Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Fez Fabrications: Artisans And Handmade Textiles In A Complex Traditional Culture

INTRODUCTION This paper grows out of a group process of studying handmade fabric, embroidery, and trim in Fez, Morocco in the late 1980s and early 1990s.1 The group included three textile scholars, a video specialist and myself, an anthropologist.2 While the textile scholars began the project with an interest in the textile products and their means of production, we all became interested in more social aspects of the work. Other scholars have noted the cues cloth can give in understanding the social relations of a culture. Reddy (1986) looks for hints of the social tensions leading to the French Revolution in the changing ways merchants and others talked about cloth in a universal dictionary of commerce published several times between 1730 and 1784. He finds ...an odd combination of rigidity and flexibility...(264) which he relates to the later upheaval of the 1789 Revolution, a throwing aside of the old order and difficulty in accepting a new one. In the dictionary\u27s discussion of commodities, he sees ...the necessary intimacy that always subsists between social relationships and things (282). In their Introduction to Cloth and Human Experience (1989), Schneider and Weiner give an overview of the way textiles and their manufacture are important in ...the reproduction of social life and power (4). Of special interest here is their discussion of cloth in large scale societies, like Morocco today. While such cultures have wide access to machine made fabric, some local handmade textiles persist ...as aspects of the consolidation of cultural identities...(16). One of their examples is Ghandi\u27s adoption of homespun cotton cloth in India as a symbol, and fact, of India\u27s independence from British manufacturing. While the other papers on Morocco focus more on the textile products, though including social context, I will deal specifically with the social lives and interactions of the textile producers, merchants and consumers, and through them and their dealing with changing economic and social conditions, present a picture of one segment of Moroccan society today. THE CONTEXT OF FEZ The name Fez in association with handmade textiles may call up images of the exotic East, frozen in time. While a first visit to the old city or medina can reinforce this image, it is only one part of the total picture. Before we discuss the artisans and merchants and their products and customers in detail, the reader needs an accurate context in which to understand them. The city of Fez is located in Morocco, on the northwest shoulder of Africa. While Morocco is an Arab Muslim country, for centuries it has been a crossroads for the cultures of Europe, sub-Saharan Africa and the Middle East. In size and climate Morocco resembles California, and grows wheat as a staple crop, a wide variety of fruits and vegetables, and citrus for export. Handmade carpets and factory-produced leather jackets, bags and shoes are also exported. Fez is the traditional cultural capital of Morocco, the source of the quintessential forms of Moroccan music, food, and handicrafts, and longtime provider of the country\u27s intellectual and political leaders. Fez is also Morocco\u27s mercantile capital, where tradition is balanced with innovation, as you will see below. The coexistence of old and new is physically present in the city itself, which has modern Europeanized sections with broad tree-lined avenues strolled by young men in leather jackets and women in western dress. In older sections with narrow winding streets, one can still see traces of areas organized by different craft guilds. The city was founded in 829 A.D., soon after Islam arrived in Morocco, and new Fez dates from the 1300s

Formal And Nonformal Roles Of Moroccan Village Women.

PhDCultural anthropologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/180872/2/8008646.pd