Genome-wide association reveals genetic effects on human Aβ₄₂and τ protein levels in cerebrospinal fluids: a case control study

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is common and highly heritable with many genes and gene variants associated with AD in one or more studies, including APOE ε2/ε3/ε4. However, the genetic backgrounds for normal cognition, mild cognitive impairment (MCI) and AD in terms of changes in cerebrospinal fluid (CSF) levels of Aβ_1-42, T-tau, and P-tau_181P, have not been clearly delineated. We carried out a genome-wide association study (GWAS) in order to better define the genetic backgrounds to these three states in relation to CSF levels.</p> <p>Methods</p> <p>Subjects were participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The GWAS dataset consisted of 818 participants (mainly Caucasian) genotyped using the Illumina Human Genome 610 Quad BeadChips. This sample included 410 subjects (119 Normal, 115 MCI and 176 AD) with measurements of CSF Aβ_1-42, T-tau, and P-tau_181PLevels. We used PLINK to find genetic associations with the three CSF biomarker levels. Association of each of the 498,205 SNPs was tested using additive, dominant, and general association models while considering APOE genotype and age. Finally, an effort was made to better identify relevant biochemical pathways for associated genes using the ALIGATOR software.</p> <p>Results</p> <p>We found that there were some associations with APOE genotype although CSF levels were about the same for each subject group; CSF Aβ_1-42levels decreased with APOE gene dose for each subject group. T-tau levels tended to be higher among AD cases than among normal subjects. From adjusted result using APOE genotype and age as covariates, no SNP was associated with CSF levels among AD subjects. <it>CYP19A1 </it>'aromatase' (rs2899472), <it>NCAM2</it>, and multiple SNPs located on chromosome 10 near the <it>ARL5B </it>gene demonstrated the strongest associations with Aβ_1-42in normal subjects. Two genes found to be near the top SNPs, <it>CYP19A1 </it>(rs2899472, p = 1.90 × 10^-7) and <it>NCAM2 </it>(rs1022442, p = 2.75 × 10^-7) have been reported as genetic factors related to the progression of AD from previous studies. In AD subjects, APOE ε2/ε3 and ε2/ε4 genotypes were associated with elevated T-tau levels and ε4/ε4 genotype was associated with elevated T-tau and P-tau_181Plevels. Pathway analysis detected several biological pathways implicated in Normal with CSF β-amyloid peptide (Aβ_1-42).</p> <p>Conclusions</p> <p>Our genome-wide association analysis identified several SNPs as important factors for CSF biomarker. We also provide new evidence for additional candidate genetic risk factors from pathway analysis that can be tested in further studies.</p

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

peer-reviewedBackground: About forty human diseases are caused by repeat instability mutations. A distinct subset of these diseases is the result of extreme expansions of polymorphic trinucleotide repeats; typically CAG repeats encoding poly-glutamine (poly-Q) tracts in proteins. Polymorphic repeat length variation is also apparent in human poly-Q encoding genes from normal individuals. As these coding sequence repeats are subject to selection in mammals, it has been suggested that normal variations in some of these typically highly conserved genes are implicated in morphological differences between species and phenotypic variations within species. At present, poly-Q encoding genes in non-human mammalian species are poorly documented, as are their functions and propensities for polymorphic variation. Results: The current investigation identified 178 bovine poly-Q encoding genes (Q ≥ 5) and within this group, 26 genes with orthologs in both human and mouse that did not contain poly-Q repeats. The bovine poly-Q encoding genes typically had ubiquitous expression patterns although there was bias towards expression in epithelia, brain and testes. They were also characterised by unusually large sizes. Analysis of gene ontology terms revealed that the encoded proteins were strongly enriched for functions associated with transcriptional regulation and many contributed to physical interaction networks in the nucleus where they presumably act cooperatively in transcriptional regulatory complexes. In addition, the coding sequence CAG repeats in some bovine genes impacted mRNA splicing thereby generating unusual transcriptional diversity, which in at least one instance was tissue-specific. The poly-Q encoding genes were prioritised using multiple criteria for their likelihood of being polymorphic and then the highest ranking group was experimentally tested for polymorphic variation within a cattle diversity panel. Extensive and meiotically stable variation was identified. Conclusions: Transcriptional diversity can potentially be generated in poly-Q encoding genes by the impact of CAG repeat tracts on mRNA alternative splicing. This effect, combined with the physical interactions of the encoded proteins in large transcriptional regulatory complexes suggests that polymorphic variations of proteins in these complexes have strong potential to affect phenotype.Dairy Australia (through the Innovative Dairy Cooperative Research Center

A multinational study distinguishing Alzheimer's and healthy patients using cerebrospinal fluid tau/Aβ42 cutoff with concordance to amyloid positron emission tomography imaging.

INTRODUCTION: Changes in cerebrospinal fluid (CSF) tau and amyloid β (Aβ)42 accompany development of Alzheimer's brain pathology. Robust tau and Aβ42 immunoassays were developed to establish a tau/Aβ42 cutoff distinguishing mild-to-moderate Alzheimer's disease (AD) subjects from healthy elderly control (HC) subjects. METHODS: A CSF tau/Aβ42 cutoff criteria was chosen, which distinguished the groups and maximized concordance with amyloid PET. Performance was assessed using an independent validation cohort. RESULTS: A tau/Aβ42 = 0.215 cutoff provided 94.8% sensitivity and 77.7% specificity. Concordance with PET visual reads was estimated at 86.9% in a ∼50% PET positive population. In the validation cohort, the cutoff demonstrated 78.4% sensitivity and 84.9% specificity to distinguish the AD and HC populations. DISCUSSION: A tau/Aβ42 cutoff with acceptable sensitivity and specificity distinguished HC from mild-to-moderate AD subjects and maximized concordance to brain amyloidosis. The defined cutoff demonstrated that CSF analysis may be useful as a surrogate to imaging assessment of AD pathology

Validation of the person-centered maternity care scale in India

Abstract Background Person-centered care during childbirth is recognized as a critical component of quality of maternity care. But there are few validated tools to measure person-centered maternity care (PCMC). This paper aims to fill this measurement gap. We present the results of the psychometric analysis of the PCMC tool that was previously validated in Kenya using data from India. We aim to assess the validity and reliability of the PCMC scale in India, and to compare the results to those found in the Kenya validation. Methods We use data from a cross-sectional survey conducted from August to October 2017 with recently delivered women at 40 government facilities in Uttar Pradesh, India (N = 2018). The PCMC measure used is a previously validated scale with subscales for dignity and respect, communication and autonomy, and supportive care. We performed psychometric analyses, including iterative exploratory and confirmatory factor analysis, to assess construct and criterion validity and reliability. Results The results provide support for a 27-item PCMC scale in India with a possible score range from 0 to 81, compared to the 30-item PCMC scale in Kenya with a 0 to 90 possible score range. The overall PCMC scale has good reliability (Cronbach alpha = 0.85). Similar to Kenya, we are able to group the items in to three conceptual domains representing subscales for “Dignity and Respect,” “Communication and Autonomy,” and “Supportive Care.” The sub-scales also have relatively good reliability (Cronbach alphas range from 0.67 to 0.73). In addition, increasing scores on the scale is associated with future intentions to deliver in the same facility, suggesting good criterion validity. Conclusions This research extends the PCMC literature by presenting results of validating the PCMC scale in a new context. The psychometric analysis using data from Uttar Pradesh, India corroborates the Kenya analysis showing the scale had good content, construct, and criterion validity, as well as high reliability. The overlap in items suggests that this scale can be used across different contexts to compare women’s experiences of care, and to inform and evaluate quality improvement efforts to promote comprehensive PCMC

Marine Sclerobiofacies: Encrusting and Endolithic Communities on Shells Through Time and Space

The concept of sclerobiofacies is defined herein as suites of sclerobiont encrusters and endiont borers (collectively sclerobionts) preserved on skeletons that characterize particular facies/environments. Skeletal components provide biologically standardized substrates; when possible, comparison of encrusting assemblages on fossil shells of the same or closely related eurytopic species provides a degree of substrate control comparable to modern experimentally deployed shells. Taxonomic composition of sclerobiont suites varies rather predictably among marine environments (e.g., based upon depth) but is primarily useful for comparisons of environments within local areas and limited time frames. Parameters that may be used to compare sclerobiofacies across broader spatial and temporal dimensions include: per shell and cumulative species richness (diversity), frequency of encrustation, areal coverage, and guild structure of encrusting taxa. Herein, we summarize characteristic sclerobiofacies in a series of Recent and ancient examples. Modern subtropical marine encrusters, documented on experimentally deployed molluscan shells at sites ranging from 15 to over 200 m, show high biont richness in shallow subtidal areas. Maximal areal coverages in Bahamian samples occur at about 20–30 m, whereas species richness increases downward to the deeper euphotic zone (∼75–80 m). Below this level, rapid decline in both richness and percent coverage results in deeper Dysphotic–Aphotic zone samples yielding only a few species with coverage rarely exceeding 5%. Burial is also a key factor such that rapidly buried shells in the Shallow Euphotic zone have species coverages, richnesses, and taxonomic compositions resembling long-exposed shells in deeper areas below the euphotic zone. Shelly substrates from the Cambrian to Early Ordovician exhibit only minor encrustation by solitary attached taxa, especially echinoderms; however, by the Late Ordovician various solitary (e.g., cornulitids, craniid brachiopods) and colonial forms (e.g., trepostome and tubuliporate bryozoans) form distinctive sclerobiofacies. Photic zone-related environments, judged independently on the basis of microendoliths, show overall lower taxonomic richness than modern counterparts. However, they also show common patterns, including a general decrease of richness and percent encrustation from Shallow Euphotic to Dysphotic/Aphotic zones. Comparable trends are seen in Middle Devonian exemplars from New York State. Not only were there consistent trends toward lowered diversity/coverage into deep-water settings but also an additional factor related to turbidity and/or sedimentation rate was identified from assemblages at comparable depths arrayed along a distal to proximal gradient with respect to siliciclastic input sources. Carboniferous sclerobiont suites from varied sites in North America show many of the same traits as their Devonian counterparts, although detailed depth zonations are not documented at present. The Permo-Triassic extinctions appear to have had a strong impact on the taxonomic composition of marine sclerobiofacies, although a paucity of studies obscures details of Mesozoic and Cenozoic sclerobiofacies. In general, they appear to have taxonomic compositions and patterns similar to those observed in the Recent. The concept of sclerobiofacies provides another tool for paleoenvironmental analysis. Together with litho-, ichno-, bio-, and taphofacies, the properties of shell encrusting assemblages will yield detailed further insights into ancient environmental gradients