Salivary melatonin onset in youth at familial risk for bipolar disorder

Melatonin secretion and polysomnography (PSG) were compared among a group of healthy adolescents who were at high familial risk for bipolar disorder (HR) and a second group at low familial risk (LR). Adolescent participants (n = 12) were a mean age 14 ± 2.3 years and included 8 females and 4 males. Saliva samples were collected under standardized condition light (red light) and following a 200 lux light exposure over two consecutive nights in a sleep laboratory. Red Light Melatonin onset (RLMO) was defined as saliva melatonin level exceeding the mean of the first 3 readings plus 2 standard deviations. Polysomnography was also completed during each night. HR youth, relative to LR, experienced a significantly earlier melatonin onset following 200 lux light exposure. Polysomnography revealed that LR youth, relative to HR, spent significantly more time in combined stages 3 and 4 (deep sleep) following red light exposure. Additionally, regardless of the group status (HR or LR), there was no significant difference in Red Light Melatonin Onset recorded at home or in the laboratory, implying its feasibility and reliability

Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder

Bipolar disorder (BD) is associated with a 20–30-fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRSs)—a quantitative index of genomic risk—and variability in brain structures implicated in SA. Participants (n = 206; aged 12–30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives (“high risk”), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRSs were computed using genome-wide association data for SA in BD (SA-in-BD), SA in major depressive disorder (SA-in-MDD) (Mullins et al., 2019, The American Journal of Psychiatry, 176(8), 651–660), and risky behavior (Karlsson Linnér et al., 2019, Nature Genetics, 51(2), 245–257). Structural magnetic resonance imaging processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction. SA-in-MDD and SA-in-BD PRSs negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRSs inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the “high risk” group. SA-in-MDD and SA-in-BD PRSs positively predicted cuneus structure, irrespective of group. This study demonstrated associations between PRSs for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRSs, in conjunction with a range of biological, phenotypic, environmental, and experiential data in high risk populations, may inform predictive models for suicidal behaviors.Australian National Health and Medical Research Council (NHMRC); Lansdowne Foundation, Paul and Jenny Reid, Good Talk, and the Keith Pettigrew Family Bequest. DNA extraction was undertaken by Genetic Repositories Australia (GRA; www.neura.edu.au/GRA), Claudio Toma is a recipient of a “Ramón y Cajal” fellowship (RYC2018-024106-I) from the Spanish MINECO. This research was undertaken with the assistance of resources from the National Computational Infrastructure (NCI), which is supported by the Australian Governmen

Patterns and predictors of family environment among adolescents at high and low risk for familial bipolar disorder

Children's perceptions are important to understanding family environment in the bipolar disorder (BD) high-risk context. Our objectives were to empirically derive patterns of offspring-perceived family environment, and to test the association of family environment with maternal or paternal BD accounting for offspring BD and demographic characteristics. Participants aged 12–21 years (266 offspring of a parent with BD, 175 offspring of a parent with no psychiatric history) were recruited in the US and Australia. We modeled family environment using latent profile analysis based on offspring reports on the Conflict Behavior Questionnaire, Family Adaptability and Cohesion Evaluation Scales, and Home Environment Interview for Children. Parent diagnoses were based on the Diagnostic Interview for Genetic Studies and offspring diagnoses were based on the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. Latent class regression was used to test associations of diagnosis and family environment. Two-thirds of all offspring perceived well-functioning family environment, characterized by nurturance, flexibility, and low conflict. Two ‘conflict classes’ perceived family environments low in flexibility and cohesion, with substantial separation based on high conflict with the father (High Paternal Conflict), or very high conflict and rigidity and low warmth with the mother (High Maternal Conflict). Maternal BD was associated with offspring perceiving High Maternal Conflict (OR 2.8, p = 0.025). Clinical care and psychosocial supports for mothers with BD should address family functioning, with attention to offspring perceptions of their wellbeing. More research is needed on the effect of paternal BD on offspring and family dynamics

Substance Use Disorders in Adolescent and Young Adult Relatives of Probands with Bipolar Disorder: What Drives the Increased Risk?

Background Adults with bipolar disorder (BD) have higher rates of substance use disorders (SUDs) compared to the general population. SUD rates in young offspring/relatives of BD probands, as well as factors which drive those rates, are not as well-characterized. Methods We aimed to examine SUD prevalence among adolescent/young adult offspring and relatives of probands with and without BD. Data were collected from five sites in the US and Australia during 2006–2011. Youth offspring/relatives (“Relatives of BD probands;” n = 267; mean age = 16.8 years; ± 2.9 S.D.), identified through a proband family member with DSM-IV BD (Type I or II), were compared to offspring/relatives of control probands (“relatives of control probands;” n = 149; mean age = 17.4 years; ± 2.9 S.D.). Logistic regression with generalized estimating equations was used to compare the groups across a range of substance use and SUD variables. Odds ratios were calculated for lifetime prevalence of substance outcomes. Results Bivariate analyses showed DSM-IV SUDs were more prevalent among relatives of BD probands than among relatives of control probands (29% vs. 18%; p = 0.01). Generalized estimating equation models showed BD mood and childhood-onset externalizing disorders in adolescent and young adult relatives to each significantly increase the odds (OR = 2.80–3.17; p < 0.02) for the development of several substance variables among all relatives, whereas the risk of SUDs in relatives was not increased when the relatives had no mood or externalizing disorders themselves. Conclusion Relatives of BD probands with lifetime mood and externalizing disorders report more substance use/SUDs than relatives of control probands. In contrast, SUD outcomes in relatives of BD probands without mood or externalizing disorders were no different from control relatives without psychopathology. Early recognition and treatment of psychiatric disorders may lead to less substance use in this highly vulnerable population

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113761/1/ajmgb32344.pd

Using linkage studies combined with whole-exome sequencing to identify novel candidate genes for familial colorectal cancer

Colorectal cancer (CRC) is a complex disorder for which the majority of the underlying germline predisposition factors remain still unidentified. Here, we combined whole‐exome sequencing (WES) and linkage analysis in families with multiple relatives affected by CRC to identify candidate genes harboring rare variants with potential high‐penetrance effects. Forty‐seven affected subjects from 18 extended CRC families underwent WES. Genome‐wide linkage analysis was performed under linear and exponential models. Suggestive linkage peaks were identified on chromosomes 1q22-q24.2 (maxSNP = rs2134095; LODlinear = 2.38, LODexp = 2.196), 7q31.2-q34 (maxSNP = rs6953296; LODlinear = 2.197, LODexp = 2.149) and 10q21.2-q23.1 (maxSNP = rs1904589; LODlinear = 1.445, LODexp = 2.195). These linkage signals were replicated in 10 independent sets of random markers from each of these regions. To assess the contribution of rare variants predicted to be pathogenic, we performed a family‐based segregation test with 89 rare variants predicted to be deleterious from 78 genes under the linkage intervals. This analysis showed significant segregation of rare variants with CRC in 18 genes (weighted p‐value > 0.0028). Protein network analysis and functional evaluation were used to suggest a plausible candidate gene for germline CRC predisposition. Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data. This approach can be used with already available NGS data from families with several sequenced members to further identify candidate genes involved germline predisposition to disease. This approach resulted in one candidate gene associated with increased risk of CRC but needs evidence from further studies

Traumatic Stress Interacts With Bipolar Disorder Genetic Risk to Increase Risk for Suicide Attempts

Objective Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls). Method Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score. Results After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p = .014), and BD polygenic risk score was marginally associated with attempts (p = .061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p = .041). Conclusion BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability

Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing

SUPPLEMENTARY MATERIAL accompanies this paper athttp://links.lww.com/CTG/A114OBJECTIVES: Serrated polyposis syndrome (SPS) is a complex disorder with a high risk of colorectal cancer for which the germline factors remain largely unknown. Here, we combined whole-exome sequencing (WES) and linkage studies in families with multiple members affected by SPS to identify candidate genes harboring rare variants with higher penetrance effects. METHODS: Thirty-nine affected subjects from 16 extended SPS families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. The contribution of rare coding variants selected to be highly pathogenic was assessed using the gene-based segregation test. RESULTS: significant linkage peak was identified on chromosome 3p25.2-p22.3 (maxSNP = rs2293787; LODlinear = 2.311, LODexp = 2.11), which logarithm of the odds (LOD) score increased after fine mapping for the same marker (maxSNP = rs2293787; LODlinear = 2.4, LODexp = 2.25). This linkage signal was replicated in 10 independent sets of random markers from this locus. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 11 rare variants predicted to be deleterious from 10 genes under the linkage intervals. This analysis showed significant segregation of rare variants with SPS in CAPT7, TMEM43, NGLY1, and FBLN2 genes (weighted Pvalue > 0.007). DISCUSSION: Protein network analysis suggested FBLN2 as the most plausible candidate genes for germline SPS predisposition. Etiologic rare variants implicated in disease predisposition may be identified by combining traditional linkage with WES data. This powerful approach was effective for the identification of a new candidate gene for hereditary SPS.M.D.-G. was supported by a contract from Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (Generalitat de Catalunya, 2018FI_B1_00213). S.F.-E., C.A.-C. and J.M. were supported by a contract from CIBEREHD. Y.S.L. was supported by a fellowship (LCF/BQ/DI18/11660058) from "la Caixa" Foundation (ID 100010434) funded EU Horizon 2020 Programme (Marie Sklodowska-Curie grant agreement no. 713673). LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). CIBEREHD and CIBERONC are funded by the Instituto de Salud Carlos III. CT, BJO, and JMF were supported by Australian National Health and Medical Research (NHMRC) Project Grants 1063960 and 1066177. This research was supported by grants from Fondo de Investigacion Sanitaria/FEDER (16/00766, 17/00878), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya), and Agencia de Gestio d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). This article is based on work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). www.cost.eu.Potential competing interests: None to report

Involvement of the 14-3-3 gene family in autism spectrum disorder and schizophrenia: Genetics, transcriptomics and functional analyses

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10-7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia