Leukocyte CCR2 expression is associated with mini-mental state examination score in older adults

This is a copy of an article published in Rejuvenation Research © 2012 Mary Ann Liebert, Inc.; Rejuvenation Research is available online at: http://online.liebertpub.com.Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample

Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.

Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10(-06) (false discovery rate ∼5%)] and one of eight biomarker associations at P < 8 × 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect

Original Article

The present paper deals with an investigation on the changes appearing in the mucous membrane of the nose (physiologic atrophy) in normal persons of different age groups, as contrasted with a wasting of the mucous mambrane of the nose in cases of atrophic rhinitis. The investigation has been performed for the purpose of contributing to the studies of the pathology of atrophic rhinitis. 1. Pathologic changes of a considerable degree were. observed in the epithelium in quite a large section of infants and children where it had been considered normal as a results of macroscopic examinations. 2. Metaplasia of the epithelial cells developing in the mucous membrane in the forepart of the respiratory region seems to occur as a result of the stimulus applied from without. The phenomenon was marked in the front and along the lower edge of the inferior turbinal, showing a tendency to increase in magnitude as the age advance. It did not, however, spread over a wide area, nor was there any marked development of cornification. An increase in mucus secretion, as well as in the number of goblet cells, was noticed in the epithelium as the age advance. Mucous degeneration gradually set in at the end of forties, becoming marked in the sixties. 4. In the basal membrane, the hyaline layer, which is its secondary form, grew in size with age, and a substance which stains with Hale\u27s stain was detected in it. This substance seems to have an important share in the mucus secreting function of the epithelium. 5. It seems that the epithelium of the mucous membrane of the upper respiratory tract continues to function even in considerably advanced ages. 6. The lymphoid tissue situated underneath the epithelium attained the largest quantity in persons about 20 years old; it began to diminish and grow less thick in persons over 40. The presence of the elastic fiber was noticed in the subepithelial layer in all age groups, though the number of persons with this phenomenon was small.7. The glands wers under-developed in children of about 10; they grew rapidly after that age until about 40 when they began to show a tendency to atrophy. 8. It seems that the periglandular lymphocytes, which infiltrate without bringing about the disintegration of the glands, take charge of the metabolism of the glands. A large number of them were found in infancy but they showed a marked decrease in number in persons over about 40. It would seem that, in highly advanced ages, non-inflammatory disintegration of the glands could possibly occur as a result of the infiltration of the lymphoid tissue. 9. The formation of the oncocyte, an unusual cell of the epithelium of the gland which characterizes the old age, was noticed in 7 cases. 10. The blood vessels manifested changes of a high degree in persons of advanced ages: they revealed evidences of functional disturbance of a high degree when stained by the stains of H. E, Weigert, PAS and Hale. This would show the measure of the influence that has been exerted on the function of the mucous membrane. 11. Corpora cavernosa was under-developed in infancy but became well-developed in persons of about 20; a decrease in the number of bodies and a diminution in size of the inner lumen became marked in persons over 40, becoming more marked in persons over 50

Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24

Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.American Kennel Club Canine Health Foundation (grant CHF 0407)American Kennel Club Canine Health Foundation (grant CHF 0925)Old English Sheepdog Club of AmericaTarTan Gordon Setter ClubEuropean Science Foundation (EURYI)Canine Health Information Center (DNA Repository

A comprehensive assessment of benign genetic variability for neurodegenerative disorders

Over the last few years, as more and more sequencing studies have been performed, it has become apparent that the identification of pathogenic mutations is, more often than not, a complex issue. Here, with a focus on neurodegenerative diseases, we have performed a survey of coding genetic variability that is unlikely to be pathogenic. We have performed whole-exome sequencing in 478 samples derived from several brain banks in the United Kingdom and the United States of America. Samples were included when subjects were, at death, over 60 years of age, had no signs of neurological disease and were subjected to a neuropathological examination, which revealed no evidence of neurodegeneration. This information will be valuable to studies of genetic variability as a causal factor for neurodegenerative syndromes. We envisage it will be particularly relevant for diagnostic laboratories as a filter step to the results being produced by either genome-wide or gene-panel sequencing. We have made this data publicly available at www.alzforum.org/exomes/hex

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studie

A meta-analysis of gene expression signatures of blood pressure and hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension