Search

Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P

Abstract Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P

Abstract Background Early detection of Parkinson’s disease (PD), a neurodegenerative disease with central and peripheral nerve involvement, ensures timely treatment access. Microbes influence nervous system health and are altered in PD. Methods We examined gut and mouth microbiomes from recently diagnosed patients in a geographically diverse, matched case-control, shotgun metagenomics study. Results Here, we show greater alpha-diversity in 445 PD patients versus 221 controls. The microbial signature of PD includes overabundance of 16 OTUs, including Streptococcus mutans and Bifidobacterium dentium, and depletion of 28 OTUs. Machine learning models indicate that subspecies level oral microbiome abundances best distinguish PD with reasonably high accuracy (area under the curve: 0.758). Microbial networks are disrupted in cases, with reduced connectivity between short-chain fatty acid-producing bacteria the the gut. Importantly, microbiome diversity metrics are associated with non-motor autonomic symptom severity. Conclusions Our results provide evidence that predictive oral PD microbiome signatures could possibly be used as biomarkers for the early detection of PD, particularly when there is peripheral nervous system involvement.

Coeliac disease is a common condition for which the only current treatment is a gluten-free diet. Adherence to this diet is not always easy and is associated with a reduction in quality of life for the patient and their family. Non-adherence is associated with complications of varying severity. The lack of control at the outpatient care level in a high percentage of these patients evinces the need to improve follow-up protocols and the approach to care delivery with coordination of paediatric gastroenterology units (PGU) and primary care paediatricians. With this aim in mind, the present document was developed by consensus to offer a set of recommendations adapted to our region, based on the recent recommendations published by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), and with participation of the pertinent scientific societies, including those concerning the adult population, for the management and follow-up of adolescents and the transition to adult care. Resumen: La enfermedad celíaca es una patología frecuente y cuyo único tratamiento en el momento actual es la dieta sin gluten. El seguimiento de esta dieta no siempre es fácil e implica limitaciones en la calidad de vida del paciente y su familia. La no adherencia se asociaría a complicaciones de distinta gravedad. La falta de control de estos pacientes en consultas en un alto porcentaje de casos plantea la necesidad de mejorar los protocolos de seguimiento y de abordarlos de forma coordinada entre las Unidades de Gastroenterología Pediátrica (UGP) y los pediatras de Atención Primaria. Con ese objetivo se han consensuado en este documento, basándose en las recomendaciones recientemente publicadas por la Sociedad Europea de Gastroenterología, Hepatología y Nutrición Pediátrica (ESPGHAN), un conjunto de recomendaciones adaptadas a nuestro entorno y contando con la participación de las Sociedades Científicas implicadas, incluyendo a las Sociedades de adultos para el abordaje del seguimiento del adolescente y de la transición de cuidados a los profesionales de adultos.

Purpose: The aim of this study is to establish which specific cognitive abilities are phenotypically related to reading skill in adolescence and determine whether this phenotypic correlation is explained by polygenetic overlap. Method: In an Australian population sample of twins and non-twin siblings of European ancestry (734 [less than or equal to] N [less than or equal to] 1542 [50.7% < F < 66%], mean age = 16.7, range = 11-28 years) from the Brisbane Adolescent Twin Study, mixed-effects models were used to test the association between a dyslexia polygenic score (based on genome-wide association results from a study of 51,800 dyslexics versus >1 million controls) and quantitative cognitive measures. The variance in the cognitive measure explained by the polygenic score was compared to that explained by a reading difficulties phenotype (scores that were lower than 1.5 SD below the mean reading skill) to derive the proportion of the association due to genetic influences. Results: The strongest phenotypic correlations were between poor reading and verbal tests R[superscript 2] up to 6.2%); visuo-spatial working memory was the only measure that did not show association with poor reading. Dyslexia polygenic scores could completely explain the phenotypic covariance between poor reading and most working memory tasks and were most predictive of performance on a test of arithmetic (R[superscript 2] = 2.9%). Conclusion: Shared genetic pathways are thus highlighted for the commonly found association between reading and mathematics abilities, and for the verbal short-term/working memory deficits often observed in dyslexia.

Purpose: It has been demonstrated that AI-powered, data-driven tools' usage is not universal, but deeply linked to socio-cultural contexts. The purpose of this paper is to display the need of adopting situated lenses, relating to specific personal and professional learning about data protection and privacy. Design/methodology/approach: The authors introduce the results of a case study based on a large educational intervention at a fully online university. The views of the participants from degrees representing different knowledge areas and contexts of technology adoption (work, education and leisure) were explored after engaging in the analysis of the terms and conditions of use about privacy and data usage. After consultation, 27 course instructors (CIs) integrated the activity and worked with 823 students (702 of whom were complete and correct for analytical purposes). Findings: The results of this study indicated that the intervention increased privacy-conscious online behaviour among most participants. Results were more contradictory when looking at the tools' daily usage, with overall positive considerations around the tools being mostly needed or "indispensable". Research limitations/implications: Though appliable only to the authors' case study and not generalisable, the authors' results show both the complexity of privacy views and the presence of forms of renunciation in the trade-off between data protection and the need of using a specific software into a personal and professional context. Practical implications: This study provides an example of teaching and learning activities that supports the development of data literacy, with a focus on data privacy. Therefore, beyond the research findings, any educator can build over the authors' proposal to produce materials and interventions aimed at developing awareness on data privacy issues. Social implications: Developing awareness, understanding and skills relating to data privacy is crucial to live in a society where digital technologies are used in any area of our personal and professional life. Well-informed citizens will be able to obscure, resist or claim for their rights whenever a violation of their privacy takes place. Also, they will be able to support (through adoption) better quality apps and platforms, instead of passively accepting what is evident or easy to use. Originality/value: The authors specifically spot how students and educators, as part of a specific learning and cultural ecosystem, need tailored opportunities to keep on reflecting on their degrees of freedom and their possibilities to act regarding evolving data systems and their alternatives.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N = 123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N = 130,684). Because these GWAS implicated the gene CADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American). Finally, we produced Cadm2 mutant mice and used them to perform a Mouse-PheWAS ("MouseWAS") by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (~6-11%), and moderate genetic correlations (rg = 0.20-0.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such as TCF4 and PTPRF, and also identified nominal associations proximal to DRD2 and CRHR1. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.

This paper presents an exploratory study to examine the practices of outstanding primary school teachers in their professional development for ICT integration in teaching and learning, as a means of understanding how their learning ecologies develop and function. Outstanding teachers in the context of this study are teachers who innovate pedagogically and who are influential in the community, having successfully developed their learning ecology. Using a qualitative approach, we explore the concept of learning ecologies as a driver for innovation in the professional development of teachers, using a carefully selected sample of nine outstanding teachers. Drawing from in-depth interviews, specific coding and NVIVO analysis, our results show that these teachers develop organized systems for activities, relationships and resource usage and production, which can be characterized as the components of their professional learning ecology, to continuously keep up to date. We also identified some characteristics of teachers that perform outstandingly and factors that potentially facilitate or hinder their learning ecology development. Further research in the field will enable an improved understanding of the professional learning ecologies of school teachers and support future interventions and recommendations for professional development through the cultivation of emerging professional learning ecologies.

Abstract is missing (Quiz)

The development of sustainable aquaculture relies on replacing marine raw materials like fish meal (FM) and fish oil (FO). Emerging alternatives, such as single-cell proteins and alternative lipids, offer promise. This study explored the effects of partially substituting FM with 10% bacterial protein (Methylococcus capsulatus) and completely replacing FO with a blend of poultry oil (PO) and DHA-rich microalgae oil in European sea bass (Dicentrarchus labrax) of unselected (WT) and selected (HG) genotypes. The results indicated that bacterial protein had no adverse impact on fish growth. The HG group demonstrated better growth and feed conversion due to genetic selection. This study also analysed the dietary and genotype effects on body lipid composition and fatty acid profiles. Notably, the HG fish had lower levels of major fatty acids (EPA, DHA, n-3 FAs, and n-3 LC-PUFAs) in their fillets, but not in their whole-body composition. These differences influenced sensory and qualitative aspects. Electronic sensory analyses (the first e-sensory profiling conducted for genetic purposes in fish) showed more significant differences due to diet in the WT group, with a less variable pattern in the e-tongue score in for the HG group. The volatile profiles showed no significant differences. In summary, combining selected fish genotypes with innovative feeds is a step forward in aquaculture. It maximizes nutrient utilization, enhances fish growth, and improves product quality. This approach becomes increasingly important in scenarios with limited FM/FO availability, promoting sustainability in aquaculture.

Abstract Background Broodstock nutritional programming improves the offspring utilization of plant-based diets in gilthead sea bream through changes in hepatic metabolism. Attention was initially focused on fatty acid desaturases, but it can involve a wide range of processes that remain largely unexplored. How all this can be driven by a different genetic background is hardly underlined, and the present study aimed to assess how broodstock nutrition affects differentially the transcriptome and genome-wide DNA methylome of reference and genetically selected fish within the PROGENSA® selection program. Results After the stimulus phase with a low fish oil diet, two offspring subsets of each genetic background received a control or a FUTURE-based diet. This highlighted a different hepatic transcriptome (RNA-seq) and genome-wide DNA methylation (MBD-seq) pattern depending on the genetic background. The number of differentially expressed transcripts following the challenge phase varied from 323 in reference fish to 2,009 in genetically selected fish. The number of discriminant transcripts, and associated enriched functions, were also markedly higher in selected fish. Moreover, correlation analysis depicted a hyper-methylated and down-regulated gene expression state in selected fish with the FUTURE diet, whereas the opposite pattern appeared in reference fish. After filtering for highly represented functions in selected fish, 115 epigenetic markers were retrieved in this group. Among them, lipid metabolism genes (23) were the most reactive following ordering by fold-change in expression, rendering a final list of 10 top markers with a key role on hepatic lipogenesis and fatty acid metabolism (cd36, pitpna, cidea, fasn, g6pd, lipt1, scd1a, acsbg2, acsl14, acsbg2). Conclusions Gene expression profiles and methylation signatures were dependent on genetic background in our experimental model. Such assumption affected the magnitude, but also the type and direction of change. Thus, the resulting epigenetic clock of reference fish might depict an older phenotype with a lower methylation for the epigenetically responsive genes with a negative methylation-expression pattern. Therefore, epigenetic markers will be specific of each genetic lineage, serving the broodstock programming in our selected fish to prevent and mitigate later in life the risk of hepatic steatosis through changes in hepatic lipogenesis and fatty acid metabolism.

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids 'not as prescribed'. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (rg = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg = 0.74), smoking initiation (rg = 0.63), pain relief medication intake (rg = 0.49), major depressive disorder (rg = 0.44), chronic pain (rg = 0.42), insomnia (rg = 0.39), and loneliness (rg = 0.28). Although POU was positively genetically correlated with risk-taking (rg = 0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10-4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.

Abstract Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N = 123,509–133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N = 130,684). Because these GWAS implicated the gene CADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American). Finally, we produced Cadm2 mutant mice and used them to perform a Mouse-PheWAS (“MouseWAS”) by testing them with a battery of relevant behavioral tasks. In humans, impulsive personality traits showed modest chip-heritability (~6–11%), and moderate genetic correlations (r g = 0.20–0.50) with other personality traits, and various psychiatric and medical traits. We identified significant associations proximal to genes such as TCF4 and PTPRF, and also identified nominal associations proximal to DRD2 and CRHR1. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Our MouseWAS recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI. Our results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries and species.

Nowadays, including vegetable ingredients in fish diets without growth effects is common; however, their intestinal oxidative status under these conditions is less known. Five isonitrogenous and isolipidic diets with 75% vegetable oil (VO) inclusion were formulated for juvenile gilthead sea bream (Sparus aurata). As VO, one diet contained palm oil (diet P), another rapeseed oil (diet R), and the other three included linseed oil (L) combined with the above-mentioned VOs (named PL, RL and RPL diets). After 18 weeks, pyloric caeca (PC) and proximal intestine (PI) were analyzed for oxidative stress biomarkers, lipid peroxidation (LPO), and gene expression. Dietary linseed oil diminished the superoxide dismutase activity in both intestinal regions, catalase in PC and glutathione reductase in PI; rapeseed oil reduced the glutathione peroxidase (GPx) and glutathione-S-transferase activities in PC, and palm oil upregulated GPx activity in PI. The PL diet triggered LPO levels in the PI, and RPL-fed fish showed the highest levels of LPO in the PC due to lower antioxidant activities, while RL-fed fish presented the best oxidative status. The results suggest that the dietary amount of n-6 and the unsaturated/saturated fatty acids ratio are factors to be considered in aquafeed formulation, including VOs, to improve the intestinal oxidative status in fish.

El texto aborda la importancia del románico del Valle de Arán. Debido a su ubicación geográfica, el Valle de Arán estuvo relativamente aislado, lo que contribuyó a conservar estructuras organizativas antiguas y a la renovación de edificios eclesiásticos entre los siglos XI y XIII. El estudio se enfoca en la clasificación y datación de las iglesias románicas de Arán, y se destacan métodos arqueológicos como el análisis estratigráfico para establecer una cronología relativa y absoluta de las iglesias. El texto concluye con la discusión sobre la cronología de las iglesias del Valle de Arán, agrupándolas según sus características arquitectónicas y técnicas de construcción. Estas agrupaciones se comparan con estudios documentales y se relacionan con periodos específicos, proporcionando una visión detallada de la evolución del románico en esta región.

The objective of this study was to determine if selected fish genotypes could benefit from the use of functional additives in novel aqua feed formulations to improve growth performance, gut microbiota, immune response, and disease resistance in fish. Two batches of juvenile European sea bass selected for high growth (HG; selected sires x selected dams), and wild types (WT; wild sires x selected females) were fed a “future diet” coated with three different functional additives for 12 weeks as follows: (i) 2 weeks with a high dose, followed by (ii) 10 weeks with a low dose. The functional additives tested were a mixture of probiotics (PROB), organic acids (ORG), and phytogens (PHYTO). A pathogen challenge test (Vibrio anguillarum) and a stress condition (overcrowding) were performed after each dose. At the end of the feeding experiment, fish from the HG group performed better than fish from the WT group in terms of body weight, relative growth, SGR, and DGI. The results of the two challenge tests performed after two weeks of high dose and ten weeks of low dose showed a significant effect of diet on fish survival. GALT-associated gene expression analysis revealed an interaction between the genotype and diet for il-1β in the distal gut. Finally, regarding the gut microbiota, discriminant analysis showed no clear separation between fish fed the future diet and those fed the same diet with experimental additives. Nevertheless, the relative abundance of certain taxa varied between experimental groups. For example, fish fed the ORG diet had higher relative abundance of Streptococcus in both genotypes, whereas fish fed the PHYTO diet had higher abundance of Lactobacillales. In contrast, fish fed PROB had lower abundance of Pseudomonas and Acinetobacter.

Factor analyses suggest that impulsivity traits that capture tendencies to act prematurely or take risks tap partially distinct constructs. We applied genomic structure equation modeling to evaluate the genetic factor structure of two well-established impulsivity questionnaires, using published statistics from genome-wide association studies of up to 22,861 participants. We also tested the hypotheses that delay discounting would be genetically separable from other impulsivity factors and that emotionally triggered facets of impulsivity (urgency) would be those most strongly genetically correlated with an internalizing latent factor. A five-factor model best fitted the impulsivity data. Delay discounting was genetically distinct from these five factors. As expected, the two urgency subscales were most strongly related to an internalizing-psychopathology latent factor. These findings provide empirical genetic evidence that impulsivity can be broken down into distinct categories of differential relevance for internalizing psychopathology. They also demonstrate how measured genetic markers can be used to inform theories of psychology and personality.

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common skin cancers and have genetic overlap. Here, the authors use a multi-trait genetic and phenotypic analysis to reveal susceptibility loci for BCC and SCC, and report an optimised polygenic risk score for risk stratification.

Reliable and predictive in vitro models would support the search for new raw materials that can improve current fish diets. We recently developed some rainbow trout (RT) intestinal cell-based organotypic platforms demonstrating that the platform type modulates the degree of cell differentiation achieved in vitro and here we studied whether such differentiation correlates with their response to a prolonged exposure to a diet rich in fish meal. We compared three options, seeding the RTpiMI and RTdiMI cell lines derived respectively from the proximal or the distal intestine on (1) the polyethylene terephthalate (PET) culture inserts ThinCert™ (TC); (2) the TC coated with RT fibroblasts embedded within Matrigel® (MMfb); and (3) the highly porous polystyrene scaffold Alvetex™ also populated with fibroblasts (AV). Platforms have been exposed for 21 days to increasing concentrations of feed pellets digested in vitro by gastric and intestinal RT enzymes (IVD). Cells exposed to culture medium without IVD in each platform were used as controls. TEER values became significantly higher than their respective controls in most culture conditions. At the end of culture, epithelial cells formed multilayers irrespective of cell line or platforms if exposed to IVD, but not in the controls. This proliferative activity followed a dose-dependent pattern in the AV, did not vary in MMfb, and was highly variable in the TC. Moreover, IVD induced the formation of a few goblet-like cells characterized by rounded vacuoles. In parallel, alanine aminopeptidase activity completely disappeared in the MMfb, significantly decreased in the AV, but did not change in TC. These changes suggest a de-differentiation of the enterocytes and their partial differentiation towards the secretory lineages. Overall, the three platforms reacted differently to a pronged exposure to IVD: TC quenched most of the cell responses, MMfb generated overly sensitive reactions, while the AV react mostly in a dose-dependent manner possibly generating more physiological results.

Aquaculture is the fastest-growing food production sector and nowadays provides more food than extractive fishing. Studies focused on the understanding of how teleost growth is regulated are essential to improve fish production. Cysteamine (CSH) is a novel feed additive that can improve growth through the modulation of the GH/IGF axis; however, the underlying mechanisms and the interaction between tissues are not well understood. This study aimed to investigate the effects of CSH inclusion in diets at 1.65 g/kg of feed for 9 weeks and 1.65 g/kg or 3.3 g/kg for 9 weeks more, on growth performance and the GH/IGF-1 axis in plasma, liver, stomach, and white muscle in gilthead sea bream (Sparus aurata) fingerlings (1.8 ± 0.03 g) and juveniles (14.46 ± 0.68 g). Additionally, the effects of CSH stimulation in primary cultured muscle cells for 4 days on cell viability and GH/IGF axis relative gene expression were evaluated. Results showed that CSH-1.65 improved growth performance by 16% and 26.7% after 9 and 18 weeks, respectively, while CSH-3.3 improved 32.3% after 18 weeks compared to control diet (0 g/kg). However, no significant differences were found between both experimental doses. CSH reduced the plasma levels of GH after 18 weeks and increased the IGF-1 ones after 9 and 18 weeks. Gene expression analysis revealed a significant upregulation of the ghr-1, different igf-1 splice variants, igf-2 and the downregulation of the igf-1ra and b, depending on the tissue and dose. Myocytes stimulated with 200 µM of CSH showed higher cell viability and mRNA levels of ghr1, igf-1b, igf-2 and igf-1rb compared to control (0 µM) in a similar way to white muscle. Overall, CSH improves growth and modulates the GH/IGF-1 axis in vivo and in vitro toward an anabolic status through different synergic ways, revealing CSH as a feasible candidate to be included in fish feed.

High-fat diets (HFDs) enhance fish growth by optimizing nutrient utilization (i.e., protein-sparing effect); however, their potential negative effects have also encouraged the search for feed additives. This work has investigated the effects of an extract rich in a polyphenolic antioxidant, hydroxytyrosol (HT), supplemented (0.52 g HT/kg feed) in a HFD (24% lipid) in gilthead sea bream (Sparus aurata). Fish received the diet at two ration levels, standard (3% of total fish weight) or restricted (40% reduction) for 8 weeks. Animals fed the supplemented diet at a standard ration had the lowest levels of plasma free fatty acids (4.28 ± 0.23 mg/dL versus 6.42 ± 0.47 in the non-supplemented group) and downregulated hepatic mRNA levels of lipid metabolism markers (ppara, pparb, lpl, fatp1, fabp1, acox1, lipe and lipa), supporting potential fat-lowering properties of this compound in the liver. Moreover, the same animals showed increased muscle lipid content and peroxidation (1.58- and 1.22-fold, respectively, compared to the fish without HT), suggesting the modulation of body adiposity distribution and an enhanced lipid oxidation rate in that tissue. Our findings emphasize the importance of considering this phytocompound as an optimal additive in HFDs for gilthead sea bream to improve overall fish health and condition.

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

Impulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse and attention-deficit/hyperactivity disorder (ADHD). In collaboration with the genetics company 23andMe, we performed 10 genome-wide association studies on measures of impulsive personality traits [the short version of the UPPS-P Impulsive Behavior Scale, and the Barratt Impulsiveness Scale (BIS-11)] and drug experimentation (the number of drug classes an individual had tried in their lifetime) in up to 22,861 male and female adult human research participants of European ancestry. Impulsive personality traits and drug experimentation showed single nucleotide polymorphism heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with UPPS-P Sensation Seeking (p = 8.3 × 10-9, rs139528938) and showed a suggestive association with Drug Experimentation (p = 3.0 × 10-7, rs2163971; r2 = 0.68 with rs139528938). Furthermore, genetic variants in the CACNA1I locus were significantly associated with UPPS-P Negative Urgency (p = 3.8 × 10-8; rs199694726). The role of these genes was supported by single variant, gene- and transcriptome-based analyses. Multiple subscales from both UPPS-P and BIS showed strong genetic correlations (>0.5) with Drug Experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPS-P and BIS subscales were genetically correlated with ADHD (rg = 0.30-0.51), supporting their validity as endophenotypes. Our findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.SIGNIFICANCE STATEMENT Impulsive personality traits (IPTs) are heritable traits that are governed by frontal-subcortical circuits and are associated with neuropsychiatric disorders, particularly substance use disorders. We have performed genome-wide association studies of IPTs to identify regions and genes that account for this heritable variation. IPTs and drug experimentation were modestly heritable (5-11%). We identified an association between single nucleotide polymorphisms in CADM2 and both sensation seeking and drug experimentation; and between variants in CACNA1I and negative urgency. The role of these genes was supported by single variant, gene- and transcriptome-based analyses. This study provides evidence that impulsivity can be genetically separated into distinct components. We showed that IPT are genetically associated with substance use and ADHD, suggesting impulsivity is an endophenotype contributing to these psychiatric conditions.

The author list was in the wrong order in the HTML version of the original article and in the HTML version of the original correction notice. This has been corrected to show the 23andMe Research Team as the fourth author and Abraham A. Palmer as the last author in both places.

ObjectiveAlcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.MethodThis study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank [N=121,604] and 23andMe [N=20,328]) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P).ResultsThe GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (rg=0.76-0.92) and DSM-IV alcohol dependence (rg=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (rg=0.22), major depressive disorder (rg=0.26), and attention deficit hyperactivity disorder (rg=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (rg=-0.24) and ADHD (rg=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (rg=0.82) while retaining most subjects.ConclusionsAUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.

Genetic factors contribute to the risk for developing alcohol use disorder (AUD). In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association study of the alcohol use disorder identification test (AUDIT), an instrument designed to screen for alcohol misuse over the past year. Our final sample consisted of 20 328 research participants of European ancestry (55.3% females; mean age = 53.8, SD = 16.1) who reported ever using alcohol. Our results showed that the 'chip-heritability' of AUDIT score, when treated as a continuous phenotype, was 12%. No loci reached genome-wide significance. The gene ADH1C, which has been previously implicated in AUD, was among our most significant associations (4.4 × 10-7 ; rs141973904). We also detected a suggestive association on chromosome 1 (2.1 × 10-7 ; rs182344113) near the gene KCNJ9, which has been implicated in mouse models of high ethanol drinking. Using linkage disequilibrium score regression, we identified positive genetic correlations between AUDIT score, high alcohol consumption and cigarette smoking. We also observed an unexpected positive genetic correlation between AUDIT and educational attainment and additional unexpected negative correlations with body mass index/obesity and attention-deficit/hyperactivity disorder. We conclude that conducting a genetic study using responses to an online questionnaire in a population not ascertained for AUD may represent a cost-effective strategy for elucidating aspects of the etiology of AUD.

Abstract Objective To develop a clinico‐genetic predictor of impulse control disorder (ICD) risk in Parkinson's disease (PD). Methods In 5770 individuals from three PD cohorts (the 23andMe, Inc.; the University of Pennsylvania [UPenn]; and the Parkinson's Progression Markers Initiative [PPMI]), we used a discovery‐replication strategy to develop a clinico‐genetic predictor for ICD risk. We first performed a Genomewide Association Study (GWAS) for ICDs anytime during PD in 5262 PD individuals from the 23andMe cohort. We then combined newly discovered ICD risk loci with 13 ICD risk loci previously reported in the literature to develop a model predicting ICD in a Training dataset (n = 339, from UPenn and PPMI cohorts). The model was tested in a non‐overlapping Test dataset (n = 169, from UPenn and PPMI cohorts) and used to derive a continuous measure, the ICD‐risk score (ICD‐RS), enriching for PD individuals with ICD (ICD+ PD). Results By GWAS, we discovered four new loci associated with ICD at p‐values of 4.9e‐07 to 1.3e‐06. Our best logistic regression model included seven clinical and two genetic variables, achieving an area under the receiver operating curve for ICD prediction of 0.75 in the Training and 0.72 in the Test dataset. The ICD‐RS separated groups of PD individuals with ICD prevalence of nearly 40% (highest risk quartile) versus 7% (lowest risk quartile). Interpretation In this multi‐cohort, international study, we developed an easily computed clinico‐genetic tool, the ICD‐RS, that substantially enriches for subgroups of PD at very high versus very low risk for ICD, enabling pharmacogenetic approaches to PD medication selection.

Resumen: Introducción: La cefalea es muy frecuente entre la población general y un motivo habitual de consulta médica. Objetivos: Describir las características clínicas de los pacientes que acuden a urgencias por cefalea. Métodos: Estudio descriptivo con recogida prospectiva de pacientes consecutivos mayores de 15 años que acuden al Servicio de Urgencias del Hospital Universitario Marqués de Valdecilla por cefalea como motivo principal de consulta. Resultados: Se recogieron 100 pacientes. La cefalea como motivo de consulta supuso el 1,4% de las urgencias atendidas. El grupo mayoritario fue el de edades comprendidas entre los 31 y 45 años, con predominio de mujeres (61%). Se diagnosticaron 67 cefaleas primarias y 33 secundarias. El diagnóstico más frecuente fue el de migraña, con un 36% del total de cefaleas. Uno de cada 3 pacientes tenía antecedentes de cefalea y 4 de cada 5 acudieron a urgencias por decisión propia. Solo un pequeño porcentaje de los pacientes atendidos en urgencias llegaron a ingresar (12%), y 3 de cada 5 fueron derivados a atención primaria. Se realizaron pruebas complementarias al 84% de los pacientes atendidos. Se realizó un TAC craneal por cada 3 pacientes. Un 80% de los pacientes fueron correctamente diagnosticados por los médicos de urgencias. Conclusiones: La cefalea es un motivo frecuente de consulta en los servicios de urgencias, siendo más habituales las cefaleas primarias, y dentro de estas, la migraña. En nuestro medio se realiza un buen cribado y diagnóstico de las cefaleas, así como un adecuado uso de los recursos disponibles en urgencias para su diagnóstico y manejo. Abstract: Introduction: Headache is common in the general population and a frequent reason for medical consultation. Objectives: To describe the characteristics of patients attending the Emergency Department (ED) for headache. Methods: A descriptive study with prospective collection of 100 consecutive patients over 15 years old who attended our ED due to headache as the main complaint. Results: Headache accounted for 1,4% of ED visits. The most common age range is between 31 and 45 years and the majority of the patients are females (61%). We diagnosed 67 primary and 33 secondary headaches. The most frequent diagnosis was migraine, with 36% of cases. One out of 3 patients had a history of headache and 4 out of 5 consulted by their own decision. Only a small percentage of patients were admitted as inpatients (12%), and 3 out of 5 were referred to Primary Care. Complementary tests were performed on 84% of the patients. One CT scan was performed for every 3 patients. A total of 80% patients was correctly diagnosed by the ED physicians. Conclusions: Headache is a frequent complaint in the ED, where primary headaches are the most common with migraine being the most frequent reason for consultation. In our setting, there is a good screening and diagnosis of headaches, as well as an adequate use of the available resources in the ED for their diagnosis and management.

Many reptiles are maintained in captivity and heavily traded, although welfare measures for many species are not well established and are under-researched compared to other animals. In this study, we focused on two of these species: crested geckos (Correlophus ciliatus) and leopard geckos (Eublepharis macularius). To better interpret their behavior in captivity, the individual reaction to novel objects and the fecal glucocorticoid metabolite levels were measured in an attempt to identify the potential correlation between them. Also, we explored if some characteristic of the objects (e.g., color, shape, or smell) resulted in being more attractive to some species and/or individuals. Equivalent responses to different objects were not obtained for all the geckos, the behavioral response being highly individual and context-dependent, although modulated by the species. Individuals which manipulated earlier and interacted longer with novel objects showed lower basal fecal corticosterone metabolite (FCM) levels. Differences according to the species suggested that crested geckos have significantly greater and more variable FCM levels than leopard geckos. Our results can help to understand the reaction of geckos to novelty and have the potential to serve in their welfare assessment, although more studies are needed to proper establish welfare protocols.

In recent years, the impact of learning analytics has been investigated and explored in higher education contexts. This article aims to show how their application in online educational contexts is providing great support for teaching performance, especially in relation to the methodology applied, the monitoring of students’ interactions and participation, and the evaluation of activities, and how it can favor improvements in student performance and satisfaction. We therefore present the results obtained from use of the DIANA (DIAlog ANAlysis) tool designed for the research project “Use of learning analytics in digital environments: impact on the improvement of university teaching practice” (LAxDigTeach-21085GE). This study followed a mixed methodology (qualitative and quantitative) to better complement the data provided by learning analytics, given that the numerical data must be meaningful in the specific context in which they are collected. The results obtained are in line with previous research and show that the use of learning analytics have helped to improve teaching performance in relation to monitoring student interactions, participation, and evaluation, but are limited in terms of improving their performance and satisfaction. No generalized conclusions can be drawn as yet in light of the fact that the research project of which this study is a part has recently completed the pilot stage and we have only analyzed the information obtained in one of the participating subjects.

Following asynchronous online discussion activities as a complex communication process is a demanding task for teachers. In this paper, the authors have explored the potential in supporting such activity through learning analytics. From the beginning, the authors acknowledged the limitations of technology to support the complexities of a pedagogical activity. Therefore, the methodology used was participatory design-based research (DBR) divided into two main stages. The first design phase dealt with the engagement of teachers and pedagogical experts in defining the data and metrics to be used to support the pedagogical concepts. The second consisted of an implementation phase including pilots with students and with crucial engagement of teachers in commenting their understanding over students' learning processes and the feedback the teachers could offer to them. Overall, the students shown improvements in their performance as monitored through the learning analytics group in contrast with control groups. The discussion over the design and its results could be potentially extrapolated to other educational contexts.

Substitution of fish-based ingredients may alter the nutritional profile of the feeds, including the vitamin contents, ultimately leading to unbalanced vitamin supply. Vitamin A plays an essential role in epithelium preservation, cell differentiation, reproduction, and vision. It also intervenes in skeletogenesis through chondrocytes development. Therefore, low levels of vitamin A may cause poor growth and abnormal bone development among other symptoms. Besides, in gilthead seabream excess vitamin A altered bone structure and homeostasis, indicating that an upper level for vitamin A in feeds for this species must be defined. For this purpose, a practical plant-based diet (FM 10% and FO 6%) containing five increasing levels of vitamin A (24,000, 26,000, 27,000, 31,000, and 37,000 IU/kg) supplemented as retinyl acetate was formulated to identify the effects of high levels of vitamin A for gilthead seabream juveniles. The trial was conducted with 450 total fish distributed into 15 tanks, where each diet was tested in triplicates for 70 days. At the end of the trial, samples were taken for analyses of vitamin A—relevant markers. At the end of the trial the high levels of vitamin A supplementation did not cause a reduction in growth, whereas no significant effect was observed for the feed efficiency, specific growth rate, and feed convertion ratio. Although not significant, retinol content in liver showed a tendency to increase with the elevation of dietary vitamin A levels. Although minor, the highest level of vitamin A dietary content (37,000 IU/kg) caused a significant increase in caudal vertebrae partial fusion as well as caudal vertebrae malformations. Increasing dietary vitamin A was related to a reduction in the occurrence of microhemorrhages in the liver and a reduction in the presence of eosinophils associated to the pancreas. Overall, the results of the present study suggested that gilthead seabream juveniles fed a plant-based diet are able to tolerate very high levels of vitamin A supplementation when supplemented as retinyl acetate. Nevertheless, further supplementation should be avoided in order to reduce the prevalence of anomalies affecting the caudal vertebrae.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

In the version of this article initially published, the consortium authorship was not presented correctly. The 23andMe Research Team was listed as the last author, rather than the fourth, and a line directing readers to the Supplementary Note for a list of members did appear but was not directly associated with the consortium name. Also, the Supplementary Note description stated that both member names and affiliations were included; in fact, only names are given. Finally, the URL for S-PrediXcan was given in the Methods as https://github.com/hakyimlab/S-PrediXcan; the correct URL is https://github.com/hakyimlab/MetaXcan. The errors have been corrected in the HTML and PDF versions of the article.

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

Delay discounting (DD), the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated single-nucleotide polymorphism was rs6528024 (P = 2.40 × 10-8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition and body weight.