International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Considering social work assessment of families

Since the 1990s the way in which social workers respond to referrals of children to Children’s Social Care departments has evolved. It has moved through a process that ‘screens families out’ of child protection assessment to a system aiming to ‘screen families in’ where necessary, and now uses a holistic assessment aiming to screen for both risk and need. The assessment framework developed to assess children in need and their families is the modern social work response to all referrals. Little research has been carried out to assess its suitability as a widespread social work response. This article considers the debates that have emerged in relation to its use and concludes that insufficient consideration has been given to evaluating assessment as an appropriate measure of need and risk. Wider provision of non-assessed universal services would reduce the need for assessment

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Municipal Law- Negligence- Failure of Police to Provide Protection to the Holder of Family Court Order of Protection States a Valid Cause of Action

In defining family, it is possible to include a group home designed by the state to emulate a traditional family unit. This case examines the Group House of Port Washington, Inc. v. Board of Zoning and Appeals of the Town of North Hempstead

New-Onset Rheumatologic Disease in an Elderly Patient Initially Presenting as Worsening Sequelae of Longstanding Peripheral Vascular Disease

Systemic lupus erythematosus (SLE) is an autoimmune disease that is believed to activate and attack nuclear antigens in genetically susceptible individuals after exposure to environmental factors causing cell damage.1,2 Although it is most common in females of child-bearing age, initial presentation is not strictly limited to this population, as onset over the age of 50 years is reported in 3-18% of cases.2 The common manifestations of SLE affect nearly every system of the body and may include arthralgia, myalgia, fever, rash, hepatosplenomegaly, lymphadenopathy, pleuritis, glomerulonephritis, pericarditis and neuropsychiatric manifestations.1-3 Common laboratory findings in SLE with varying degrees of sensitivity and specificity include anti-nuclear antibodies (ANA), anti-doublestranded DNA antibodies (anti-dsDNA), anti-histone antibodies, elevated inflammatory markers, and decreased levels of complements C3 and C4.1 Treatment is typically aimed toward symptom management and prevention of organ damage; thus, treatment regimens are typically dictated by the organ systems involved and symptoms experienced.1 Hydralazine, a vasodilating drug used for treatment of hypertension, has been demonstrated to cause various rheumatologic complications, including a lupus-like syndrome and an anti-neutrophil cytoplastic antibody (ANCA) vasculitis, which tend to present with overlapping features.3-5 Notably, both of these hydralazine-induced rheumatologic diseases tend to present similarly to their primary counterparts but with less severity and less organ involvement; however, hydralazine-induced lupus is particularly prevalent in the elderly population whereas the limited data available regarding hydralazine-induced ANCA vasculitis is inconclusive regarding a predominant age-group affected.3-5 The definitive treatment of both of these complications of hydralazine therapy is early identification and intervention with cessation of hydralazine therapy, given that in both diseases, symptoms typically resolve upon cessation of the offending agent.3,4 With this treatment in mind, cessation of the offending agent can also be diagnostic in terms of determining whether a patient’s clinical presentation is due to primary or drug-induced rheumatologic disease. Here, we present a 78-year-old woman, Mrs. J, who was on long-term hydralazine therapy with apparently worsening complications of her known peripheral artery disease, chronic kidney disease, and type 2 diabetes mellitus and was subsequently found to have several findings concerning for new-onset underlying rheumatologic disease, possibly hydralazine-induced

Poor sleep Quality and Obstructive Sleep Apnea are Associated with Maternal Mood, and Anxiety Disorders in Pregnancy

Background: Previous studies suggest sleep quality and obstructive sleep apnea (OSA) may be associated with psychiatric symptoms, including depression, anxiety, and posttraumatic stress disorder (PTSD). However, few studies have examined the relationship between sleep quality and OSA with maternal psychiatric symptoms during pregnancy, a state of vulnerability to these disorders. Objective: The objective of our study is to examine the association between poor sleep quality and sleep apnea with antepartum depression, anxiety, and PTSD among pregnant women. Methods: A cross-sectional study was conducted among women seeking prenatal care in Lima, Peru. Sleep quality was measured using the Pittsburgh Sleep Quality Index, and the Berlin questionnaire was used to identify women at high risk for OSA. Depression, generalized anxiety, and PTSD symptoms were measured using the Patient Health Questionnaire-9, Generalized Anxiety Disorder Assessment, and PTSD Checklist – Civilian Version. Multivariate logistic regression procedures were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Results: Approximately 29.0X% of women had poor sleep quality, and 6.2% were at high risk for OSA. The prevalence of psychiatric symptoms was high in this cohort with 25.1%, 32.5%, and 30.9% of women reporting symptoms of antepartum depression, antepartum anxiety, and PTSD, respectively. Women with poor sleep quality had higher odds of antepartum depression (aOR = 3.28; 95%CI: 2.64–4.07), generalized anxiety (aOR = 1.94; 95%CI: 1.58–2.38), and PTSD symptoms (aOR = 2.81; 95% CI: 2.28–3.46) as compared with women who reported good sleep quality. Women with a high risk of OSA had higher odds of antepartum depression (aOR = 2.36; 95% CI: 1.57–3.56), generalized anxiety (aOR = 2.02, 95% CI: 1.36–3.00), and PTSD symptoms (aOR = 2.14; 95%CI: 1.43–3.21) as compared with those with a low risk of sleep apnea. Conclusions: Poor sleep quality and high risk of OSA are associated with antepartum depression, generalized anxiety, and PTSD symptoms among pregnant women. Further characterizations of the associations of these prevalent sleep, mood, and anxiety conditions among pregnant women could aid in evaluating and delivering optimal perinatal care to women with these comorbidities.National Institutes of HealthRevisión por pare