468 research outputs found
Plasma Protein Levels Analysis in Multiple Sclerosis Sardinian Families Identified C9 and CYP24A1 as Candidate Biomarkers
No full textHere we investigate protein levels in 69 multiple sclerosis (MS) cases and 143 healthy controls (HC) from twenty Sardinian families to search for promising biomarkers in plasma. Using antibody suspension bead array technology, the plasma levels of 56 MS-related proteins were obtained. Differences between MS cases and HC were estimated using Linear Mixed Models or Linear Quantile Mixed Models. The proportion of proteins level variability, explained by a set of 119 MS-risk SNPs as to the literature, was also quantified. Higher plasma C9 and CYP24A1 levels were found in MS cases compared to HC (p < 0.05 after Holm multiple testing correction), with protein level differences estimated as, respectively, 0.53 (95% CI: 0.25, 0.81) and 0.42 (95% CI: 0.19, 0.65) times plasma level standard deviation measured in HC. Furthermore, C9 resulted in both statistically significantly higher relapsing-remitting MS (RRMS) and secondary-progressive MS (SPMS) compared to HC, with SPMS showing the highest differences. Instead, CYP24A1 was statistically significantly higher only in RRMS as compared to HC. Respectively, 26% (95% CI: 10%, 44%) and 16% (95% CI: 9%, 39%) of CYP24A1 and C9 plasma level variability was explained by known MS-risk SNPs. Our results highlight C9 and CYP24A1 as potential biomarkers in plasma for MS and allow us to gain insight into molecular disease mechanisms
Heritability Estimation of Multiple Sclerosis Related Plasma Protein Levels in Sardinian Families with Immunochip Genotyping Data
No full textThis work aimed at estimating narrow-sense heritability, defined as the proportion of the phenotypic variance explained by the sum of additive genetic effects, via Haseman–Elston regression for a subset of 56 plasma protein levels related to Multiple Sclerosis (MS). These were measured in 212 related individuals (with 69 MS cases and 143 healthy controls) obtained from 20 Sardinian families with MS history. Using pedigree information, we found seven statistically significant heritable plasma protein levels (after multiple testing correction), i.e., Gc ([Formula: see text] = 0.77; 95%CI: 0.36, 1.00), Plat ([Formula: see text] = 0.70; 95%CI: 0.27, 0.95), Anxa1 ([Formula: see text] = 0.68; 95%CI: 0.27, 1.00), Sod1 ([Formula: see text] = 0.58; 95%CI: 0.18, 0.96), Irf8 ([Formula: see text] = 0.56; 95%CI: 0.19, 0.99), Ptger4 ([Formula: see text] = 0.45; 95%CI: 0.10, 0.96), and Fadd ([Formula: see text] = 0.41; 95%CI: 0.06, 0.84). A subsequent analysis was performed on these statistically significant heritable plasma protein levels employing Immunochip genotyping data obtained in 155 healthy controls (92 related and 63 unrelated); we found a meaningful proportion of heritable plasma protein levels’ variability explained by a small set of SNPs. Overall, the results obtained, for these seven MS-related proteins, emphasized a high additive genetic variance component explaining plasma levels’ variability
A bayesian mendelian randomization approach to identify disease causing proteins via pedigree data, partially observed exposures and correlated
No full textGreater vulnerability to warming of marine versus terrestrial ectotherms
No full textUnderstanding which species and ecosystems will be most severely affected by warming as climate change advances is important for guiding conservation and management. Both marine and terrestrial fauna have been affected by warming1,2 but an explicit comparison of physiological sensitivity between the marine and terrestrial realms has been lacking. Assessing how close populations live to their upper thermal limits has been challenging, in part because extreme temperatures frequently drive demographic responses3,4 and yet fauna can use local thermal refugia to avoid extremes5–7. Here we show that marine ectotherms experience hourly body temperatures that are closer to their upper thermal limits than do terrestrial ectotherms across all latitudes—but that this is the case only if terrestrial species can access thermal refugia. Although not a direct prediction of population decline, this thermal safety margin provides an index of the physiological stress caused by warming. On land, the smallest thermal safety margins were found for species at mid-latitudes where the hottest hourly body temperatures occurred; by contrast, the marine species with the smallest thermal safety margins were found near the equator. We also found that local extirpations related to warming have been twice as common in the ocean as on land, which is consistent with the smaller thermal safety margins at sea. Our results suggest that different processes will exacerbate thermal vulnerability across these two realms. Higher sensitivities to warming and faster rates of colonization in the marine realm suggest that extirpations will be more frequent and species turnover faster in the ocean. By contrast, terrestrial species appear to be more vulnerable to loss of access to thermal refugia, which would make habitat fragmentation and changes in land use critical drivers of species loss on land.Peer reviewe
The cognitive science of religion: past, present, and possible futures
No full textThis paper provides an overview of research in the Cognitive Science of Religion over more than three decades and considers where the field might be headed in the future. The perspective we bring draws on the experiences of some of the field's founders (Barrett, Boyer, Lawson, McCauley, and Whitehouse) and on insights from the author of the field's first single-authored introductory textbook (White)
Multiple Sclerosis heritability estimation on Sardinian and French ascertained families using Bayesian liability threshold model
No full textAn analysis of reading- abilities of fifty-seven rural school pupils in the second and third grades of Haralson County, Georgia, 1954
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Genetic and phenotypic dissection of autism susceptibility
No full textAutism is a severe neurodevelopmental disorder characterized by deficits in language and social interaction, and patterns of repetitive and stereotyped behaviors, interests and activities. Evidence indicates that autism has a predominantly genetic etiology, and that as many as fifteen genes may contribute to disease susceptibility. One model suggests autism may result from oligogenic inheritance, with locus heterogeneity, such that different families or individuals possess a different mix of susceptibility alleles. In this dissertation, I present genome-wide linkage studies of autism and traits comprising the aspects of the broader phenotype to identify autism susceptibility loci. I further document detailed molecular and genetic analyses of candidate genes in regions detected by linkage, and in the case of 15q11-q13, as chromosomal duplications found in 1-3% of autism cases. A unifying theme to my dissertation is the focus of genetic studies on genes acting within candidate neurobiological systems suspected of involvement in autism. Genetic analyses include linkage, linkage refinement, construction of detailed linkage disequilibrium (LD) and corresponding haplotype maps across candidate loci, and tests for transmission disequilibrium of single markers and haplotypes. Molecular studies of select candidates aim to identify functional variation on associated alleles; in the absence of association they seek to identify potential rare disease-related variants considering for example evolutionarily conserved sequence. I hypothesize that there are allelic variants, which underlie genetic linkage and/or association to autism and related traits, and these contribute to autism susceptibility through both direct and interactive effects. The goal of this study is to dissect the genetic etiology of autism by leveraging trait-based phenotypic subsets of autism using the approaches and tools I have outlined here
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On the Allelic Architecture of Multiple Sclerosis in Sardinia
No full textMultiple Sclerosis (MS) is a demyelinating disease of the central nervous system with autoimmune etiology. It affects approximately 2.3 million people worldwide, but prevalence is distributed unequally with countries closer to the equator manifesting a lower prevalence of MS. The Italian island of Sardinia is an exception, with prevalence rates that are among the highest in the world. Sardinia is inhabited by a unique, isolated population that was founded approximately 10,000 years ago. The reasons for this enrichment of MS cases in Sardinia are unknown. Like most complex diseases, MS has both genetic and environmental components of susceptibility. To date, research has uncovered the identity of 114 Single Nucleotide Polymorphisms (SNPs) which tag loci that explain approximately 27% of the genetic factors that drive MS susceptibility, in populations of Northern European ancestry. With the exception of the effect exerted by polymorphisms in the Human Leukocyte Antigen DRB1gene, these genetic susceptibility alleles have small to moderate effect sizes (Odds Ratio range 1.03 to 1.34) and are largely common in the population (Risk Allele Frequency range 0.09 to 0.95). There are multiple reasons to explore the hypothesis that the Sardinian population may be enriched for the risk alleles that drive MS susceptibility, such as the high prevalence of MS and predictions made by population genetics theory with regard to the genetic landscape of isolated populations. Past studies in the genetics of MS in Sardinia have uncovered regions of the genome with possible roles in MS pathogenesis that display little overlap with regions identified in other populations. In the present study, I examined the presence of established MS-associated SNPs in a dataset of 19 multiplex Sardinian families. Although the Northern European-derived risk variants are present in Sardinians, these are able to differentiate patients from unaffected Sardinian individuals only when considered cumulatively, with the use of a weighted genetic burden score. The presence of multiple MS cases in the same family afforded us the opportunity to search for genetic variation that affected relative pairs may share from a common ancestor. Five regions with suggestive amounts of allele sharing were detected (logarithm of the odds (LOD*) score ≥ 1); fine-mapping underneath these linkage peaks identified four genes that may be relevant in MS pathogenesis in Sardinia (EPHA7 on 6q16.1, JAZF1 on 7p15.1, KLRC2 on 12p13.2 and CD226 on 18q22.2). Interestingly, the chromosome 12 peak spans the natural killer cell gene cluster at that location. I therefore used whole exome sequencing data of the affected individuals from 5 of the Sardinian multiplex families to search for rare, nonsynonymous variants. I identified two variants in IKZF1 at 7p12 and MANBA at 4q24, two genes that are implicated in MS via the established associations. These variants are conserved and predicted to be probably damaging to the protein product. I also found a range of variants in the genes underneath the linkage peaks, highlighting the importance of cumulative assessments of the burden of rare and common variants in disease. In total, these data indicate that the overall MS susceptibility landscape in Sardinia is not markedly different from that of outbred European populations, and likely includes both common and rare risk alleles. However, these data also highlight the utility of multiplex families from an isolated population in the initial identification of possible risk alleles. Replication in large population samples is required to assess the relevance of the identified variants in MS pathogenesis.</p
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