Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

A compendium of multi-omics data illuminating host responses to lethal human virus infections

Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Men’s comfort in distributing or receiving HIV self-test kits from close male social network members in Dar Es Salaam, Tanzania: baseline results from the STEP project

Background: A variety of strategies have been used to reach men with HIV self-testing services, including social network-based HIV self-test kits distribution. However, few studies have assessed men’s comfort to distribute to or receive HIV self-test kits from close male friends within the same social network. In this study, we assessed men’s comfort to distribute to and/or receive HIV self-test kits from close male friends and associated factors among men who socialize in networks locally referred to as “camps” in Tanzania. Methods: Data are from the baseline survey of a cluster-randomized controlled trial conducted in June 2019 with 18 social networks or “camps” in Dar es Salaam, Tanzania. Participants were 18-year-old or older male camp members who were HIV-negative at the time of enrolment. We used the Generalized Estimating Equations (GEE) to assess factors associated with being comfortable to distribute to and/or receive HIV self-test kits from close male members within one’s social network. Results: Of 505 participants, 67.9% (n = 342) reported being comfortable to distribute to while 68.2% (n = 344) were comfortable to receive HIV self-test kits from their close male friends. Ever having heard about HIV self-testing (Adjusted Prevalence Ratio (Adj. PR): 1.6; 95% Confidence Interval [CI]: 1.3, 1.9), willingness to self-test for HIV in front of a sexual partner (Adj. PR: 3.0; 95%CI: 1.5, 6.1) and exposure to peer-led HIV self-testing education and promotion (Adj. PR: 1.4; 95%CI: 1.2, 1.7) were significantly associated with being comfortable to distribute HIV self-test kits to close male members within one’s social network. Similar results were observed for being comfortable to receive HIV self-test kits from a close male friend within one’s social network. Conclusions: Overall, these findings suggest that distribution of HIV self-test kits through close male friends could improve the proportion of men reached with HIV self-testing services and improve HIV testing rates in this population where uptake remains low. However, additional promotional strategies such as peer-led HIV self-testing education are needed to raise awareness and increase the proportion of men who are comfortable to receive and/or distribute HIV self-testing kits