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Background: Evidence from family and twin studies suggests that mood and anxiety disorders, and related temperamental factors may share common etiologic factors. We examine the familial aggregation and coaggregation of anxiety disorder subtypes and anxiety-related temperamental traits, and their association with mood disorders.Methods: A total of 477 probands and 549 first-degree adult relatives from a large community based family study of affective spectrum disorders completed semi-structured diagnostic interviews and self-reported assessments of temperamental traits including: negative affectivity on the 'Positive and Negative Affect Schedule' (PANAS), neuroticism anxiety on the 'Zuckerman-Kuhlman Personality Questionnaire' (ZKPQ), and anxiety sensitivity on the 'Anxiety Sensitivity Index' (ASI).Results: The anxiety-related temperamental traits of negative affectivity, neuroticism anxiety and anxiety sensitivity had significant familial specificity, even after controlling for comorbid mood and anxiety disorders in probands and relatives. Yet, these traits in probands did not predict anxiety disorders in relatives. Although some anxiety subtypes were familial, there were no longer familial links between anxiety disorder subtypes (generalized anxiety disorder, social anxiety or panic disorder) after controlling for mood disorder subtypes in probands and relatives.Limitations: Cross-sectional interviews were used to estimate disorders, and self-report measures were used for temperamental traits.Conclusions: These results confirm previous research regarding familial overlap between anxiety subtypes and mood disorders, however their shared liability cannot be fully explained by anxiety-related temperamental traits. These findings suggest that anxiety-related temperamental traits may indicate a vulnerability for mood and anxiety disorders or a potential consequence of these conditions. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder (BD) has considerable heritability, with genome-wide association studies indicating that multiple common genetic variants contribute to risk. Less work has been undertaken to assess the contribution of rare variation in the development of this complex disorder, particularly in isolated populations. Using whole-exome sequencing (WES), the aim of this study was to identify rare, potentially damaging variants contributing to risk for BD in the Afrikaner population.Methods: WES was performed on eight Afrikaner family members, five affected and three unaffected. The analyses focused on i) the identification of rare, damaging variation, and ii) the molecular pathways in which these rare variants play a role using in silico prediction tools such as wANNOVAR and KOBAS 3.0.Results: Two rare and potentially damaging missense variants in FAM71B and SLC26A9 were shared by affected family members but were absent in unaffected members. In addition, variants in genes that play a role in pathways involved in signal transduction and synaptic transmission were shared by the five affected individuals.Limitations: Two main limitations affect this study: the limited number of cases and controls, and the fact that whole-exome sequencing can only capture a small fragment of the genome which may harbor mutations.Conclusion: This is the first WES study of BD in an Afrikaner family, and findings suggest that novel candidate genes may contribute to risk for BD in this population. Future work in larger samples of this population as well as in other populations is needed to fully investigate the role of the candidate genes found here. [ABSTRACT FROM AUTHOR]

Background: Scarce research has focused on Visual Memory (VM) deficits as a possible neurocognitive endophenotype of bipolar disorder (BD). The main aim of this longitudinal, family study with healthy controls was to explore whether VM dysfunction represents a neurocognitive endophenotype of BD.Methods: Assessment of VM by Rey-Osterrieth Complex Figure Test (ROCF) was carried out on a sample of 317 subjects, including 140 patients with BD, 60 unaffected first-degree relatives (BD-Rel), and 117 genetically-unrelated healthy controls (HC), on three occasions over a 5-year period (T1, T2, and T3). BD-Rel group scores were analyzed only at T1 and T2.Results: Performance of BD patients was significantly worse than the HC group (p < 0.01). Performance of BD-Rel was also significantly different from HC scores at T1 (p < 0.01) and T2 (p = 0.05), and showed an intermediate profile between the BD and HC groups. Only among BD patients, there were significant differences according to sex, with females performing worse than males (p = 0.03). Regarding other variables, education represented significant differences only in average scores of BD-Rel group (p = 0.01).Limitations: Important attrition in BD-Rel group over time was detected, which precluded analysis at T3.Conclusions: BD patients show significant deficits in VM that remain stable over time, even after controlling sociodemographic and clinical variables. Unaffected relatives also show stable deficits in VM. Accordingly, the deficit in VM could be considered a potential endophenotype of BD, which in turn may be useful as a predictor of the evolution of the disease. Further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Highlights • BMI and overweight were associated with the atypical subtype of depression. • BMI/overweight in probands was associated with BMI/overweight in their relatives. • Atypical depression in probands was associated with BMI/overweight in relatives. Abstract Background We previously demonstrated the specificity of familial transmission of the atypical subtype of depression, primarily characterized by overeating and oversleeping. However, the specific components of this subtype that are familial have not been established. The aim of this paper is to examine whether the familial specificity of atypical depression can be attributed to the association between Body Mass Index (BMI) and overweight/obesity with mood disorders. Methods The sample included 293 probands recruited from the community and their 544 adult first-degree relatives. Diagnostic assignment was based on a direct semi-structured interview. Mixed effect models were employed to test the familial aggregation and the familial cross-aggregation of mood disorders and BMI/overweight. Results There were significant within-individual associations between overweight and the atypical subtype of depression (p -value = 0.003). There was also an association for BMI/overweight between probands and relatives (β = 0.23, p -value < 0.001; odds ratio [OR] = 1.57, 95% confidence interval [CI] = 1.02–2.43, respectively). Atypical depression in probands was significantly associated with BMI and overweight in relatives (β = 0.001, p -value = 0.040; OR = 2.79, 95%CI = 1.20–6.49, respectively). Limitations The cross-sectional design impedes our ability to evaluate the direction of these associations. Other potential risk factors, such as diabetes, physical activity and unhealthy diet were not considered. Conclusions These findings imply that overweight may be either a precursor or consequence of atypical depression rather than a manifestation of a common diathesis underlying depression in families. Clinicians should pay particular attention to this subtype that could be at increased risk for the development of cardiovascular risk factors and diseases. [ABSTRACT FROM AUTHOR]

Introduction: There are contradictory findings regarding the associations of parental depression on the hypothalamic-pituitary-adrenal axis activity of their offspring. We aimed to explore the associations of parental depression on the diurnal salivary cortisol profile in their child and adolescent offspring.Methods: A total of 189 unaffected child and adolescent offspring as determined by structured clinical interview were divided into 3 groups according to their parental history of depression, namely current parental depression (CPD, n = 27), past parental depression (PPD, n = 57), and no parental depression (NPD, n = 105). Diurnal saliva samples were collected to measure the cortisol awakening response and diurnal cortisol profile.Results: CPD group had significantly higher basal cortisol level (mean ± SE = 11.9 ± 0.80 nmol/dl) than PPD group (mean ± SE = 9.7 ± 0.73 nmol/dl, post hoc p = .024) and NPD group (mean ± SE = 10.2 ± 0.52 nmol/dl, post hoc p = .031) and lower cortisol level at noon, but comparable cortisol levels in other time points. The cortisol awakening response reference to increase (AUCi) were significantly blunted in CPD group when compared with PPD and NPD (post hoc p < .01). Adjustment for potential confounding factors did not change major findings. Further analyses revealed that main influences were derived from current maternal depression.Limitations: A single day of saliva sample.Conclusion: Current but not past (lifetime) parental depression is associated with higher basal salivary cortisol and blunted cortisol awakening response in their children and adolescents. [ABSTRACT FROM AUTHOR]

Background: Few studies have examined Manual Motor Speed (MMS) in bipolar disorder (BD). The aim of this longitudinal, family study was to explore whether dysfunctional MMS represents a neurocognitive endophenotype of BD.Methods: A sample of 291 subjects, including 131 BD patients, 77 healthy first-degree relatives (BD-Rel), and 83 genetically-unrelated healthy controls (HC), was assessed with the Finger-Tapping Test (FTT) on three occasions over a 5-year period. Dependence of FTT on participants´ age was removed by means of a lineal model of HC samples, while correcting simultaneously the time and learning effect. Differences between groups were evaluated with an ANOVA test.Results: The patients' performance was significantly worse than that of HC over time (p≤0.006), and these deficits remained when non-euthymic BD patients (n=9) were excluded from analysis. Some significant differences between BD patients and BD-Rel (p≤0.037) and between BD-Rel and HC (p≤0.033) were found, but they tended to disappear as time progressed (p≥0.057). Performance of the BD-Rel group was intermediate to that of BD and HC. Most sociodemographic and clinical variables did not affect these results in patients. (p≥0.1). However, treatment with carbamazepine and benzodiazepines may exert a iatrogenic effect on MMS performance (p≤0.006).Limitations: Only right-handed subjects were included in this study. Substantial attrition over time was detected.Conclusions: There were significant differences between the patients´ MMS performance and that of healthy relatives and controls, regardless of most clinical and sociodemographic variables. Dysfunctional MMS could be considered an endophenotype of BD. Further studies are needed to rule out possible iatrogenic effects of some psychopharmacological treatments. [ABSTRACT FROM AUTHOR]

Background The use of the family history method is recommended in family studies as a type of proxy interview of non-participating relatives. However, using different sources of information can result in bias as direct interviews may provide a higher likelihood of assigning diagnoses than family history reports. The aims of the present study were to: 1) compare diagnoses for threshold and subthreshold mood syndromes from interviews to those relying on information from relatives; 2) test the appropriateness of lowering the diagnostic threshold and combining multiple reports from the family history method to obtain comparable prevalence estimates to the interviews; 3) identify factors that influence the likelihood of agreement and reporting of disorders by informants. Methods Within a family study, 1621 informant–index subject pairs were identified. DSM-5 diagnoses from direct interviews of index subjects were compared to those derived from family history information provided by their first-degree relatives. Results 1) Inter-informant agreement was acceptable for Mania, but low for all other mood syndromes. 2) Except for Mania and subthreshold depression, the family history method provided significantly lower prevalence estimates. The gap improved for all other syndromes after lowering the threshold of the family history method. 3) Individuals who had a history of depression themselves were more likely to report depression in their relatives. Limitations Low proportion of affected individuals for manic syndromes and lack of independence of data. Conclusions The higher likelihood of reporting disorders by affected informants entails the risk of overestimation of the size of familial aggregation of depression. [ABSTRACT FROM AUTHOR]

Abstract: Background: Unaffected relatives (URs) of individuals with major depressive disorder (MDD) are biologically more vulnerable to depression. We compare healthy URs and controls at the level of phenotype (symptoms and functioning) and endophenotype (negative emotion bias), and further investigate the interrelation between these and the contribution of environmental early life stress. Methods: URs (n=101), identified using Family History Screen interview methods and matched controls completed written and interview questions assessing symptoms of depression and anxiety, negative cognitive style, life functioning and early life stress. Biases in emotion processing were measured using a facial expression of emotion identification paradigm. Results: Compared to controls, URs reported higher levels of depression and anxiety, a stronger negative cognitive bias, and poorer functioning and lower satisfaction with life. URs were slower to correctly identify fear and sad facial expressions. A slower response time to identify sad faces was correlated with lower quality of life in the social domain. Early life stress (ELS) did not contribute significantly to any outcome. Limitations: The methodology relies on accurate reporting of participants' own psychiatric history and that of their family members. The degree of vulnerability varies among URs. Conclusions: A family history of depression accounts for subtle differences in symptom levels and functioning without a necessary role of ELS. A negative emotion bias in processing emotion may be one vulnerability marker for MDD. Biological markers may affect functioning measures before symptoms at the level of experience. [Copyright &y& Elsevier]

Abstract: Background: Since little is known as to whether sex differences affect the clinical presentation of pediatric BP-I disorder, it is an area of high clinical, scientific and public health relevance. Methods: Subjects are 239 BP-I probands (65 female probands, 174 male probands) and their 726 first-degree relatives, and 136 non-bipolar, non-ADHD control probands (37 female probands, 99 male probands) and their 411 first-degree relatives matched for age and sex. We modeled the psychiatric and cognitive outcomes as a function of BP-I status, sex, and the BP-I status-gender interaction. Results: BP-I disorder was equally familial in both sexes. With the exception of duration of mania (shorter in females) and number of depressive episodes (more in females), there were no other meaningful differences between the sexes in clinical correlates of BP-I disorder. With the exception of a significant sex effect for panic disorder and a trend for substance use disorders (p=0.05) with female probands being at a higher risk than male probands, patterns of comorbidity were similar between the sexes. Despite the similarities, boys with BP-I disorder received more intensive and costly academic services than girls with the same disorder. Limitations: Since we studied children referred to a family study of bipolar disorder, our findings may not generalize to clinic settings. Conclusions: We found more similarities than differences between the sexes in the personal and familial correlates of BP-I disorder. Clinicians should consider bipolar disorder in the differential diagnosis of both boys and girls afflicted with symptoms suggestive of this disorder. [Copyright &y& Elsevier]

Abstract: Background: Suicide aggregates within families and the relatives of suicide completers are at an increased risk for suicide. Though neurocognitive changes are gaining increasing attention as part of the vulnerability for suicide, the literature on neurocognitive alterations among suicide relatives as possible endophenotypes of suicide is sparse. Method: Normothymic first-degree relatives (n=14) of suicide completers without personal histories of suicide attempts were compared to individuals without family histories of suicide (n=14) matched for age-, sex- and education. Participants completed the Wisconsin card sorting test, a well validated test of cognitive control in a changing environment. Results: First-degree relatives of suicide completers made significantly more perseverative errors and have a lower level of conceptual responses than comparison subjects. Conclusion: Alterations found in first-degree relatives of suicide completers suggest a decreased responsiveness to changing, yet unambiguous, conditions. These neurocognitive impairments are similar to deficits observed among individuals engaging in suicide attempts. Neurocognitive impairments revealed by the Wisconsin card sorting test may represent a neurocognitive endophenotype of suicide. [Copyright &y& Elsevier]

Abstract: Objective: To estimate an upper limit on the heritability of self-reported symptoms of anxiety and depression in a large and population representative nuclear family sample. Method: The ten-item symptom checklist (SCL-10) was administered as part of a health survey in a Norwegian county. The SCL-10 is a shortened version of the SCL-25, assessing symptoms of anxiety and depression. In all, 46,064 people responded, and with data from Statistics Norway, responses of first-degree relatives could be linked. Polychoric correlations between family members score on SCL-10 were calculated, and a structural equation model was fitted to these correlations using the software package R. Results: All correlations between nuclear family members were in the range of 0.12 to 0.16, indicating small but significant familial influences on SCL-10. In the best fitting model, heritability was estimated at 0.25 (95% CI=0.22–0.27), and sibling specific environmental effects could be discarded. Conclusions: The estimated upper level heritability for SCL-10 in our sample was lower than what has been reported in twin studies of similar measures. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: This study investigates the role of harm avoidance (HA) as a possible risk factor in the familiality of obsessive-compulsive disorder (OCD). HA is considered to be a genetically influenced personality trait with an increasingly understood neuroanatomical basis. Method: 75 subjects with OCD from hospital sites and a community sample and their 152 first degree relatives and 75 age and sex matched controls with their 143 first degree relatives were evaluated with structured clinical interviews (DSM-IV). HA was assessed with Cloninger''s Tridimensional Personality Questionnaire (TPQ). Results: Subjects with OCD had higher scores of HA than controls (p ≤0.001). First degree relatives of OCD cases also showed higher HA than relatives of control subjects (p =0.001).These results remained stable when comparing only OCD subjects versus controls (p ≤0.001) and relatives of OCD cases versus relatives of controls (p =0.005) without current comorbid disorders. Limitations: The investigation of HA alone does not allow to disentangle the transmission of biological versus psychological factors related to an elevated level of anxiety in families of OCD cases. Conclusion: This is the first study to extent previous findings of elevated HA in OCD cases to their first degree relatives. Thus, HA may partially mediate the familial risk for OCD. [Copyright &y& Elsevier]

Abstract: Background: The disability and hardship associated with affective disorder is shared by the family members of affective patients and might affect the family member''s quality of life. Method: In a cross-sectional, high-risk, case–control study, monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (the control group/Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. The aim of the present study was to investigate the hypothesis that a genetic liability to affective disorder is associated with a lower perception of quality of life. Results: Univariate analyses showed that quality of life in all domains was impaired for the 121 High-Risk twins compared to the 84 Low-Risk twins. In multiple regression analyses, the differences remained significant after adjustment for sex, age, marital status and years of education. Adjusted for the effect of subclinical anxiety and depressive symptoms, the differences were significant on the domain environment and total WHOQoL-BREF and marginally significant on the domain physical health and overall quality of life. Limitations: It is not possible from the cross-sectional analyses to distinguish between subsyndromal state and trait scores. Conclusions: Perceived health related quality of life might share common familial vulnerability with affective disorders. Having a co-twin with affective disorder seem to have a negative influence on quality of life of the healthy co-twin and this influence might be due to the genetic liability to affective disorder. These findings need to be replicated in future family studies. [Copyright &y& Elsevier]

Abstract: Background: While major depressive disorder (MDD) is familial, it is not clear whether distinct familial-genetic factors influence vulnerability to depression during or after pregnancy. Here we examine familial aggregation of perinatal major depression (PND, any episode during pregnancy or the month after childbirth) and the subset of post-partum depression (PPD) in families with multiple cases of recurrent, early-onset MDD from the Genetics of Recurrent Early-Onset Depression dataset. Methods: The dataset included 691 childbearing women who could be classified as PND (27.6%) or non-PND (NPND), of whom 328 were members of 148 sibships with two or more PND or NPND women. PND and NPND subjects were compared for differences in putative predictors. Prediction of sibling PND or PPD by the proband''s history was examined using logistic regression and general estimating equation methods. Results: PND was associated with fewer episodes and younger current age. Odds ratios for prediction of sibling status were significant for PND (2.28) and PPD (3.96), particularly when current age was under 46 (2.87 and 4.39, respectively). ORs for PPD were not significantly different from those for PND. The OR for PPD (3.52), but not for PND, remained significant after current age was introduced as a covariate, but not when both current age and number of episodes were included in the model. Limitations: Because detailed data were not collected for all pregnancies, we cannot determine whether current age and number of episodes mediated the observed effects due to recall bias or other factors (cohort effect, number of episodes). Conclusions: A familial component to PND, and particularly PPD, is suggested by the results. However more systematic study is needed to confirm this result. A greater understanding of both genetic and non-genetic familial factors could lead to improved prevention and clinical management. [Copyright &y& Elsevier]

Background: The aims of this study were to identify the dominant affective temperamental characteristics of patients with bipolar disorder (BP) and their clinically well first-degree relatives and to compare the prevalence rates of these temperaments with those in healthy control subjects. Methods: One hundred bipolar I probands and their 219 unaffected first-degree relatives were enrolled in the study. The control group consisted of healthy subjects without any personal or family history of bipolar disorder, matched with the age and gender of the probands and first-degree relatives. To identify the dominant affective temperaments, the Turkish version of TEMPS-A scale was used. Results: At least one dominant temperament was found in 26% of the proband group, in 21.9% of the relative group, and 6.0% and 10.0% of the control groups, respectively. The most noteworthy finding was that both the probands and their relatives had significantly higher frequency of hyperthymic temperament than the controls. Limitations: Temperament had not been assessed premorbidly in the probands with bipolar disorder. Conclusions: The study supports the familial, possibly genetic, basis for the hyperthymic temperament in the genesis of bipolar I dosorder. That the cyclothymic temperament was not similarly represented, may be due to the higher specificity of the cyclothymic temperament to the bipolar II sybtype (which we did not study). More research is needed on the relevance of cyclothymic and other temperaments to the genetics of bipolar disorders selected by rigorous subtyping along the clinical spectrum of bipolarity. [Copyright &y& Elsevier]

Background: Whereas a growing body of evidence suggests that cycloid psychoses have to be separated from schizophrenic psychoses, their relations to bipolar affective disorder are less clear. To further clarify this issue a controlled family study was undertaken. Methods: All living and traceable adult first-degree relatives of 45 cycloid psychotic, 32 manic-depressive and 27 control probands were personally examined by an experienced psychiatrist blind to the diagnosis of the index proband. Data about not traceable relatives were collected by the “Family-History”-Method. A catamnestic diagnosis was established for each of the 431 relatives blind to family data. Age-corrected morbidity risks were calculated using the life-table method. Results: Relatives of cycloid psychotic patients showed a significantly lower morbidity risk for endogenous psychoses in general and manic-depressive illness compared to relatives of patients with manic-depressive illness. The familial morbidity risk for cycloid psychoses was low and did not differ significantly in both proband groups. Relatives of cycloid psychotic patients however did not differ significantly from relatives of controls regarding familial morbidity. Limitations: Our time-consuming methodical procedure implicated a relatively small number of participants due to restricted personnel resources. The restriction to hospitalised probands could possibly cause a limited representativity of the study sample. Conclusions: Our results suggest that cycloid psychoses are aetiologically different from manic-depressive illness and could not be integrated into a spectrum of bipolar affective disorders. The findings provide further evidence for a nosological independence of cycloid psychoses. [Copyright &y& Elsevier]

Background: Most investigators accept that schizophrenia and bipolar disorders are distinct entities. The proponents of continuum model have challenged this dichotomy model. Methods: Information about the first-degree relatives of probands with DSM-IV diagnosis of schizophrenia (n=90), bipolar disorder (n=90), and epilepsy (n=60) was collected by using the Family Interview for Genetic Studies (FIGS). A trained psychiatrist blind to the status of index probands obtained the information. Morbid risk in relatives was calculated using abridged Weinberg’s method of age correction. Results: Rates of schizophrenia and bipolar disorder were elevated in the relatives of schizophrenia and bipolar probands, but there was no evidence of coaggregation. The risk for major depression was significantly elevated in the relatives of schizophrenia probands and was comparable to the risk in the relatives of bipolar probands. Limitations: Family history method was used to obtain information about relatives. Schizoaffective disorder patients were not included in the study and this may have amplified the distinction between schizophrenia and bipolar disorder. Conclusions: The findings suggest that schizophrenia and bipolar disorders are familially independent, but there could be a familial relationship between the predisposition to schizophrenia and to major depression. [Copyright &y& Elsevier]