Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

Objective To identify shared polygenic risk and causal associations in amyotrophic lateral sclerosis (ALS). Methods Linkage disequilibrium score regression and Mendelian randomization were applied in a large-scale, data-driven manner to explore genetic correlations and causal relationships between >700 phenotypic traits and ALS. Exposures consisted of publicly available genome-wide association studies (GWASes) summary statistics from MR Base and LD-hub. The outcome data came from the recently published ALS GWAS involving 20,806 cases and 59,804 controls. Multivariate analyses, genetic risk profiling, and Bayesian colocalization analyses were also performed. Results We have shown, by linkage disequilibrium score regression, that ALS shares polygenic risk genetic factors with a number of traits and conditions, including positive correlations with smoking status and moderate levels of physical activity, and negative correlations with higher cognitive performance, higher educational attainment, and light levels of physical activity. Using Mendelian randomization, we found evidence that hyperlipidemia is a causal risk factor for ALS and localized putative functional signals within loci of interest. Interpretation Here, we have developed a public resource () which we hope will become a valuable tool for the ALS community, and that will be expanded and updated as new data become available. Shared polygenic risk exists between ALS and educational attainment, physical activity, smoking, and tenseness/restlessness. We also found evidence that elevated low-desnity lipoprotein cholesterol is a causal risk factor for ALS. Future randomized controlled trials should be considered as a proof of causality. Ann Neurol 2019;85:470-481Peer reviewe

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Linking HIV-positive Jail Inmates to Treatment, Care, and Social Services After Release: Results from a Qualitative Assessment of the COMPASS Program

Approximately 17% of individuals living with HIV/AIDS pass through the correctional system each year. Jails provide a unique opportunity to diagnose and treat HIV infection among high-risk, transient populations with limited access to medical services. In 2007, the US Health Resources and Services Administration funded a multi-site demonstration project entitled Enhancing Linkages to HIV Primary Care in Jail Settings that aims to improve diagnosis and treatment services for HIV-positive jail detainees and link them to community-based medical care and social services upon release. We performed an evaluation of the Rhode Island demonstration site entitled Community Partnerships and Supportive Services for HIV-Infected People Leaving Jail (COMPASS). Through in-depth qualitative interviews among 20 HIV-positive COMPASS participants in Rhode Island, we assessed how COMPASS impacted access to health care and social services utilization. Most individuals were receiving HIV treatment and care services upon enrollment, but COMPASS enhanced linkage to medical care and follow-up visits for HIV and other co-morbidities for most participants. Several participants were successfully linked to new medical services as a result of COMPASS, including one individual newly diagnosed with HIV and another who had been living with HIV for many years and was able to commence highly active antiretroviral therapy (HAART). While many individuals reported that COMPASS support prevented substance abuse relapse, ongoing substance abuse nevertheless remained a challenge for several participants. Most participants enrolled in one or more new social services as a result of COMPASS, including Medicaid, Supplemental Security Income, food assistance, and housing programs. The primary unmet needs of COMPASS participants were access to mental health services and stable housing. Intensive case management of HIV-positive jail detainees enhances access to medical and social support services and helps prevent relapse to substance abuse. Expanding intensive case management programs, public housing, and mental health services for recently released HIV-positive detainees should be public health priorities