

Alcoholism and major depression appear together at much higher than chance rates, but reasons for this are obscure. We used the direct diagnostic assessment of 177 probands with primary, unipolar depression and 619 of their first degree relatives to explore the significance of concomitant alcoholism. The male relatives of alcoholic probands of both sexes had substantially higher rates of alcoholism than did the male relatives of non-alcoholic probands. Among female probands, but not among male probands, alcoholism was associated with markedly higher familial rates of primary depression, particularly among female relatives. These data contained no evidence that comorbidity itself was familial. The appearance of alcoholism in depressed women may indicate depression spectrum disease, a disorder which manifests as depression in women and alcoholism in men. In contrast, men with both primary depression and alcoholism may be exhibiting two distinct illnesses.