Unaffected Siblings Of Patients Research Articles

Risk of traumatic brain injury among patients with ADHD and their unaffected siblings

BackgroundAs the relationship between attention deficit hyperactivity disorder (ADHD) and traumatic brain injury (TBI) is gaining increasing attention, the TBI risk in patients with ADHD, unaffected siblings of ADHD probands, and non-ADHD controls remains unclear.MethodsOverall, 18,645 patients with ADHD, 18,880 unaffected siblings of ADHD probands, and 188,800 age-/sex-matched controls were followed up from enrollment to the end of 2011. The cases of TBI and TBI requiring hospitalization were identified during follow-up.ResultsPatients with ADHD (hazard ratio [HR]: 1.57) and unaffected siblings (HR: 1.20) had an increased risk of any TBI compared with non-ADHD controls. Surprisingly, the likelihood of developing TBI requiring hospitalization during follow-up was higher in the unaffected siblings group (HR: 1.21) than in the control group, whereas it was lower in the ADHD probands group (HR: 0.86).ConclusionsPatients with ADHD and unaffected siblings of ADHD probands were more likely to develop any TBI during follow-up than controls. Unaffected siblings of patients with ADHD exhibited the highest risk of subsequent TBI requiring hospitalization compared with patients with ADHD and healthy controls. Therefore, TBI risk in patients with ADHD and their unaffected siblings would require further investigation.ImpactADHD diagnosis and ADHD trait are associated with risk of traumatic brain injury (TBI).Both patients with ADHD and their unaffected siblings were more likely to develop TBI during the follow-up compared with the control group.TBI requiring hospitalization occurred more in the sibling group than in the proband group.TBI risk should be closely monitored among unaffected siblings of patients with ADHD.

Association of celiac disease with eosinophilic esophagitis: Nationwide register-based cohort study with sibling analyses

Celiac disease (CeD) is associated with several immune-mediated disorders, but it is unclear whether it is associated with eosinophilic esophagitis (EoE). We sought to examine the risk of EoE in patients with biopsy-verified CeD compared with matched controls and siblings. Using nationwide population-based histopathology data, we identified 27,338 patients with CeD diagnosed in the period 2002 to 2017 in Sweden. Patients with CeD were age- and sex-matched with up to 5 reference individuals (n= 134,987) from the general population. Cox Regression was used to estimate hazard ratios (HRs) for developing biopsy-verified EoE. In a secondary analysis, we used unaffected siblings of patients with CeD as comparators to adjust for intrafamilial confounding. The median age at CeD diagnosis was 27 years, and 63.3% were female patients. During a median follow-up of 8.1 years, 17 patients with CeD and 13 matched reference individuals were diagnosed with EoE. This corresponded to incidence rates of 0.08 versus 0.01 per 1000 person-years, respectively, and an adjusted HR for EoE of 6.65 (95% CI, 3.26-13.81). Compared with their siblings without CeD, patients with CeD were however at a no increased risk of EoE (HR, 1.39; 95% CI, 0.55-3.51). In this study, individuals with CeD were at a 6.6-fold increased risk of later EoE compared with the general population. This association might be explained by an altered health-seeking behavior or through shared genetic or early environmental factors because the excess risk disappeared in sibling analyses.

Neurocognition and brain functional connectivity in a non-clinical population-based sample with psychotic experiences

We characterized the neurocognitive profile of communed-based individuals and unaffected siblings of patients with psychosis from Brazil reporting psychotic experiences (PEs). We also analyzed associations between PEs and the intra and inter-functional connectivity (FC) in the Default Mode Network (DMN), the Fronto-Parietal Network (FPN) and the Salience Network (SN) measured by functional magnetic resonance imaging. The combined sample of communed-based individuals and unaffected siblings of patients with psychosis comprised 417 (neurocognition) and 85 (FC) volunteers who were divided as having low (<75th percentile) and high (≥75th percentile) PEs (positive, negative, and depressive dimensions) assessed by the Community Assessment of Psychic Experiences. The neurocognitive profile and the estimated current brief intellectual quotient (IQ) were assessed using the digit symbol (processing speed), arithmetic (working memory), block design (visual learning) and information (verbal learning) subtests of Wechsler Adult Intelligence Scale-third edition. Logistic regression models were performed for neurocognitive analysis. For neuroimaging, we used the CONN toolbox to assess FC between the specified regions, and ROI-to-ROI analysis. In the combined sample, high PEs (all dimensions) were related to lower processing speed performance. High negative PEs were related to poor visual learning performance and lower IQ, while high depressive PEs were associated with poor working memory performance. Those with high negative PEs presented FPN hypoconnectivity between the right and left lateral prefrontal cortex. There were no associations between PEs and the DMN and SN FC. Brazilian individuals with high PEs showed neurocognitive impairments like those living in wealthier countries. Hypoconnectivity in the FPN in a community sample with high PEs is coherent with the hypothesis of functional dysconnectivity in schizophrenia.

Transdiagnostic dimensions of symptoms and experiences associated with immune proteins in the continuity of psychosis.

There is limited evidence as to whether the immune protein profile is associated with a particular symptomatology pattern across the psychosis continuum. We estimated two bifactor models of general and specific dimensions of psychotic experiences in unaffected siblings of patients (n = 52) and community controls (n = 200), and of psychotic symptoms in first-episode psychosis (FEP) patients (n = 110). We evaluated associations between these transdiagnostic dimensions and trait (TNF-α, IFN-γ), state (IL-6, IL-1β), and regulatory (TGF-β, IL-10, IL-4) cytokines. We explored whether schizophrenia genetic liability (schizophrenia polygenic risk score; SZ-PRS) modified the associations. High levels of trait marker IFN-γ were associated with the severity of general psychosis dimension in the unaffected siblings and community controls, expanding to the depressive dimension in siblings and to the manic dimension in FEP. High TNF-α levels were associated with more positive psychotic experiences in unaffected siblings and manic symptoms in FEP. Low levels of state markers IL-6 and IL-1β were observed in unaffected siblings presenting more depressive experiences. Still, high levels of IL-6 and IL-1β were associated with the severity of the depressive and negative symptom dimensions at FEP. The severity of transdiagnostic dimension scores across the three groups was associated with lower regulatory cytokines. Exploratory analysis suggested that a high SZ-PRS contributed mostly to associations with psychotic dimensions. IFN-γ mapped onto the multidimensional expression of psychosis, reinforcing the trait concept. State markers IL-6 and IL-1β may fluctuate along the spectrum. Dysfunction in the regulatory arm may disinhibit the inflammatory system. Associations with psychotic dimensions may be more prone to SZ-PRS susceptibility.

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.

Subclinical memory impairment in unaffected siblings of patients with dementia

Objective: Family history of dementia is a known risk factor for dementia. The cognitive performance of unaffected siblings of dementia patients has been poorly studied. We aimed to determine whether clinically unaffected siblings of dementia patients have significant cognitive impairment compared to individuals who do not have first-degree relatives with dementia. Methods: We compared the cognitive performance of 67 patients with dementia (24 males; mean age 69.5), 90 healthy siblings of those patients (34 males; mean age 61.56) and 92 healthy adults (35 males; mean age 60.96) who have no first-degree relatives with dementia. We assessed learning and memory (Rey Auditory Verbal Learning Test (RAVLT)), short-term/working memory (Digit Span) executive functions (Stroop Test) and general intelligence (Raven Progressive Matrices). Test scores were compared among three groups, with regression-based adjustments for age, sex, and education. Results: As expected, the patients with dementia were impaired in all cognitive domains. In the Sibling Group, RAVLT total learning was significantly lower compared to controls (B = −3.192, p = .005). In a subgroup analysis, compared to controls, RAVLT delayed recall was poorer in the siblings of patients with early-onset (<65 years) dementia. No significant differences were observed in other cognitive domains. Conclusion: Clinically unaffected siblings of dementia patients seem to have a selective subclinical impairment in memory encoding. This impairment seems to be more prominent in siblings of patients with early-onset dementia who also have deficits in delayed recall. Future studies are needed to determine if the observed cognitive impairment deteriorates to dementia.

Bidirectional Association Between Obsessive-Compulsive Disorder and Systemic Autoimmune Diseases Among Probands and Unaffected Siblings: A Nationwide Population-Based Study.

Studies have reported a biological link between obsessive-compulsive disorder (OCD) and systemic autoimmune disease (SAID). However, whether the unaffected siblings of patients with OCD or SAID are more likely to develop subsequent SAID or OCD later in life remains unclear. We examined the Taiwan National Health Insurance Research Database data of 17,135 patients with SAID, 30,672 unaffected siblings, and 467,211 non-SAID reference subjects born before 2000 for subsequent OCD during 1996-2011 and those of 25,364 patients with OCD, 42,546 unaffected siblings, and 654,207 non-OCD reference subjects to identify subsequent SAID during 1996-2011. Patients with SAID (odds ratio = 1.74, 95% confidence interval = 1.31-2.31) and unaffected siblings (1.25, 0.92-1.70) were more likely to develop OCD later in life than the non-SAID reference group. Moreover, patients with OCD (odds ratio = 1.53, 95% confidence interval = 1.15-2.05) and unaffected siblings (1.51, 1.21-1.87) were more likely to develop any form of SAID during the follow-up than the non-OCD reference group. The bidirectional association of OCD and SAID between probands and siblings may indicate a familial coaggregation of these two conditions. Additional studies elucidating the genetic and environmental mechanisms underlying this coaggregation are warranted.

Serum concentrations of aminoacylase 1 in schizophrenia as a potential biomarker: a case-sibling-control study

Purpose Aminoacylase 1 (ACY1) catalyzes the hydrolysis reaction during protein degradation. N-acetylamino acids are accumulated in the urine in Aminoacylase 1 deficiency (ACY1D). This study attempts to evaluate the potential of ACY1 as a biomarker for schizophrenia and predict genetic vulnerability in the high-risk population. Material and methods Seventy patients with schizophrenia, twenty-five of which have newly diagnosed, forty-nine unaffected siblings of patients, and fifty-six healthy controls were included in the study. The ELISA method was used to measure serum ACY1. The Positive and Negative Syndrome Scale (PANSS) and The Clinical Global Impression – Severity scale (CGI-S) were used to analyze the severity of the symptoms. Data were analysed statistically by non-parametric tests. Results The finding of the study indicated that the serum levels of ACY1 in patients and siblings were lower compared to healthy controls (p < 0.001 and p = 0.023). There was no statistically significant difference between patients and siblings (p = 0.067). The duration of disease, PANSS total scores, and CGI-S scores did not have a significant association with the ACY1 levels in the patient group (p > 0.005). ACY1 levels among the drug-using patient group and the newly diagnosed patient group showed no notable difference (respectively, p = 0.120 and p = 0.843). Conclusion This study is the first to evaluate the serum ACY1 levels in patients with schizophrenia. The result of the study provides us insight regarding the first hints that ACY1 might be a potential biomarker. Being aware of the molecule will pave the way for further explorations in the field.

Developmental and mental health risks among siblings of patients with autism spectrum disorder: a nationwide study

Studies have suggested that unaffected siblings of patients with autism spectrum disorder (ASD) have some other neurodevelopmental abnormalities. However, the risks of mental and developmental disorders have rarely been investigated among unaffected siblings. Using Taiwan's National Health Insurance Research Database, 1304 unaffected siblings born between 1980 and 2010 with ASD probands and 13,040 age-/sex-/family structure-matched controls were included in our study and followed up from 1996 or birth to the end of 2011. Developmental delay, language delay, developmental coordination disorder, attention-deficit hyperactivity disorder (ADHD), anxiety disorders, disruptive behavior disorders, unipolar disorder, and bipolar disorder were identified during the follow-up period. Unaffected siblings were more likely to develop any developmental delay, developmental speech or language disorder, developmental coordination disorder, intelligence disability, ADHD, anxiety disorders, unipolar depression, and disruptive behavior disorders compared with the control group. Brothers of patients with ASD had a higher risk of neurodevelopmental abnormalities, ADHD, anxiety disorders, and disruptive behavior disorders; sisters were prone to having neurodevelopmental abnormalities, ADHD, anxiety disorders, unipolar depression, and disruptive behavior disorders. Unaffected siblings of patients with ASD were prone to developing any developmental or mental disorder later in life. Clinicians and public health officials should pay more attention to the developmental condition and mental health of unaffected siblings of patients with ASD.

Cardiometabolic disease risk among siblings of patients with major depressive disorder.

Studies have suggested an association between metabolic and cerebrocardiovascular diseases and major depressive disorder (MDD). However, the risk of metabolic and cerebrocardiovascular diseases in the unaffected siblings of patients with MDD remains uncertain. Using the Taiwan National Health Insurance Research Database, 22,438 unaffected siblings of patients with MDD and 89,752 age-/sex-matched controls were selected and followed up from 1996 to the end of 2011. Individuals who developed metabolic and cerebrocardiovascular diseases during the follow-up period were identified. Compared with the controls, the unaffected siblings of patients with MDD had a higher prevalence of metabolic diseases, such as hypertension (5.0% vs. 4.5%, p = 0.007), dyslipidemia (5.6% vs. 4.8%, p < 0.001), and obesity (1.7% vs. 1.5%, p = 0.028), and cerebrocardiovascular diseases, such as ischemic stroke (0.6% vs. 0.4%, p < 0.005) and ischemic heart disease (2.1% vs. 1.7%, p < 0.001). Logistic regression analyses revealed that the unaffected siblings of patients with MDD were more likely to develop hypertension, dyslipidemia, ischemic stroke, and ischemic heart diseases during the follow-up period than the controls. Our study revealed a familial coaggregation between MDD and metabolic and cerebrocardiovascular diseases. Additional studies are required to investigate the shared pathophysiology of MDD and metabolic and cerebrocardiovascular diseases.

Cognitive performance and psychosocial functioning in unaffected siblings of bipolar disorder patients in comparison with healthy controls.

We aimed to evaluate the cognitive domains for endophenotypes and their bearing on psychosocial functioning in unaffected siblings of patients with bipolar type I disorder (BD-I). We recruited unaffected siblings (n = 60) and age (±2 years), gender and education-matched healthy control subjects (n = 60) after screening with Structured clinical interview for DSM-IV-TR axis I disorders (SCID-I) - Research Version, Young Mania rating scale (YMRS), Hamilton depression rating scale (HDRS) and Family Interview for Genetic Studies scale (FIGS). Cognitive functioning was evaluated using Addenbrooke's Cognitive Examination III Revised (ACE-III R) and Trail making tests A and B, whereas psychosocial functioning was evaluated using the Social and Occupational Functioning Assessment Scale (SOFAS). The siblings had scored significantly lower in memory tasks of ACE-III R (p < 0.001) than controls, whereas other cognitive domains were comparable. Psychosocial functioning did not differ significantly between the groups. No correlation existed between cognitive performance and psychosocial functioning. Memory functions can be considered as a possible endophenotype for BD-I.

Abnormal Regional Homogeneity in Patients With Obsessive-Compulsive Disorder and Their Unaffected Siblings: A Resting-State fMRI Study.

Objective: Previous studies suggest that abnormal brain structure and function may be neuroimaging endophenotypes of obsessive-compulsive disorder (OCD). Comparing the intrinsic brain activity of OCD patients and their unaffected siblings will help to further understand the susceptibility to, and pathological mechanisms of, OCD. We used a case–control study design aiming to establish whether the abnormal regional homogeneity (ReHo) found in OCD patients also exists in their unaffected siblings. Method: Fifteen unmedicated OCD patients, 15 of their unaffected siblings, and 30 healthy controls (HCs) received resting-state functional magnetic resonance imaging (r-s fMRI) scanning and clinical evaluation. We used the ReHo method to analyze the inter-regional synchronized activity of all participants. One-way analysis of covariance with post hoc tests was used to compare the ReHo maps across groups. A Pearson correlation analysis was conducted to assess the correlations between clinical characteristics and abnormal ReHo in OCD patients. Results: Relative to HCs, OCD patients and their unaffected siblings showed overlapping higher ReHo values in the right dorsolateral prefrontal cortex (DLPFC). Patients with OCD showed increased ReHo in left middle frontal gyrus (MFG) relative to both their unaffected siblings and HCs. In addition to the right DLPFC and left MFG, OCD patients, compared with HCs, also showed abnormal ReHo in other regions, including higher ReHo in the right superior parietal cortex and lower ReHo in the left inferior parietal cortex, right parahippocampal region, left thalamus, and right inferior temporal cortex. Compared with HCs, the unaffected siblings of patients with OCD had significantly higher ReHo in the right inferior parietal cortex, right MFG, and right supplementary motor area. There was no association between clinical symptoms and abnormal ReHo values in OCD patients. Conclusions: This study found overlapping higher ReHo values in the right DLPFC of OCD patients and their unaffected siblings. Our results suggest that the higher ReHo in the right DLPFC may be a potential neuroimaging endophenotype, which may reflect an increased genetic risk of OCD.

Risk of Atopic Diseases among Siblings of Patients with Attention-Deficit Hyperactivity Disorder: A Nationwide Population-Based Cohort Study

Background: Increasing evidence suggests a positive association between attention-deficit hyperactivity disorder (ADHD) and atopic diseases. However, the risk of atopic diseases in unaffected siblings of patients with ADHD has not been investigated. Objective: To investigate the risk of developing atopic diseases among unaffected siblings of ADHD probands. Methods: Using data from the Taiwan National Health Insurance Research Database, 20,170 unaffected siblings of patients with ADHD born between 1980 and 2000 and 80,680 age-, birth time-, and residence-matchedcontrols were included in this study. Diagnoses of atopic diseases, including asthma, atopic dermatitis, allergic rhinitis, and allergic conjunctivitis, were ascertained from 1996 or the birth time until the end of 2011. Results: Breslow-Cox proportional hazard regression analyses with adjustment for demographic data showed that compared with the controls, unaffected siblings of patients with ADHD had a higher risk of developing asthma (relative risk [RR], 1.19; 95% confidence interval [CI], 1.15–1.24), atopic dermatitis (RR, 1.10; 95% CI, 1.04–1.16), allergic rhinitis (RR, 1.17; 95% CI, 1.14–1.21), allergic conjunctivitis (RR, 1.13; 95% CI, 1.09–1.17), and any of these atopic diseases (RR, 1.13; 95% CI, 1.10–1.15). Conclusion: The unaffected siblings of ADHD probands were more likely to develop atopic diseases compared with the controls, suggesting shared risk factors for both diseases.

Risk of cardiometabolic diseases among siblings of patients with bipolar disorder

BackgroundCardiometabolic diseases are suggested to be associated with bipolar disorder. However, the risk of metabolic disorders in unaffected siblings of patients with bipolar disorder remains unclear. MethodsFrom the Taiwan National Health Insurance Research Database, 7,225 unaffected siblings of bipolar probands and 28,900 age-/sex-/income-/residence-matched control individuals were included and followed until the end of 2011. Individuals who developed metabolic disorders during the follow-up period were identified. ResultsThe unaffected siblings of bipolar probands had a higher prevalence of dyslipidemia (5.4% vs. 4.5%, p = 0.001), younger age at diagnosis of type 2 diabetes mellitus (34.81 vs. 37.22, p = 0.024), and higher prevalence of any stroke (1.5% vs. 1.1%, p = 0.007) than the controls. Moreover, only male siblings of bipolar probands had an increased risk of dyslipidemia (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.10–1.48) and higher rates of any stroke (OR: 1.38, 95% CI: 1.02–1.85) and ischemic stroke (OR: 2.43, 95% CI: 1.60–3.70) during the follow-up compared with the controls. DiscussionUnaffected siblings of bipolar patients, particularly brothers, had a higher prevalence of dyslipidemia and ischemic stroke compared with the controls. The result suggests the familial association between cardiometabolic diseases and bipolar disorder. Further research may be necessary to identify this shared etiology between the disorders.

Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents

Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology. To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations. Voxelwise genome-wide association study in a cohort of healthy adolescents aged 14 years and validation of the findings using 4 independent samples across the life span with allele-specific expression analysis of top hits. Group comparison of the identified gene-brain association among patients with schizophrenia, unaffected siblings, and healthy control individuals. This was a population-based, multicenter study combined with a clinical sample that included participants from the IMAGEN cohort, Saguenay Youth Study, Three-City Study, and Lieber Institute for Brain Development sample cohorts and UK biobank who were assessed for both brain imaging and genetic sequencing. Clinical samples included patients with schizophrenia and unaffected siblings of patients from the Lieber Institute for Brain Development study. Data were analyzed between October 2015 and April 2018. Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip. The discovery sample included 1721 adolescents (873 girls [50.7%]), with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of 8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the life span. A nonsynonymous genetic variant (minor T allele of rs13107325 in SLC39A8, a gene implicated in schizophrenia) was associated with greater gray matter volume of the putamen (variance explained of 4.21% in the left hemisphere; 8.66; 95% CI, 6.59-10.81; P = 5.35 × 10-18; and 4.44% in the right hemisphere; t = 8.90; 95% CI, 6.75-11.19; P = 6.80 × 10-19) and also with a lower gene expression of SLC39A8 specifically in the putamen (t127 = -3.87; P = 1.70 × 10-4). The identified association was validated in samples across the life span but was significantly weakened in both patients with schizophrenia (z = -3.05; P = .002; n = 157) and unaffected siblings (z = -2.08; P = .04; n = 149). Our results show that a missense mutation in gene SLC39A8 is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. These results may suggest a role for aberrant ion transport in the etiology of psychosis and provide a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation.

Increased risk of type 2 diabetes among the siblings of patients with schizophrenia.

Research suggests an association between metabolic disorders, such as type 2 diabetes mellitus (T2DM), and schizophrenia. However, the risk of metabolic disorders in the unaffected siblings of patients with schizophrenia remains unclear. Using the Taiwan National Health Insurance Research Database, 3135 unaffected siblings of schizophrenia probands and 12,540 age-/sex-matched control subjects were included and followed up to the end of 2011. Individuals who developed metabolic disorders during the follow-up period were identified. The unaffected siblings of schizophrenia probands had a higher prevalence of T2DM (3.4% vs. 2.6%, p = 0.010) than the controls. Logistic regression analyses with the adjustment of demographic data revealed that the unaffected siblings of patients with schizophrenia were more likely to develop T2DM (odds ratio [OR]: 1.39, 95% confidence interval [CI]: 1.10-1.75) later in life compared with the control group. Moreover, only female siblings of schizophrenia probands had an increased risk of hypertension (OR: 1.47, 95% CI: 1.07-2.01) during the follow-up compared with the controls.DiscussionThe unaffected siblings, especially sisters, of schizophrenia probands had a higher prevalence of T2DM and hypertension compared with the controls. Our study revealed a familial link between schizophrenia and T2DM in a large sample. Additional studies are required to investigate the shared pathophysiology of schizophrenia and T2DM.

Evidence for a genetic effect in altered cortical surface area but not in cortical thinning in siblings of patients with mesial temporal lobe epilepsy: Commentary on: "Abnormal temporal lobe morphology in asymptomatic relatives of patients with hippocampal sclerosis: A replication study".

Although studies have shown cortical and subcortical changes in first-degree relatives of patients with familial forms of temporal lobe epilepsy, few studies have addressed extrahippocampal morphology changes in unaffected siblings of patients with sporadic mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Alhusaini et al1 described subtle reduced cortical volumes in the anteromedial temporal cortex of asymptomatic siblings of sporadic MTLE-HS patients, suggesting that such localized traits are possibly heritable. In this issue of Epilepsia, Yaakub et al2 replicated these findings in first-degree asymptomatic relatives of patients with MTLE-HS.2 A positive history of simple febrile convulsions before the age of 4 years was present in two relatives in this study.2 Both these relatives had values above the median of the relative group for the reduced surface area in the anteromedial temporal cortex, further strengthening the possibility that these subtle morphological changes are inherited.2 Limitations of this study include the small number of subjects studied and that they side-flipped the images to increase power to detect differences, thus treating both hemispheres as if they were equal, which is not the case, as shown recently by Kong et al.3 The study by Alhusaini et al1 showed that the alterations of cortical morphology found in anteromedial regions of unaffected siblings of subjects with left MTLE-HS (more in the left entorhinal cortex and parahippocampal gyrus) differed from those found in unaffected siblings of subjects with right MTLE-HS (more in the right entorhinal cortex and temporal pole). It is of relevance that both studies1, 2 used FreeSurfer (http://surfer.nmr.mgh.harvard.edu), which measures cortical volume as a product of two distinct aspects of the cortical architecture: cortical thickness and surface area.4 Cortical thickness and surface area measurements appear to represent different early neurodevelopmental events with distinct genetic influences, as shown by Panizzon et al5 in a magnetic resonance imaging study of twins. They found that, although cortical thickness and surface area are both highly heritable (>0.80), they are mostly unrelated genetically (genetic correlation = 0.08).5 These results suggest some independence of these two surface-based measures, and potentially, their asymmetry patterns. A recent study that mapped cortical brain asymmetry in 17 141 healthy individuals showed regions with different asymmetrical patterns in cortical thickness and surface area and a significant heritability of these asymmetry characteristics.3 Effect sizes of cortical thickness and surface area were independent, and the asymmetry was generally more prominent for surface area compared with that of cortical thickness.3 Most regions showed significant asymmetry in surface area, although with no clear directional pattern affecting neighboring regions, or along the anterior-posterior axis, as they observed for cortical thickness.3 Widespread cerebral cortical thinning has been identified in patients with MTLE as compared to healthy controls within several cortical regions, including the mesiotemporal, limbic, and central sensorimotor cortices.6 This pattern of cortical thinning appeared progressive in patients with medically refractory epilepsy,6 but also to a lesser degree in MTLE patients under seizure control.7 Less attention has been paid to cortical surface area in studies of MTLE patients. Interestingly, both Alhusaini et al1 and Yaakub et al2 found reduced cortical surface areas in anteromedial temporal regions of asymptomatic siblings of sporadic MTLE-HS patients, but no significant changes in cortical thickness. This lack of cortical thickness changes has been confirmed in 127 asymptomatic first-degree relatives of MTLE-HS patients from three independent cohorts, each with a healthy control group.8 These findings altogether indicate that the previously characterized progressive cortical thinning in patients with MTLE-HS is not heritable and is likely driven by disease-related factors, whereas changes in the cortical surface area may represent an inherited trait that preceded seizure onset. This hypothesis needs to be confirmed in further studies with multiple large cohorts, also taking into account the asymmetric nature of cerebral hemispheres. The author has no conflict of interest to disclose. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Glucocorticoid receptor exon 1F methylation and the cortisol stress response in health and disease

Childhood trauma has been proposed to increase vulnerability to develop psychopathology in part through an altered cortisol stress response. Research in rats has suggested that this effect is mediated by methylation in the glucocorticoid receptor 17 region (GR-17 or GR-1F in humans), with higher methylation after poor maternal care leading to an increased cortisol stress response in adulthood. In humans, the associations between childhood trauma and GR-1F methylation or the cortisol stress response are equivocal. Remarkably, evidence for the relation between GR-1F methylation and the cortisol stress response has been conflicting as well. To further explore this, we investigated the associations of peripheral GR-1F methylation (52 CpGs) with the cortisol stress response (Trier Social Stress Test) and with childhood trauma in three independent studies (total N = 241) including healthy controls, patients with schizophrenia and bipolar disorder and unaffected siblings of patients with one of these disorders. We did not find any significant association between GR-1F methylation and the cortisol stress response (areas under the curve) or childhood trauma, nor did we observe any group differences between patients, siblings and healthy controls. Our findings do not support GR-1F methylation as a proxy for the cortisol stress response, nor its link with childhood trauma or psychopathology. These results suggest that multifactorial models for stress-related psychopathology are needed. Alternatively, future longitudinal studies may reveal GR-1F methylation to be a useful parameter at an individual level.

Higher schizotypy predicts better metabolic profile in unaffected siblings of patients with schizophrenia.

Type 2 diabetes (T2D) is more frequent in schizophrenia (Sz) than in the general population. This association is partly accounted for by shared susceptibility genetic variants. We tested the hypotheses that a genetic predisposition to Sz would be associated with higher likelihood of insulin resistance (IR), and that IR would be predicted by subthreshold psychosis phenotypes. Unaffected siblings of Sz patients (n = 101) were compared with a nonclinical sample (n = 305) in terms of IR, schizotypy (SzTy), and a behavioural experiment of "jumping to conclusions". The measures, respectively, were the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Structured Interview for Schizotypy-Revised (SIS-R), and the Beads Task (BT). The likelihood of IR was examined in multiple regression models that included sociodemographic, metabolic, and cognitive parameters alongside group status, SIS-R scores, and BT performance. Insulin resistance was less frequent in siblings (31.7%) compared to controls (43.3%) (p < 0.05), and negatively associated with SzTy, as compared among the tertile groups for the latter (p < 0.001). The regression model that examined all relevant parameters included the tSzTy tertiles, TG and HDL-C levels, and BMI, as significant predictors of IR. Lack of IR was predicted by the highest as compared to the lowest SzTy tertile [OR (95%CI): 0.43 (0.21-0.85), p = 0.015]. Higher dopaminergic activity may contribute to both schizotypal features and a favourable metabolic profile in the same individual. This is compatible with dopamine's regulatory role in glucose metabolism via indirect central actions and a direct action on pancreatic insulin secretion. The relationship between dopaminergic activity and metabolic profile in Sz must be examined in longitudinal studies with younger unaffected siblings.

The Role of Intrinsic Brain Functional Connectivity in Vulnerability and Resilience to Bipolar Disorder.

Bipolar disorder is a heritable disorder characterized by mood dysregulation associated with brain functional dysconnectivity. Previous research has focused on the detection of risk- and disease-associated dysconnectivity in individuals with bipolar disorder and their first-degree relatives. The present study seeks to identify adaptive brain connectivity features associated with resilience, defined here as avoidance of illness or delayed illness onset in unaffected siblings of patients with bipolar disorder. Graph theoretical methods were used to examine global and regional brain network topology in head-motion-corrected resting-state functional MRI data acquired from 78 patients with bipolar disorder, 64 unaffected siblings, and 41 healthy volunteers. Global network properties were preserved in patients and their siblings while both groups showed reductions in the cohesiveness of the sensorimotor network. In the patient group, these sensorimotor network abnormalities were coupled with reduced integration of core default mode network regions in the ventromedial cortex and hippocampus. Conversely, integration of the default mode network was increased in the sibling group compared with both the patient group and the healthy volunteer group. The authors found that trait-related vulnerability to bipolar disorder was associated with reduced resting-state cohesiveness of the sensorimotor network in patients with bipolar disorder. However, integration of the default mode network emerged as a key feature differentiating disease expression and resilience between the patients and their siblings. This is indicative of the presence of neural mechanisms that may promote resilience, or at least delay illness onset.