Interstitial cystitis/painful bladder syndrome (IC) is a chronic pelvic pain condition which has high comorbidity with other nociplastic, or unexplained, pain disorders [e.g. fibromyalgia (FM), irritable bowel syndrome (IBS), and myalgic encephalomyelitis/chronic fatigue (ME/CFS)] and some psychiatric conditions [major depressive disorder (MDD) and panic disorder (PD)]. Here we investigated the shared familiality of IC and these other nociplastic and psychiatric conditions.

Subjects were identified in the Utah Population Database, which links genealogy data back to the 1800s to medical record diagnosis billing code data back to 1995. We computed the relative risk of each of these disorders among first (FDR), second (SDR), and third-degree relatives (TDR) of six proband groups: IC, FM, IBS, ME/CFS, PD, and MDD. Given the known familial aggregation of each of these disorders, we conducted our analyses to test for heritable interrelationships using proband subgroups whose members did not have the diagnosis assessed in their relatives.

We observed strong evidence for heritable interrelationships among all six disorders. Most analyses indicated significantly increased risk for each of the six disorders in FDR, SDR, and TDR of all or most proband groups. Out of 30 possible bidirectional disorder interrelationships, 26 were significant among FDR, 23 were significant among SDR, and 7 were significant among TDR. Clustering was observed in both close and distant relatives.

Our results support a common, heritable component to IC and other nociplastic and psychiatric conditions.

Mood disorders (MDs) are associated with somatic diseases and tend to aggregate in families. But there are limited studies on the risk of somatic diseases for relatives of patients with MDs.

To assess whether a patient’s mood disorder diagnosis is associated with a family history of somatic disorders.

This cross-sectional family study included 36 patients with MDs (66.7% women; age - 32 [11.2] years) and 68 of their relatives, and 23 healthy individuals (56,5% women; age - 30.5 [6.9] years) and 53 of their relatives. A Pearson’s χ2 test was used to compare the frequencies of family history of somatic disease. Logistic regression models were used to determine the independent association of MDs, after adjusting for the effects of sex, age, with binary characteristics.

Individuals with and without MDs had different frequencies of family history of cardiovascular (66,7% vs. 43,4%; p=0,03) and endocrinological diseases (47,2% vs. 39,1%; p=0,04). There were no statistically significant differences in the frequency of family history of gastrointestinal, pulmonary, urogenital and musculoskeletal diseases (p>0,05). Logistic regression revealed that MDs diagnosis in patients was a risk factor for cardiovascular (p=0.03, OR=3.5) and endocrinological disease (p=0.04, OR=3.7) in their relatives.

MDs are associated with the aggregation of somatic diseases in families. Future research is needed to clarify the biological reasons for this association.

No significant relationships.

Awareness of adult separation anxiety (ASA) is growing, but there is a dearth of knowledge about how separation anxiety aggregates in families. We examined the intergenerational associations of separation anxiety and other forms of internalizing problems in an American community sample of 515 predominantly white children and their parents.

Children's separation anxiety (CSA), depression, and other anxiety disorders were modeled as latent factors using diagnoses from interviews and symptom scores from questionnaires completed by mothers, fathers, and children when children were 9 years old and again 3 years later. Parents' separation anxiety was assessed via a questionnaire and parents' other anxiety, depressive, and substance use disorders were assessed with a diagnostic interview when children were nine. Relationships between parents' and children's psychopathology were modeled using s.e.m.

Mothers' and fathers' ASA were related to all three psychopathology factors in offspring, over and above other parental disorders, in concurrent and prospective analyses. CSA was also related to maternal depression concurrently and prospectively and to maternal anxiety prospectively. Of all paternal psychopathology variables, only ASA was significantly related to children's psychopathology in either model.

Results indicate that parental separation anxiety is an important, but non-specific, risk factor for children's psychopathology. The pathway by which this risk is transmitted may be genetic or environmental, and the observed statistical associations likely also encompass child-to-parent effects.

We sought to explore whether obstetric complications (OCs) are more likely to occur in the presence of familial/genetic susceptibility for schizophrenia or whether they themselves represent an independent environmental risk factor for schizophrenia.

The presence of OCs was assessed through maternal interview on 216 subjects, comprising 36 patients with schizophrenia from multiply affected families, 38 of their unaffected siblings, 31 schizophrenic patients with no family history of psychosis, 51 of their unaffected siblings and 60 normal comparison subjects. We examined the familiality of OCs and whether OCs were commoner in the patient and sibling groups than in the control group.

OCs tended to cluster within families, especially in multiply affected families. Patients with schizophrenia, especially those from multiply affected families, had a significantly higher rate of OCs compared to normal comparison subjects, but there was no evidence for an elevated rate of OCs in unaffected siblings.

Our data provides little evidence for a link between OCs and genetic susceptibility to schizophrenia. If high rates of OCs are related to schizophrenia genes, this relationship is weak and will only be detected by very large sample sizes.

Causes of the comorbidity of substance misuse with anxiety-related and depressive disorders (anxiety/depression) remain poorly known. We estimated associations of substance misuse and anxiety/depression in the general population and tested them while accounting for genetic and shared environmental factors.

We studied individuals born in Sweden 1968–1997 (n = 2 996 398) with follow-up in nationwide register data for 1997–2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Substance misuse was defined as ICD-10 alcohol or drug use disorder or an alcohol/drug-related criminal conviction. Three dimensions of ICD-10 anxiety and depressive disorders and a substance misuse dimension were identified through exploratory factor analysis.

Substance misuse was associated with a 4.5-fold (95% CI 4.50–4.58) elevated risk of lifetime generalized anxiety/depression, 4.7-fold (95% CI 4.63–4.82) elevated risk of panic disorder and agora/social phobia, and 2.9-fold elevated risk of phobias/OCD (95% CI 2.82–3.02) as compared to those without substance misuse. The associations were attenuated in within-family analyses but we found elevated risks in monozygotic twin pairs discordant for substance misuse as well as significant non-shared environmental correlations. The association between anxiety/depression and substance misuse was mainly driven by generalized anxiety/depression, whereas other anxiety/depression dimensions had minor or no independent associations with substance misuse.

Substance misuse and anxiety/depression are associated at the population level, and these associations are partially explained by familial liabilities. Our findings indicate a common genetic etiology but are also compatible with a potential partially causal relationship between substance misuse and anxiety/depression.

Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed.

The error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27).

Increased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes.

Alterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control.

Borderline personality disorder (BPD) is characterized by a heterogeneous clinical phenotype that emerges from interactions among genetic, biological, neurodevelopmental, and psychosocial factors. In the present family study, we evaluated the familial aggregation of key clinical, personality, and neurodevelopmental phenotypes in probands with BPD (n = 103), first-degree biological relatives (n = 74; 43% without a history of psychiatric disorder), and non-psychiatric controls (n = 99).

Participants were assessed on DSM-IV psychiatric diagnoses, symptom dimensions of emotion dysregulation and impulsivity, ‘big five’ personality traits, and neurodevelopmental characteristics, as part of a larger family study on neurocognitive, biological, and genetic markers in BPD.

The most common psychiatric diagnoses in probands and relatives were major depression, substance use disorders, post-traumatic stress disorder, anxiety disorders, and avoidant personality disorder. There was evidence of familial aggregation for specific dimensions of impulsivity and emotion dysregulation, and the big five traits neuroticism and conscientiousness. Both probands and relatives reported an elevated neurodevelopmental history of attentional and behavioral difficulties.

These results support the validity of negative affectivity- and impulse-spectrum phenotypes associated with BPD and its familial risk. Further research is needed to investigate the aggregation of neurocognitive, neural and genetic factors in families with BPD and their associations with core phenotypes underlying the disorder.

A recent family study of young adult males suggests a shared familial liability between attention-deficit/hyperactivity disorder (ADHD) and high body mass index (BMI), and a genome-wide meta-analysis reported a genetic correlation of 0.26 between ADHD and BMI. To date, it is unclear whether these findings generalize to the relationship between ADHD and clinically diagnosed obesity.

By linking the Swedish national registers, we identified 25 38 127 individuals born between 1973 and 2000, together with their siblings and cousins. The risk of clinical obesity in individuals with ADHD was compared with the risk in those without ADHD. The relative contributions of genetic and environmental factors to the association between ADHD and clinical obesity were examined via assessment of the familial co-aggregation of the two conditions and quantitative genetic analysis.

Individuals with ADHD were at an increased risk of clinical obesity compared with those without (risk difference 3.73%, 95% confidence interval (CI) 3.55–3.90%; risk ratio 3.05, 95% CI 2.95–3.15). Familial co-aggregation of ADHD and clinical obesity was detected and the strength of the co-aggregation decreased by decreasing genetic relatedness. The correlation between the liabilities to ADHD and clinical obesity can be entirely attributed to their genetic correlation (rg 0.30, 95% CI 0.17–0.44).

The association between ADHD and clinical obesity in adolescence and young adulthood can be entirely attributed to genetic underpinnings shared by the two conditions. Children with ADHD should be monitored for weight gain so that preventive measures can be taken for those on a suboptimal trajectory.

To investigate if the association between maternal pre-pregnancy BMI and offspring’s body composition in late adolescence and young adulthood varies by offspring birth order and sex.

Family cohort study, with data from registers, questionnaires and physical examinations. The main outcome under study was offspring body composition (percentage fat mass (%FM), percentage lean mass (%LM)) measured by dual-energy X-ray absorptiometry.

Uppsala, Sweden.

Two hundred and twenty-six siblings (first-born v. second-born; average age 19 and 21 years) and their mothers.

In multivariable linear regression models, maternal pre-pregnancy BMI was positively associated with daughter’s %FM, with stronger estimates for first-born (β=0·97, 95 % CI 0·14, 1·80) v. second-born daughters (β=0·64, 95 % CI 0·08, 1·20). Mother’s BMI before her first pregnancy was associated with her second-born daughter’s body composition (β=1·05, 95 % CI 0·31, 1·79 (%FM)) Similar results albeit in the opposite direction were observed for %LM. No significant associations were found between pre-pregnancy BMI and %FM (β=0·59, 95 % CI−0·27, 1·44 first-born; β=−0·13, 95 % CI−0·77, 0·52 second-born) or %LM (β=−0·54, 95 % CI−1·37, 0·28 first-born; β=0·11, 95 % CI−0·52, 0·74 second-born) for sons.

A higher pre-pregnancy BMI was associated with higher offspring %FM and lower offspring %LM in late adolescence and young adulthood, with stronger associations for first-born daughters. Preventing obesity at the start of women’s reproductive life might reduce the risk of obesity in her offspring, particularly for daughters.

We aimed to provide unbiased estimates of familial risk and heritability of social anxiety disorder (SAD) and avoidant personality disorder (AVPD).

We identified 18 399 individuals diagnosed with SAD and 2673 with AVPD in the Swedish National Patient Register between 1997 and 2009. Risks (odds ratios; OR) for SAD in all biological and non-biological relatives of probands, compared to relatives of unaffected individuals were calculated. We also estimated the risks for AVPD in relatives of probands with SAD.

The risk for SAD among relatives of SAD probands increased proportionally to the degree of genetic relatedness. The risks for first-degree relatives [OR 4.74, 95% confidence interval (CI) 4.28–5.25] were significantly higher than for second-degree and third-degree relatives. Second-degree relatives (OR 2.30, 95% CI 2.01–2.63) had significantly higher risk than third-degree relatives (OR 1.72, 95% CI 1.52–1.94). Relatives at similar genetic distances had similar risks for SAD, despite different degrees of shared environment. Heritability was estimated to be approximately 56%. There were no significant sex differences in the familial patterns. The risk of AVPD in relatives of SAD probands was significantly elevated, even after excluding individuals with both diagnoses (first-degree OR 3.54, second-degree OR 2.20, third-degree OR 1.62). Non-biological relatives (spouses/partners) also had elevated risks for both SAD (OR 4.01) and AVPD (OR 3.85).

SAD clusters in families primarily due to genetic factors. SAD and AVPD are aetiologically related and may represent different expressions of the same vulnerability. The strong marital concordance observed in SAD/AVPD may indicate assortative mating but the exact mechanisms and implications require further investigation.

Individuals with borderline personality disorder (BPD) frequently display co-morbid mental disorders. These disorders include ‘internalizing’ disorders (such as major depressive disorder and anxiety disorders) and ‘externalizing’ disorders (such as substance use disorders and antisocial personality disorder). It is hypothesized that these disorders may arise from latent ‘internalizing’ and ‘externalizing’ liability factors. Factor analytic studies suggest that internalizing and externalizing factors both contribute to BPD, but the extent to which such contributions are familial is unknown.

Participants were 368 probands (132 with BPD; 134 without BPD; and 102 with major depressive disorder) and 885 siblings and parents of probands. Participants were administered the Diagnostic Interview for DSM-IV Personality Disorders, the Revised Diagnostic Interview for Borderlines, and the Structured Clinical Interview for DSM-IV.

On confirmatory factor analysis of within-person associations of disorders, BPD loaded moderately on internalizing (factor loading 0.53, s.e. = 0.10, p < 0.001) and externalizing latent variables (0.48, s.e. = 0.10, p < 0.001). Within-family associations were assessed using structural equation models of familial and non-familial factors for BPD, internalizing disorders, and externalizing disorders. In a Cholesky decomposition model, 84% (s.e. = 17%, p < 0.001) of the association of BPD with internalizing and externalizing factors was accounted for by familial contributions.

Familial internalizing and externalizing liability factors are both associated with, and therefore may mutually contribute to, BPD. These familial contributions account largely for the pattern of co-morbidity between BPD and internalizing and externalizing disorders.

Relatives of schizophrenia patients demonstrate abnormalities in prefrontal cortical activation during executive processing as measured by functional neuroimaging, albeit not consistently. A meta-analysis was conducted to determine whether reliable patterns of brain hypo- and hyperactivity, especially in the middle frontal region, were present in the relatives of patients.

Seventeen studies, containing 18 samples of relatives and controls, were included in this meta-analysis. Studies were included if relatives of schizophrenia patients were compared to controls, an executive processing task was used, and standard space coordinates were reported for the functional activations. Activation likelihood estimation (ALE) was implemented to find convergence across functional neuroimaging experiment coordinates. A separate analysis was conducted to assess the potential impact of a priori hypothesis testing used in region-of-interest (ROI) approaches on the meta-analysis results.

Relatives demonstrated hypo- and hyperactivity in statistically overlapping right middle frontal regions [Brodmann area (BA) 9/10]. Use of an ROI analysis that a priori focused on prefrontal regions resulted in more findings of reduced activity in the middle frontal region.

The cortical regions identified by this meta-analysis could potentially serve as intermediate biological markers in the search for candidate genes for schizophrenia. As neurocognitive deficits are related to functional impairments in patients, a better understanding of neural and genetic vulnerabilities would be beneficial in our efforts to remediate these important deficits.

To estimate the spectrum of familial risk for psychopathology in first-degree relatives of children with unabridged DSM-IV bipolar-I disorder (BP-I).

We conducted a blinded, controlled family study using structured diagnostic interviews of 157 children with BP-I probands (n=487 first-degree relatives), 162 attention deficit hyperactivity disorder (ADHD) (without BP-I) probands (n=511 first-degree relatives), and 136 healthy control (without ADHD or BP-I) probands (n=411 first-degree relatives).

The morbid risk (MR) of BP-I disorder in relatives of BP-I probands (MR=0.18) was increased 4-fold [95% confidence interval (CI) 2.3–6.9, p<0.001] over the risk to relatives of control probands (MR=0.05) and 3.5-fold (95% CI 2.1–5.8, p<0.001) over the risk to relatives of ADHD probands (MR=0.06). In addition, relatives of children with BP-I disorder had high rates of psychosis, major depression, multiple anxiety disorders, substance use disorders, ADHD and antisocial disorders compared with relatives of control probands. Only the effect for antisocial disorders lost significance after accounted for by the corresponding diagnosis in the proband. Familial rates of ADHD did not differ between ADHD and BP-I probands.

Our results document an increased familial risk for BP-I disorder in relatives of pediatric probands with DSM-IV BP-I. Relatives of probands with BP-I were also at increased risk for other psychiatric disorders frequently associated with pediatric BP-I. These results support the validity of the diagnosis of BP-I in children as defined by DSM-IV. More work is needed to better understand the nature of the association between these disorders in probands and relatives.

There has been increasing interest in the validity and familial transmission of subthreshold psychiatric conditions and the relationship between subthreshold conditions and full syndrome (FS) disorders. However, most of these studies examined a single subthreshold condition and thus fail to take into account the high co-morbidity among subthreshold conditions and between subthreshold conditions and FS disorders.

A family study of subthreshold psychiatric conditions was conducted with 739 community-drawn young adults and their 1744 relatives. We examined (1) whether relatives of probands with subthreshold major depression, bipolar disorder, anxiety disorders, alcohol use, substance use, and/or conduct disorder exhibited an increased rate of the corresponding (homotypic) FS disorder; (2) whether subthreshold disorders were associated with increased familial rates of other (heterotypic) FS disorders; (3) whether subthreshold and FS conditions are associated with similar familial liabilities; and (4) whether these homotypic and heterotypic associations persisted after controlling for co-morbidity.

Significant homotypic associations were observed for subthreshold anxiety, alcohol, conduct, and a trend was observed for major depression. Only the homotypic association for alcohol and conduct remained after controlling for co-morbid subthreshold and FS conditions. Many heterotypic associations were observed and most remained after controlling for co-morbidity.

It is important to broaden the study of subthreshold psychopathology to multiple disorders. In particular cases, controlling for co-morbidity with other subthreshold and FS conditions altered the patterns of familial aggregation. Etiological processes that are common to particular disorders and subthreshold conditions are discussed.