Sira Díaz-Morán

Combined sequence-based and genetic mapping analysis of complex traits in outbred rats

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

Context-dependent differences in grooming behavior among the NIH heterogeneous stock and the Roman high- and low-avoidance rats

Grooming occurs during/after stress and seems to accompany dearousal. Here, grooming was investigated under testing situations involving different levels of aversiveness, taking advantage of differences among three rat strains in fearfulness/anxiety. Inbred Roman High Avoidance (RHA-I) rats are less anxious/fearful than inbred Roman Low Avoidance (RLA-I). The outbred genetically heterogeneous stock of rats (NIH-HS), which resembles the RLA-I in many behavioral traits, was also studied. Adult male rats (RLA-I: n=9, RHA-I: n=10, NIH-HS: n=12) were observed for 30min in: a novel open-field, a novel hole-board and in the home-cage. They were also observed during two-way active avoidance training. Differences in grooming depended on test situation: (a) No differences were found in the home-cage. (b) While tested in a novel environment, RHA-I showed less grooming activity than the other rats. (c) After avoidance responses appeared, differences among the strains were opposite to the observed in novelty tests. Furthermore, results suggest that (i) grooming is mostly suppressed when assured aversive experience is under way; (ii) rostral grooming prevails when experience with aversive stimuli is unpredictable (novelty) or potential (avoidance training); (iii) body grooming increases for a period in novel environments. In general, our results support that grooming takes place during dearousal.

High-resolution genome screen for bone mineral density in heterogeneous stock rat

We previously demonstrated that skeletal mass, structure, and biomechanical properties vary considerably in heterogeneous stock (HS) rat strains. In addition, we observed strong heritability for several of these skeletal phenotypes in the HS rat model, suggesting that it represents a unique genetic resource for dissecting the complex genetics underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone mineral density in HS rats. We measured bone phenotypes from 1524 adult male and female HS rats between 17 and 20 weeks of age. Phenotypes included dual‐energy X‐ray absorptiometry (DXA) measurements for bone mineral content and areal bone mineral density (aBMD) for femur and lumbar spine (L3–L5), and volumetric BMD measurements by CT for the midshaft and distal femur, femur neck, and fifth lumbar vertebra (L5). A total of 70,000 polymorphic single‐nucleotide polymorphisms (SNPs) distributed throughout the genome were selected from genotypes obtained from the Affymetrix rat custom SNPs array for the HS rat population. These SNPs spanned the HS rat genome with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent for each genotyped locus from each of the eight founder HS strains. The haplotypes were tested for association with each bone density phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for BMD phenotypes on chromosomes 2, 9, 10, and 13 meeting a conservative genomewide empiric significance threshold (false discovery rate [FDR] = 5%; p < 3 × 10−6). Importantly, most QTLs were localized to very small genomic regions (1–3 megabases [Mb]), allowing us to identify a narrow set of potential candidate genes including both novel genes and genes previously shown to have roles in skeletal development and homeostasis.

Self-perceived quality of life in cocaine dependents with or without dual diagnosis

Introduction. Although impairment in the quality of life is common among cocaine dependent patients, there are but a few researches about the interaction between addiction and quality of life. Objective. To study different parameters of quality of life in a sample of cocaine dependent patients and to compare patients with or without dual diagnosis. Also, to promote the importance of subjectivity in the quality of life and to propose to incorporate patients’ self-perception into their treatment. Method. Three diagnostic interviews were administered (SCID-I, SCID-II and PRISM) and a quality of life questionnaire (SF-36) was applied between two different patient groups: Group I (cocaine dependent patients) and Group II (cocaine dependent patients with other mental disorder). Results. Patients diagnosed with dual disorders (Group II) showed broader differences in perceptions of their quality of life in comparison with their clinicians. The perception of quality of life may vary depending on the presence and severity of mental disorders, and these different appreciations may explain the difficulties that clinicians face in understanding their patients’ expectations and motivations. Discussion and conclusion. A systematic evaluation of the subjective quality of life should be included in the management of cocaine dependent patients in order to more accurately understand the patients’ perception of their treatment, motivations and expectations.

Fine mapping of bone structure and strength QTLs in heterogeneous stock rat

We previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3×10(-6)). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3 Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis.

Religious upbringing and current religiosity in Spanish nursing and medicine students

The influence of religious education in the family upon current spiritual and religious tendencies was assessed in a sample of 599 Spanish nurse and medicine students using a religiosity scale and answers to a series of belief/disbelief statements. Results showed that nursing and medicine students were equally low-religious, with no differences in religiosity total scores between participants coming from religious families; however, medical students coming from nonreligious families showed higher religiousness than the corresponding nursing trainees. This distinction appeared both across religiosity items and in a variety of responses to belief/disbelief of Christian/secular assertions. Regression analysis showed that religious family background was a consistent predictor of religious beliefs at young adulthood, and its influence was higher for medical students. In addition to establish religious upbringing as an important factor modulating enduring religiosity, these findings provide distinctions between nurse and medical trainees, and reproduce, in a Spanish mainly catholic sample, the structure of religiosity factors previously found on North American mainline protestants.