The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource.

The NHGRI-EBI GWAS Catalog (www.ebi.ac.uk/gwas) is a FAIR knowledgebase providing detailed, structured, standardised and interoperable genome-wide association study (GWAS) data to >200 000 users per year from academic research, healthcare and industry. The Catalog contains variant-trait associations and supporting metadata for >45 000 published GWAS across >5000 human traits, and >40 000 full P-value summary statistics datasets. Content is curated from publications or acquired via author submission of prepublication summary statistics through a new submission portal and validation tool. GWAS data volume has vastly increased in recent years. We have updated our software to meet this scaling challenge and to enable rapid release of submitted summary statistics. The scope of the repository has expanded to include additional data types of high interest to the community, including sequencing-based GWAS, gene-based analyses and copy number variation analyses. Community outreach has increased the number of shared datasets from under-represented traits, e.g. cancer, and we continue to contribute to awareness of the lack of population diversity in GWAS. Interoperability of the Catalog has been enhanced through links to other resources including the Polygenic Score Catalog and the International Mouse Phenotyping Consortium, refinements to GWAS trait annotation, and the development of a standard format for GWAS data.

Global Public Perceptions of Genomic Data Sharing: What Shapes the Willingness to Donate DNA and Health Data?

Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this.

Population structure and hybridisation in a population of Hawaiian feral chickens.

Chickens are believed to have inhabited the Hawaiian island of Kauai since the first human migrations around 1200AD, but numbers have peaked since the tropical storms Iniki and Iwa in the 1980s and 1990s that destroyed almost all the chicken coops on the island and released large numbers of domestic chickens into the wild. Previous studies have shown these now feral chickens are an admixed population between Red Junglefowl (RJF) and domestic chickens. Here, using genetic haplotypic data, we estimate the time of the admixture event between the feral population on the island and the RJF to 1981 (1976-1995), coinciding with the timings of storm Iwa and Iniki. Analysis of genetic structure reveals a greater similarity between individuals inhabiting the northern and western part of the island to RJF than individuals from the eastern part of the island. These results point to the possibility of introgression events between feral chickens and the wild chickens in areas surrounding the Koke'e State Park and the Alaka'i plateau, posited as two of the major RJF reservoirs in the island. Furthermore, we have inferred haplotype blocks from pooled data to determine the most plausible source of the feral population. We identify a clear contribution from RJF and layer chickens of the White Leghorn (WL) breed. This work provides independent confirmation of the traditional hypothesis surrounding the origin of the feral populations and draws attention to the possibility of introgression of domestic alleles into the wild reservoir.

Targeting Agents in Biomaterial-Mediated Bone Regeneration.

Bone diseases are a global public concern that affect millions of people. Even though current treatments present high efficacy, they also show several side effects. In this sense, the development of biocompatible nanoparticles and macroscopic scaffolds has been shown to improve bone regeneration while diminishing side effects. In this review, we present a new trend in these materials, reporting several examples of materials that specifically recognize several agents of the bone microenvironment. Briefly, we provide a subtle introduction to the bone microenvironment. Then, the different targeting agents are exposed. Afterward, several examples of nanoparticles and scaffolds modified with these agents are shown. Finally, we provide some future perspectives and conclusions. Overall, this topic presents high potential to create promising translational strategies for the treatment of bone-related diseases. We expect this review to provide a comprehensive description of the incipient state-of-the-art of bone-targeting agents in bone regeneration.

Causal dispositionalism in behaviour genetics.

Causal dispositionalism developed in metaphysics of science offers a useful tool to conceptualize shallow causes in behaviour genetics, in a way such that (a) it accounts for complex aetiology and heterogeneity of effects, and (b) genetic causal contribution can be considered to be explanatory. Genes are thus causal powers that make a difference.

Return of genomic results does not motivate intent to participate in research for all: Perspectives across 22 countries.

PURPOSE: The aim of this study was to determine how attitudes toward the return of genomic research results vary internationally. METHODS: We analyzed the "Your DNA, Your Say" online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle-, and high-income countries, and these were gathered in 15 languages. We analyzed how participants responded when asked whether return of results (RoR) would motivate their decision to donate DNA or health data. We examined variation across the study countries and compared the responses of participants from other countries with those from the United States, which has been the subject of the majority of research on return of genomic results to date. RESULTS: There was substantial variation in the extent to which respondents reported being influenced by RoR. However, only respondents from Russia were more influenced than those from the United States, and respondents from 20 countries had lower odds of being partially or wholly influenced than those from the United States. CONCLUSION: There is substantial international variation in the extent to which the RoR may motivate people's intent to donate DNA or health data. The United States may not be a clear indicator of global attitudes. Participants' preferences for return of genomic results globally should be considered.

The genomics of phenotypically differentiated Asellus aquaticus cave, surface stream and lake ecotypes.

Organisms well suited for the study of ecotype formation have wide distribution ranges, where they adapt to multiple drastically different habitats repeatedly over space and time. Here we study such ecotypes in a Crustacean model, Asellus aquaticus, a commonly occurring isopod found in freshwater habitats as diverse as streams, caves and lakes. Previous studies focusing on cave vs. surface ecotypes have attributed depigmentation, eye loss and prolonged antennae to several south European cave systems. Likewise, surveys across multiple Swedish lakes have identified the presence of dark-pigmented "reed" and light-pigmented "stonewort" ecotypes, which can be found within the same lake. In this study, we sequenced the first draft genome of A. aquaticus, and subsequently use this to map reads and call variants in surface stream, cave and two lake ecotypes. In addition, the draft genome was combined with a RADseq approach to perform a quantitative trait locus (QTL) mapping study using a laboratory bred F2 and F4 cave × surface intercross. We identified genomic regions associated with body pigmentation, antennae length and body size. Furthermore, we compared genome-wide differentiation between natural populations and found several genes potentially associated with these habitats. The assessment of the cave QTL regions in the light-dark comparison of lake populations suggests that the regions associated with cave adaptation are also involved with genomic differentiation in the lake ecotypes. These demonstrate how troglomorphic adaptations can be used as a model for related ecotype formation.

Obtaining EHR-derived datasets for COVID-19 research within a short time: a flexible methodology based on Detailed Clinical Models.

BACKGROUND: COVID-19 ranks as the single largest health incident worldwide in decades. In such a scenario, electronic health records (EHRs) should provide a timely response to healthcare needs and to data uses that go beyond direct medical care and are known as secondary uses, which include biomedical research. However, it is usual for each data analysis initiative to define its own information model in line with its requirements. These specifications share clinical concepts, but differ in format and recording criteria, something that creates data entry redundancy in multiple electronic data capture systems (EDCs) with the consequent investment of effort and time by the organization. OBJECTIVE: This study sought to design and implement a flexible methodology based on detailed clinical models (DCM), which would enable EHRs generated in a tertiary hospital to be effectively reused without loss of meaning and within a short time. MATERIAL AND METHODS: The proposed methodology comprises four stages: (1) specification of an initial set of relevant variables for COVID-19; (2) modeling and formalization of clinical concepts using ISO 13606 standard and SNOMED CT and LOINC terminologies; (3) definition of transformation rules to generate secondary use models from standardized EHRs and development of them using R language; and (4) implementation and validation of the methodology through the generation of the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC-WHO) COVID-19 case report form. This process has been implemented into a 1300-bed tertiary Hospital for a cohort of 4489 patients hospitalized from 25 February 2020 to 10 September 2020. RESULTS: An initial and expandable set of relevant concepts for COVID-19 was identified, modeled and formalized using ISO-13606 standard and SNOMED CT and LOINC terminologies. Similarly, an algorithm was designed and implemented with R and then applied to process EHRs in accordance with standardized concepts, transforming them into secondary use models. Lastly, these resources were applied to obtain a data extract conforming to the ISARIC-WHO COVID-19 case report form, without requiring manual data collection. The methodology allowed obtaining the observation domain of this model with a coverage of over 85% of patients in the majority of concepts. CONCLUSION: This study has furnished a solution to the difficulty of rapidly and efficiently obtaining EHR-derived data for secondary use in COVID-19, capable of adapting to changes in data specifications and applicable to other organizations and other health conditions. The conclusion to be drawn from this initial validation is that this DCM-based methodology allows the effective reuse of EHRs generated in a tertiary Hospital during COVID-19 pandemic, with no additional effort or time for the organization and with a greater data scope than that yielded by conventional manual data collection process in ad-hoc EDCs.

The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.

The GWAS Catalog delivers a high-quality curated collection of all published genome-wide association studies enabling investigations to identify causal variants, understand disease mechanisms, and establish targets for novel therapies. The scope of the Catalog has also expanded to targeted and exome arrays with 1000 new associations added for these technologies. As of September 2018, the Catalog contains 5687 GWAS comprising 71673 variant-trait associations from 3567 publications. New content includes 284 full P-value summary statistics datasets for genome-wide and new targeted array studies, representing 6 × 109 individual variant-trait statistics. In the last 12 months, the Catalog's user interface was accessed by ∼90000 unique users who viewed >1 million pages. We have improved data access with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database. Summary statistics provision is supported by a new format proposed as a community standard for summary statistics data representation. This format was derived from our experience in standardizing heterogeneous submissions, mapping formats and in harmonizing content. Availability: https://www.ebi.ac.uk/gwas/.

CariesCare International adapted for the pandemic in children: Caries OUT multicentre single-group interventional study protocol.

BACKGROUND: Comprehensive caries care has shown effectiveness in controlling caries progression and improving health outcomes by controlling caries risk, preventing initial-caries lesions progression, and patient satisfaction. To date, the caries-progression control effectiveness of the patient-centred risk-based CariesCare International (CCI) system, derived from ICCMS™ for the practice (2019), remains unproven. With the onset of the COVID-19 pandemic a previously planned multi-centre RCT shifted to this "Caries OUT" study, aiming to assess in a single-intervention group in children, the caries-control effectiveness of CCI adapted for the pandemic with non-aerosols generating procedures (non-AGP) and reducing in-office time. METHODS: In this 1-year multi-centre single-group interventional trial the adapted-CCI effectiveness will be assessed in one single group in terms of tooth-surface level caries progression control, and secondarily, individual-level caries progression control, children's oral-health behaviour change, parents' and dentists' process acceptability, and costs exploration. A sample size of 258 3-5 and 6-8 years old patients was calculated after removing half from the previous RCT, allowing for a 25% dropout, including generally health children (27 per centre). The single-group intervention will be the adapted-CCI 4D-cycle caries care, with non-AGP and reduced in-office appointments' time. A trained examiner per centre will conduct examinations at baseline, at 5-5.5 months (3 months after basic management), 8.5 and 12 months, assessing the child's CCI caries risk and oral-health behaviour, visually staging and assessing caries-lesions severity and activity without air-drying (ICDAS-merged Epi); fillings/sealants; missing/dental-sepsis teeth, and tooth symptoms, synthetizing together with parent and external-trained dental practitioner (DP) the patient- and tooth-surface level diagnoses and personalised care plan. DP will deliver the adapted-CCI caries care. Parents' and dentists' process acceptability will be assessed via Treatment-Evaluation-Inventory questionnaires, and costs in terms of number of appointments and activities. Twenty-one centres in 13 countries will participate. DISCUSSION: The results of Caries OUT adapted for the pandemic will provide clinical data that could help support shifting the caries care in children towards individualised oral-health behaviour improvement and tooth-preserving care, improving health outcomes, and explore if the caries progression can be controlled during the pandemic by conducting non-AGP and reducing in-office time. TRIAL REGISTRATION: Retrospectively-registered-ClinicalTrials.gov-NCT04666597-07/12/2020: https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000AGM4&selectaction=Edit&uid=U00019IE&ts=2&cx=uwje3h . Protocol-version 2: 27/01/2021.

Population structure of Apodemus flavicollis and comparison to Apodemus sylvaticus in northern Poland based on RAD-seq.

BACKGROUND: Mice of the genus Apodemus are one the most common mammals in the Palaearctic region. Despite their broad range and long history of ecological observations, there are no whole-genome data available for Apodemus, hindering our ability to further exploit the genus in evolutionary and ecological genomics context. RESULTS: Here we present results from the double-digest restriction site-associated DNA sequencing (ddRAD-seq) on 72 individuals of A. flavicollis and 10 A. sylvaticus from four populations, sampled across 500 km distance in northern Poland. Our data present clear genetic divergence of the two species, with average p-distance, based on 21377 common loci, of 1.51% and a mutation rate of 0.0011 - 0.0019 substitutions per site per million years. We provide a catalogue of 117 highly divergent loci that enable genetic differentiation of the two species in Poland and to a large degree of 20 unrelated samples from several European countries and Tunisia. We also show evidence of admixture between the three A. flavicollis populations but demonstrate that they have negligible average population structure, with largest pairwise FST<0.086. CONCLUSION: Our study demonstrates the feasibility of ddRAD-seq in Apodemus and provides the first insights into the population genomics of the species.

Effects of a short video feedback intervention on enhancing maternal sensitivity and infant development in low-income families.

This study evaluated the effects of a short video feedback intervention aimed at enhancing maternal sensitivity and the development of infants from low-income families in a randomized controlled trial. Forty-four mother-infant dyads living in low-income communities from Salvador, Brazil were randomly assigned between intervention and control groups. Maternal sensitivity was assessed during free-play and infant development was evaluated with a standardized scale. Intervention took place in eight home visits between the infant's third and tenth month. Results showed mothers in the intervention group interpreted the meaning of their infants' behavior more often (r = 0.33), asked babies more questions (r = 0.39), and were less intrusive (r = 0.47) when compared to controls on posttest. The absence of significant intervention effects on infant development suggests the need for additional intervention strategies and a greater time lag between maternal sensitivity and infant development assessments to detect possible delayed effects.

The Effectiveness of an Oral Sensorimotor Stimulation Protocol for the Early Achievement of Exclusive Oral Feeding in Premature Infants. A Randomized, Controlled Trial.

Aims: This study is aimed to investigate the effectiveness of an oral stimulation protocol in preterm infants compared to usual care, to reduce the time for achieving safe full oral feeding.Methods: 47 preterm infants (25- 30 weeks of gestational age) were randomized into two groups. Babies of the EG (n = 24) received a 10-minute oral stimulation protocol while the CG (n = 23) received the standard care. The primary outcome were the days from the initiation of the intervention until the achievement of full oral feeding. Secondary outcomes were: days from the first day the intervention started until achieving a first oral intake of 30% in the first 5 minutes, days from the first day the intervention started until achieving a first oral intake of 100%, and days of hospitalization. A parametric survival model with Gaussian distribution was used.Results: The EG achieved full oral feeding 8.3 days before the CG (p = 0.013). EG also achieved the first oral intake of 30% in the first five minutes, 6.03 days before (p = 0.019) and of 100%, 5.88 days before (p = 0.040). EG also spent 6.9 days less hospitalized than CG (p = 0.028).Conclusion: Oral stimulation in preterm infants significantly shortens the time to achieve full oral feeding and reduces the length of hospitalization.

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog).

The NHGRI-EBI GWAS Catalog has provided data from published genome-wide association studies since 2008. In 2015, the database was redesigned and relocated to EMBL-EBI. The new infrastructure includes a new graphical user interface (www.ebi.ac.uk/gwas/), ontology supported search functionality and an improved curation interface. These developments have improved the data release frequency by increasing automation of curation and providing scaling improvements. The range of available Catalog data has also been extended with structured ancestry and recruitment information added for all studies. The infrastructure improvements also support scaling for larger arrays, exome and sequencing studies, allowing the Catalog to adapt to the needs of evolving study design, genotyping technologies and user needs in the future.

Characterization of spliceogenic variants located in regions linked to high levels of alternative splicing: BRCA2 c.7976+5G > T as a case study.

Many BRCA1 and BRCA2 (BRCA1/2) genetic variants have been studied at mRNA level and linked to hereditary breast and ovarian cancer due to splicing alteration. In silico tools are reliable when assessing variants located in consensus splice sites, but we may identify variants in complex genomic contexts for which bioinformatics is not precise enough. In this study, we characterize BRCA2 c.7976 + 5G > T variant located in intron 17 which has an atypical donor site (GC). This variant was identified in three unrelated Spanish families and we have detected exon 17 skipping as the predominant transcript occurring in carriers. We have also detected several isoforms (Δ16-18, Δ17,18, Δ18, and ▼17q224 ) at different expression levels among carriers and controls. This study remarks the challenge of interpreting genetic variants when multiple alternative isoforms are present, and that caution must be taken when using in silico tools to identify potential spliceogenic variants located in GC-AG introns.

Reconstructing ancient mitochondrial DNA links between Africa and Europe.

Mitochondrial DNA (mtDNA) lineages of macro-haplogroup L (excluding the derived L3 branches M and N) represent the majority of the typical sub-Saharan mtDNA variability. In Europe, these mtDNAs account for <1% of the total but, when analyzed at the level of control region, they show no signals of having evolved within the European continent, an observation that is compatible with a recent arrival from the African continent. To further evaluate this issue, we analyzed 69 mitochondrial genomes belonging to various L sublineages from a wide range of European populations. Phylogeographic analyses showed that ~65% of the European L lineages most likely arrived in rather recent historical times, including the Romanization period, the Arab conquest of the Iberian Peninsula and Sicily, and during the period of the Atlantic slave trade. However, the remaining 35% of L mtDNAs form European-specific subclades, revealing that there was gene flow from sub-Saharan Africa toward Europe as early as 11,000 yr ago.

Psychometric properties of the Depression Anxiety Stress Scales (DASS-21) in women with breast cancer.

Breast cancer impacts the psychological well-being of women, leaving them at risk of developing depression, anxiety, and other stress-related disorders. The Depression Anxiety Stress Scales (DASS-21) is a widely used measure, although empirical evidence regarding its psychometric properties in the breast cancer population is limited. The purpose of this study was to conduct an exhaustive analysis of the psychometric properties of the DASS-21 in a sample of Spanish women diagnosed with breast cancer. Participants were 289 breast cancer patients who completed the DASS-21 and other questionnaires measuring life satisfaction, positive and negative affect, flourishing, perceived stress, and breast cancer-specific stressors. In terms of validity evidence based on the internal structure of the DASS-21, adequate fit indices were obtained for the model based on three first-order factors (depression, anxiety, stress) and one second-order factor (general psychological distress). Reliability coefficients (McDonald's omega) ranged from .84 to .95. Validity evidence based on relationships with other variables was also provided by moderate and strong correlations with well-being indicators and stress measures. The results support the use of the DASS-21 for measuring general psychological distress in the breast cancer context, where it may provide useful information for the design of psychological interventions with patients.