Above and beyond state-of-the-art approaches to investigate sequence data: summary of methods and results from the population-based association group at the Genetic Analysis Workshop 19

This paper summarizes the contributions from the Population-Based Association group at the Genetic Analysis Workshop 19. It provides an overview of the new statistical approaches tried out by group members in order to take best advantage of population-based sequence data. Although contributions were highly heterogeneous regarding the applied quality control criteria and the number of investigated variants, several technical issues were identified, leading to practical recommendations. Preliminary analyses revealed that Hurdle-negative binomial regression is a promising approach to investigate the distribution of allele counts instead of called genotypes from sequence data. Convergence problems, however, limited the use of this approach, creating a technical challenge shared by environment-stratified models used to investigate rare variant-environment interactions, as well as by rare variant haplotype analyses using well-established public software. Estimates of relatedness and population structure strongly depended on the allele frequency of selected variants for inference. Another practical recommendation was that dissenting probability values from standard and small-sample tests of a particular hypothesis may reflect a lack of validity of large-sample approximations. Novel statistical approaches that integrate evolutionary information showed some advantage to detect weak genetic signals, and Bayesian adjustment for confounding was able to efficiently estimate causal genetic effects. Haplotype association methods may constitute a valuable complement of collapsing approaches for sequence data. This paper reports on the experience of members of the Population-Based Association group with several novel, promising approaches to preprocessing and analyzing sequence data, and to following up identified association signals

Imputation of missing genotypes within LD-blocks relying on the basic coalescent and beyond: consideration of population growth and structure

Background Genotypes not directly measured in genetic studies are often imputed to improve statistical power and to increase mapping resolution. The accuracy of standard imputation techniques strongly depends on the similarity of linkage disequilibrium (LD) patterns in the study and reference populations. Here we develop a novel approach for genotype imputation in low-recombination regions that relies on the coalescent and permits to explicitly account for population demographic factors. To test the new method, study and reference haplotypes were simulated and gene trees were inferred under the basic coalescent and also considering population growth and structure. The reference haplotypes that first coalesced with study haplotypes were used as templates for genotype imputation. Computer simulations were complemented with the analysis of real data. Genotype concordance rates were used to compare the accuracies of coalescent-based and standard (IMPUTE2) imputation. Results Simulations revealed that, in LD-blocks, imputation accuracy relying on the basic coalescent was higher and less variable than with IMPUTE2. Explicit consideration of population growth and structure, even if present, did not practically improve accuracy. The advantage of coalescent-based over standard imputation increased with the minor allele frequency and it decreased with population stratification. Results based on real data indicated that, even in low-recombination regions, further research is needed to incorporate recombination in coalescence inference, in particular for studies with genetically diverse and admixed individuals. Conclusions To exploit the full potential of coalescent-based methods for the imputation of missing genotypes in genetic studies, further methodological research is needed to reduce computer time, to take into account recombination, and to implement these methods in user-friendly computer programs. Here we provide reproducible code which takes advantage of publicly available software to facilitate further developments in the field

Single nucleotide polymorphisms (SNPs) are inherited from parents and they measure heritable events

Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. They are used for the identification of inherited cancer susceptibility genes and those that may interact with environmental factors. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data in the nationwide Swedish Family-Cancer Database, we review familial risks for all main cancers and discuss the evidence for a heritable component in cancer. The available evidence is not conclusive but it is consistent in pointing to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. Empirical familial risks should be used as guidance for the planning of SNP studies. We provide calculations for the assessment of familial risks for assumed allele frequencies and gene effects (odds ratios) for different modes of inheritance. Based on these data, we discuss the gene effects that could account for the unexplained proportion of familial breast and lung cancer. As a conclusion, we are concerned about the indiscriminate use of a genetic tool to cancers, which are mainly environmental in origin. We consider the likelihood of a successful application of SNPs in gene-environment studies small, unless established environmental risk factors are tested on proven candidate genes

Fisiopatología del síndrome descompresivo en tortugas marinas

Hasta 2014 se consideraba que las tortugas marinas no eran susceptibles de sufrir la enfermedad descompresiva descrita en medicina humana. Pero animales capturados por redes de pesca en el mediterráneo presentaban la misma sintomatología descrita en medicina humana y respondían de forma positiva al tratamiento hiperbárico en cámara descompresiva. Hasta el presente trabajo se desconocía la fisiopatología de dicha enfermedad, pero considerábamos de gran importancia el esfínter muscular que se localiza en la arteria pulmonar de estos animales y no descrito en tortugas de agua dulce como las de la especie Trachemys sripta. El presente estudio supone una descripción anatómica, histológica y funcional de cada uno de los esfínteres situados en las arterias pulmonares de las tortugas marinas de la especie Caretta Caretta. Se han realizado necropsias de 5 ejemplares adultos y subadultos y de 8 ejemplares neonatos. Además hemos estudiado la funcionalidad de la arteria pulmonar y del parénquima pulmonar en ejemplares de Trachemys scripta para verificar que el funcionamiento es diferente respecto al de especies buceadoras. El esfínter ocupa el tercio medio de la longitud de cada una de las arterias pulmonares en el tramo extrapulmonar que discurre desde su bifurcación a la salida del corazón hasta su entrada en el hilio pulmonar. Macroscópicamente el esfínter presenta una pared más gruesa y una íntima mucho más rugosa. Histológicamente se observa un engrosamiento de la capa muscular. Para la realización de estudios de funcionalidad, se mantuvo el tejido vivo de distintos tramos de cada una de las arterias mediante DMEM high Glucose with L- Glutamine. Posteriormente se realizaron anillos de tejidos los cuales se mantuvieron fijados a un transductor mecánico en un baño de órganos al cual se añadieron distintos neurotransmisores. Los estudios de funcionalidad también se han llevado a cabo en arteria sistémica, arteria intrapulmonar y parénquima pulmonar con el fin de entender el funcionamiento vascular en su totalidad. Se observó que, específicamente en la región del esfínter, en presencia de acetilcolina o serotonina la respuesta era de contracción máxima y muy potente, mientras que en presencia de adrenalina la respuesta era de relajación, induciendo la apertura del esfínter. Esto resultados nos indican que durante el buceo el animal se encuentra bajo una respuesta predominante del sistema nervioso parasimpático manteniendo el esfínter cerrado junto con una marcada bradicardia y no permitiendo la perfusión pulmonar y la subsiguiente difusión de nitrógeno, evitando así el riesgo de descompresión durante el ascenso. Sin embargo, ante un estímulo estresante y especialmente si es prolongado, como supone la captura accidental en redes de pesca, el sistema nervioso simpático induce una liberación de adrenalina, que a concentraciones elevadas supone una marcada taquicardia además de la apertura del esfínter, facilitando la absorción del nitrógeno pulmonar por difusión pasiva desde el gas comprimido en los espacios. Para determinar la presencia y distribución de receptores muscarínicos y adrenérgicos sobre los diferentes tejidos empleamos técnicas de hisnmunohistoquímica y Western Blot. El presente estudio contribuye a la caracterización funcional y anatómica de esta estructura descrita en especies buceadoras en apnea aportando nueva información para la mejor comprensión de la fisiopatología del síndrome descompresivo en tortugas marinas. El estudio de estas estructuras también es relevante desde el punto de vista clínico ya que puede tener implicaciones importantes sobre la difusión de los gases en animales comatosos o durante la anestesia

The model of funeral heritage management applied to the Ciriego cemetery in Santander

En la última década, la gestión del patrimonio funerario ha despertado el interés de los responsables de los cementerios buscando, en la mayor parte de las ocasiones, una herramienta efectiva para preservar la identidad del recinto. En este artículo analizamos el caso particular del modelo aplicado al cementerio municipal de Ciriego en Santander, apoyado en el diseño e implantación de un plan director, encaminado a la protección tanto de los usos generales como de los bienes patrimoniales allí custodiados, así como su eficacia trascurridos más de diez años.En la última década, la gestión del patrimonio funerario ha despertado el interés de los responsables de los cementerios buscando, en la mayor parte de las ocasiones, una herramienta efectiva para preservar la identidad del recinto. En este artículo analizamos el caso particular del modelo aplicado al cementerio municipal de Ciriego en Santander, apoyado en el diseño e implantación de un plan director, encaminado a la proteccióntanto de los usos generales como de los bienes patrimoniales allí custodiados, así como su eficacia trascurridos más de diez años

Propuesta de mejora de habilidades sociales en niños con discapacidad intelectual mediante la terapia asistida por animales

Este Trabajo de Fin de Grado se centra en la aplicación práctica de un programa de mejora de la Educación Socioemocional, utilizando como herramienta innovadora la Terapia Asistida con Animales de Compañía, aplicándose a un caso real de un alumno con Parálisis Cerebral y Discapacidad Intelectual asociada. Los objetivos de las actividades están centrados en el desarrollo de la autoconciencia, el autocontrol, la conciencia social y la toma de decisiones responsables. Mediante este proyecto se pretende establecer una estructura básica que permita posteriormente modificar y mejorar el propio programa con nuevos conocimientos sobre Terapias con Animales y técnicas metodológicas, dirigidos al desarrollo socioemocional del alumno.Grado en Educación Primari

Contribution of the Defective BRCA1, BRCA2 and CHEK2 Genes to the Familial Aggregation of Breast Cancer: a Simulation Study Based on the Swedish Family-Cancer Database

The known breast cancer susceptibility genes only account for 20% to 25% of the excess familial risk of the disease [1]. The present study assessed the contribution of BRCA1/2 mutations and CHEK2 variants to the relative risk of breast cancer for women with affected mothers or sisters. The familial relative risks were estimated by Poisson regression based on the Swedish Family-Cancer Database. The Database was also used to calculate the distribution of life expectancy, the number of daughters per family and the age specific cumulative risk of female breast cancer. This information, together with the penetrances of BRCA1, BRCA2 and CHEK2 from the literature, was used to simulate the familial clustering of breast cancer under different scenarios. The excess risk explained by BRCA1, BRCA2 and CHEK2 decreased steeply with the age at diagnosis of the cancers. Around 40% of the familial risk for cases diagnosed before the age of 50 years was associated with BRCA1/2 mutations. In contrast, roughly 85% of the familial risk of breast cancer diagnosed before the age of 69 years remained unexplained. The contribution of CHEK2 to familial breast cancer was small

The updated Swedish family-cancer database used to assess familial risks of prostate cancer during rapidly increasing incidence

The Swedish Family-Cancer Database has been used for some 10 years in the study of familial risks at all common sites. In the present paper we describe some of the main features of version VII of this Database, assembled in year 2006. This update included all residents in Sweden born or immigrated in 1932 and later (offspring) with their biological parents, a total of 11.5 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from years 1958 to 2004, including over 1.2 million first and multiple primary cancers and in situ tumours. We show one application of the Database in the study of familial risks in prostate cancer, with special reference to the modification of familial risk at the time of about 50% increase in incidence due to prostate specific antigen (PSA) screening. The familial risks for prostate cancer were 1.92 for sons of affected fathers, 3.03 for brothers and 5.44 for men with an affected father and an affected brother. Familial risk for prostate cancer according to the time since the first family member was diagnosed showed significant increases for two family members being diagnosed in the same year compared to 5+ years apart. Increased surveillance and the availability of PSA screening are the likely reasons for the overestimated familial relative risk shortly after the first diagnosis. This lead time bias should be considered in clinical counselling

Gallstones, body mass index, C-reactive protein, and gallbladder cancer: mendelian randomization analysis of chilean and european genotype data

Background and Aims: Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. Approach and Results: We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10−5) and Europeans (P = 9 × 10−5). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10−6). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. Conclusions: Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk