Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Clinical Considerations for Conducting Child-Parent Psychotherapy with Young Children with Developmental Disabilities Who Have Experienced Trauma

Child-Parent Psychotherapy (CPP) is an evidence-based treatment for children age 0-5 who have experienced at least one traumatic event and/or are experiencing mental health, attachment, and/or behavioral problems. Harley, Williams, Zamora, & Lakatos (2014) use a case study approach to examine the utility of CPP for working with children with developmental disabilities. They share specific ways in which the model can be tailored for this population. In this commentary, we reflect on their work with James, a 14-month old Latino boy with global delays related to a stroke he suffered after surgery for a congenital heart defect, and Juan, a 6 year, 2 month old boy diagnosed as autistic who has also experienced multiple traumas. We highlight interventions that address core CPP goals and discuss the need to address four key topic areas when conducting CPP with children with disabilities: 1) the importance of addressing risks that present within the caregiver-child relationship, including caregivers’ unresolved grief; 2) the potential for the caregiver or child’s history of trauma to contribute to challenges in the child and caregiver’s functioning; 3) the importance of working as part of an interdisciplinary team to coordinate care and better address the complex needs of families; and 4) the importance of applying a socio-cultural lens in every aspect of the work.

Parental Representations in the Play of Preschool Aged Witnesses of Marital Violence

The play of young children has long been used clinically to understand children’s experiences and inner feelings. More recently, children’s play has been examined quantitatively to understand differences due to varying backgrounds, family relationships, etc. Forty preschool children (21 girls and 19 boys) aged 27 to 71 months from families with histories of domestic violence were observed using a play interview, The MacArthur Story Stem Battery, to determine if severity of violence, frequency of visitation with their previously violent fathers, and mother-child relationship functioning impacted how parents were represented in play. Overall, girls represented their parents more positively regardless of other family circumstances. Boys, especially those who did not visit regularly with their fathers, had negative representations of their mothers. Severity of violence did not predict negative parental representations in the sample

Assessing Angels in the Nursery: A Pilot Study of Childhood Memories of Benevolent Caregiving as Protective Influences

This pilot study provides the first empirical test of the concept of \u27Angels in the Nursery\u27 by examining whether childhood memories of benevolent caregiving experiences protect against heightened levels of psychopathology in high-risk mothers. The study hypothesized that (a) elaborated childhood memories of feeling loved by a caregiver (\u27angel memories\u27) would moderate adulthood posttraumatic stress disorder (PTSD) symptoms in mothers with childhood maltreatment histories, and (b) spontaneous traumatic intrusions (\u27ghost memories\u27) would mediate childhood maltreatment and adulthood PTSD symptoms. Participants were 54 mothers ( M = 32.79 years, SD = 8.91; 59.2% African American, 13.0% Caucasian, 5.6% Latina, 22.2% biracial/multiracial) who completed standardized assessments of childhood maltreatment and adulthood PTSD symptoms, and a novel instrument, the Angels in the Nursery Interview (\u27Angels Interview,\u27 Van Horn, Lieberman, & Harris, 2008). Results showed that angel memories significantly moderated childhood maltreatment and adulthood PTSD symptoms, consistent with a protective effect. Higher levels of ghost memories during the Angels Interview were significantly associated with more extensive childhood maltreatment, but did not mediate maltreatment and PTSD symptoms. Findings indicate that the Angels Interview can identify pathogenic intrusions rooted in childhood maltreatment and protective factors to promote maternal mental health and buffer the intergenerational transmission of trauma

The Effects of Father Visitation on Preschool Aged Witnesses of Domestic Violence

Fifty preschool children with varying amounts of visitation with their previously violent fathers were studied to determine if the amount of father visitation was related to their behavioral functioning. The possible association of the severity of violence witnessed and the quality of the mother-child relationship on child behaviors was also assessed. There was a significant negative relationship between internalizing and externalizing behaviors, as measured by the Child Behavior Checklist, and frequency of father visitation. Children who saw their fathers less frequently evidenced higher internalizing and externalizing scores. More severe levels of violence perpetrated by the father significantly predicted increased externalizing behavior scores but not internalizing scores. Severity of violence was more predictive of externalizing behaviors than frequency of father visitation

The Long-Term Consequences of Early Childhood Trauma: A Case Study and Discussion.

There is a great need to better understand the impact of traumatic events very early in life on the course of children\u27s future development. This report focuses on the intriguing case of a girl who witnessed the murder of her mother by her father at the age of 19 months and seemed to have no recollection of this incident until the age of 11, when she began to exhibit severe symptoms of posttraumatic stress disorder (PTSD) in response to a traumatic reminder. The case presentation serves as the basis for a discussion regarding pertinent issues involved in early childhood trauma. This case and accompanying discussion were originally presented at the 19th Annual Meeting of the International Society for Traumatic Stress Studies and were transcribed and revised for use in this article. Specific topics include early childhood memory and trauma, learning and the appraisal of danger, and PTSD and traumatic grief in early childhood. Clinical and public health implications are also discussed. This case illustrates the dramatic impact that preverbal traumatic memories can have on children\u27s later functioning and speaks to the importance of assisting very young children in the immediate aftermath of traumatic events