Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Tiina Paunio on työryhmän UK10K jäsen.The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.Peer reviewe

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Health care providers' perceptions of and attitudes towards induced abortions in sub-Saharan Africa and Southeast Asia : a systematic literature review of qualitative and quantitative data.

BACKGROUND: Unsafe abortions are a serious public health problem and a major human rights issue. In low-income countries, where restrictive abortion laws are common, safe abortion care is not always available to women in need. Health care providers have an important role in the provision of abortion services. However, the shortage of health care providers in low-income countries is critical and exacerbated by the unwillingness of some health care providers to provide abortion services. The aim of this study was to identify, summarise and synthesise available research addressing health care providers' perceptions of and attitudes towards induced abortions in sub-Saharan Africa and Southeast Asia. METHODS: A systematic literature search of three databases was conducted in November 2014, as well as a manual search of reference lists. The selection criteria included quantitative and qualitative research studies written in English, regardless of the year of publication, exploring health care providers' perceptions of and attitudes towards induced abortions in sub-Saharan Africa and Southeast Asia. The quality of all articles that met the inclusion criteria was assessed. The studies were critically appraised, and thematic analysis was used to synthesise the data. RESULTS: Thirty-six studies, published during 1977 and 2014, including data from 15 different countries, met the inclusion criteria. Nine key themes were identified as influencing the health care providers' attitudes towards induced abortions: 1) human rights, 2) gender, 3) religion, 4) access, 5) unpreparedness, 6) quality of life, 7) ambivalence 8) quality of care and 9) stigma and victimisation. CONCLUSIONS: Health care providers in sub-Saharan Africa and Southeast Asia have moral-, social- and gender-based reservations about induced abortion. These reservations influence attitudes towards induced abortions and subsequently affect the relationship between the health care provider and the pregnant woman who wishes to have an abortion. A values clarification exercise among abortion care providers is needed

Decision-making preceding induced abortion: a qualitative study of women’s experiences in Kisumu, Kenya

Background Unwanted pregnancies and unsafe abortions are prevalent in regions where women and adolescent girls have unmet contraceptive needs. Globally, about 25 million unsafe abortions take place every year. In countries with restrictive abortion laws, safe abortion care is not always accessible. In Kenya, the high unwanted pregnancy rate resulting in unsafe abortions is a serious public health issue. Gaps exist in knowledge regarding women’s decision-making processes in relation to induced abortions in Kenya. Decision-making is a fundamental factor for consideration when planning and implementing contraceptive services. This study explored decision-making processes preceding induced abortion among women with unwanted pregnancy in Kisumu, Kenya. Methods Individual face-to-face in-depth interviews were conducted with nine women aged 19–32 years old. Women who had experienced induced abortion were recruited after receiving post-abortion care at the Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH) or Kisumu East District Hospital (KDH) in Kisumu, Kenya. In total, 15 in-depth interviews using open-ended questions were conducted. All interviews were tape-recorded, transcribed and coded manually using inductive content analysis. Results Respondents described their own experiences regarding decision-making preceding induced abortion. This study shows that the main reasons for induced abortion were socio-economic stress and a lack of support from the male partner. In addition, deviance from family expectations and gender-based norms highly influenced the decision to have an abortion among the interviewed women. The principal decision maker was often the male partner who pressed for the termination of the pregnancy indirectly by declining his financial or social responsibilities or directly by demanding termination. In some cases, the male partner controlled decision-making by arranging an unsafe abortion without the woman’s consent. Strategic choices regarding whom to confide in were employed as protection against abortion stigma. This contributed to a culture of silence around abortion and unwanted pregnancy, a factor that made women more vulnerable to complications. Conclusions The findings suggest that financial, social and gender-based dependencies influence women’s agency and perceived options in decision-making regarding abortion.Open Access APC beslut 20/2018</p

Ovariectomy Reduces Vasocontractile Responses of Rat Middle Cerebral Arteries After Focal Cerebral Ischemia

ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized (OVX) females treated with 17β-estradiol, progesterone, or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed by reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from OVX females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine was diminished after I/R, with arteries from OVX females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of OVX females affected I/R-induced changes in endothelin B- and 5-carboxamidotryptamine-induced vasocontraction. These findings suggest that sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process

Abortion and contraceptive use stigma : a cross-sectional study of attitudes and beliefs in secondary school students in western Kenya.

Social stigma related to women's reproductive decision-making negatively impacts the health of women. However, little is known about stigmatising attitudes and beliefs surrounding abortion and contraceptive use among adolescents. The aim of this study was to measure stigmatising attitudes and beliefs regarding abortion and contraceptive use among secondary school students in western Kenya. A self-reported classroom questionnaire-survey was administered in February 2017 to students at two suburban secondary schools in western Kenya. Two scales were used to measure the stigma surrounding abortion and contraceptive use - the Adolescent Stigmatizing Attitudes, Beliefs and Actions (ASABA) scale and the Contraceptive Use Stigma (CUS) scale. 1,369 students were eligible for the study; 1,207 (females = 618, males = 582) aged 13-21 years were included in the analysis. Descriptive statistics, Pearson's χ2 test, and the t-test were used to analyse the data. Binary logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI). The students reported stigma associated with abortion (53.2%), and contraceptive use (54.4%). A larger proportion of male students reported abortion stigma (57.7%) and contraceptive use stigma (58.5%), compared to female students (49.0%, p = .003 and 50.6%, p = .007, respectively). Higher scores were displayed by younger rather than older age groups. No associations were identified between sexual debut and abortion stigma (p = .899) or contraceptive use stigma (p = .823). Abortion and contraceptive use are stigmatised by students in Kenya. The results can be used to combat abortion stigma and to increase contraceptive use among adolescents in Kenya