A Genomics England haplotype reference panel and imputation of UK Biobank.

We built a reference panel with 342 million autosomal variants using 78,195 individuals from the Genomics England (GEL) dataset, achieving a phasing switch error rate of 0.18% for European samples and imputation quality of r = 0.75 for variants with minor allele frequencies as low as 2 × 10 in white British samples.

Uncertainty in individual risk judgments associates with vulnerability and curtailed climate adaptation.

Risk assessments are key for the effective management of potential environmental threats. Across probabilistic phenomena, climate change is an exemplar of paramount uncertainties. These uncertainties have been embraced in supporting governments' decisions; yet receive scarce attention when studying individual behavior.

Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

Background: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments.

One and done? Exploring linkages between households' intended adaptations to climate-induced floods.

As climate change increases the probability and severity of natural hazards, the need for coordinated adaptation at all levels of society intensifies. Governmental-level adaptation measures are essential, but insufficient in the face of growing risks, necessitating complementary action from households. Apprehending the drivers of household adaptation is critical if governments are to stimulate protective behavior effectively.

Contextualizing cross national patterns in household climate change adaptation.

Understanding social and behavioral drivers and constraints of household adaptation is essential to effectively address increasing climate-induced risks. Factors shaping household adaptation are commonly treated as universal; despite an emerging understanding that adaptations are shaped by social, institutional, and cultural contexts. Using original surveys in the United States, China, Indonesia, and the Netherlands (N=3,789) - we explore variations in factors shaping households' adaptations to flooding, the costliest hazard worldwide.

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

Background: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.

Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis.

Purpose: Genome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease.

Methods: GS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinized by a specialized research team, and diagnoses compared with those made by 100kGP.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets.

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease.

Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis.

Objective: To identify genes underlying childhood onset psychosis.

Methods: Patients with onset of psychosis at age 13 or younger were identified from clinics across England, and they and their parents were exome sequenced and analysed for possible highly penetrant genetic contributors.

Results: We report two male childhood onset psychosis patients of different ancestries carrying hemizygous very rare possibly damaging missense variants (p.

Through the professional's eyes: transfers of care during pregnancy, childbirth and the postpartum period.

Background: In the Netherlands, the obstetric and neonatal healthcare system consists of multiple healthcare organizations. Due to this system, transfers between healthcare professionals are inevitable. Transfers can interrupt the continuity of care, which is an important aspect of care quality.

Effects of a computerised guideline support tool on child healthcare professionals' response to suspicions of child abuse and neglect: a community-based intervention trial.

Background: Healthcare professionals' adherence to guidelines on child protection is not self-evident. This study assessed the effects of a computerised support tool on child healthcare professionals' adherence to the seven recommended guideline activities, and on time spent seeking information presented in this guideline.

Methods: A community-based intervention trial design was applied, comparing access to a paper-based guideline (control) with access to a paper-based guideline supplemented with a computerised guideline support tool (intervention).

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results.

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Modulation of TARP 8-Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain.

Nonselective glutamate -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) 8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of 8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant 8-containing AMPA receptors was modulated by coexpression with other TARPs; 2 subunits affected activity more than 3 subunits.

Identity and collective action via computer-mediated communication: A review and agenda for future research.

Since the start of large-scale waves of mobilisation in 2011, the importance of identity in the study of collective action via computer-mediated communication (CMC) has been a source of contention. Hence, our research sets out to systematically review and synthesise empirical findings on identity and collective action via CMC from 2012 to 2016. We found that the literature on the topic is broad and diverse, with contributions from multiple disciplines and theoretical and methodological approaches.

Professionals' preferences and experiences with inter-organizational consultation to assess suspicions of child abuse and neglect.

This study addresses the following questions in cases of suspected child abuse and neglect (CAN) in children up to four years of age: 1) How many professionals intend to seek inter-organizational consultation? 2) What types of organizations do professionals prefer to consult? and 3) What factors can be identified as facilitator(s) or barrier(s) regarding inter-organizational consultation, based on professionals' experiences? Professionals working with children in 101 organizations in a medium-sized Dutch city were invited to fill in an online questionnaire. The questionnaire included a vignette about a suspected case. Quantitative, qualitative, and social network analysis approaches were used to analyze the data.

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis.

A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative.

Purpose: Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals.

Methods: In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred.

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure.

Functional variants in TBX2 are associated with a syndromic cardiovascular and skeletal developmental disorder.

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.

Client experiences with perinatal healthcare for high-risk and low-risk women.

Problem: It is unknown if client experiences with perinatal healthcare differ between low-risk and high-risk women.

Background: In the Netherlands, risk selection divides pregnant women into low- and high-risk groups. Receiving news that a pregnancy or childbirth has an increased likelihood of complications can cause elevated levels of emotional distress.