Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population.

BACKGROUND: A strong predictor for the development of alcohol use disorder (AUD) is altered sensitivity to the intoxicating effects of alcohol. Individual differences in the initial sensitivity to alcohol are controlled in part by genetic factors. Mice offer a powerful tool to elucidate the genetic basis of behavioral and physiological traits relevant to AUD, but conventional experimental crosses have only been able to identify large chromosomal regions rather than specific genes. Genetically diverse, highly recombinant mouse populations make it possible to observe a wider range of phenotypic variation, offer greater mapping precision, and thus increase the potential for efficient gene identification. METHODS: We have taken advantage of the Diversity Outbred (DO) mouse population to identify and precisely map quantitative trait loci (QTL) associated with ethanol sensitivity. We phenotyped 798 male J:DO mice for three measures of ethanol sensitivity: ataxia, hypothermia, and loss of the righting response. We used high-density MegaMUGA and GigaMUGA to obtain genotypes ranging from 77,808 to 143,259 SNPs. We also performed RNA sequencing in striatum to map expression QTLs and identify gene expression-trait correlations. We then applied a systems genetic strategy to identify narrow QTLs and construct the network of correlations that exists between DNA sequence, gene expression values, and ethanol-related phenotypes to prioritize our list of positional candidate genes. RESULTS: We observed large amounts of phenotypic variation with the DO population and identified suggestive and significant QTLs associated with ethanol sensitivity on chromosomes 1, 2, and 16. The implicated regions were narrow (4.5-6.9 Mb in size) and each QTL explained ~4-5% of the variance. CONCLUSIONS: Our results can be used to identify alleles that contribute to AUD in humans, elucidate causative biological mechanisms, or assist in the development of novel therapeutic interventions.

Genome-wide association for testis weight in the diversity outbred mouse population.

Testis weight is a genetically mediated trait associated with reproductive efficiency across numerous species. We sought to evaluate the genetically diverse, highly recombinant Diversity Outbred (DO) mouse population as a tool to identify and map quantitative trait loci (QTLs) associated with testis weight. Testis weights were recorded for 502 male DO mice and the mice were genotyped on the GIGAMuga array at ~ 143,000 SNPs. We performed a genome-wide association analysis and identified one significant and two suggestive QTLs associated with testis weight. Using bioinformatic approaches, we developed a list of candidate genes and identified those with known roles in testicular size and development. Candidates of particular interest include the RNA demethylase gene Alkbh5, the cyclin-dependent kinase inhibitor gene Cdkn2c, the dynein axonemal heavy chain gene Dnah11, the phospholipase D gene Pld6, the trans-acting transcription factor gene Sp4, and the spermatogenesis-associated gene Spata6, each of which has a human ortholog. Our results demonstrate the utility of DO mice in high-resolution genetic mapping of complex traits, enabling us to identify developmentally important genes in adult mice. Understanding how genetic variation in these genes influence testis weight could aid in the understanding of mechanisms of mammalian reproductive function.

The Feasibility and Acceptability of Using Technology-Based Daily Diaries with HIV-Infected Young Men Who have Sex with Men: A Comparison of Internet and Voice Modalities.

This study delivered a daily diary to 67 HIV-infected men who have sex with men (MSM) between 16 and 24 years old for 66 days to measure HIV-risk behaviors and other psychosocial variables via two diary modalities: internet (accessible via any web-enabled device) and voice (accessible via telephone). Participants were randomized to complete one diary modality for 33 days before switching to the second modality for 33 days. The study was implemented in three urban HIV health care centers in the United States where participants were receiving services. Through diary data and qualitative interview data, we examined the feasibility and acceptability of the dairies and identified barriers and facilitators of dairy compliance. Results show high participant retention in the daily diary (93.4 %) and high compliance for the number of dairies completed (72.4 %). Internet diaries were preferred by 92 % of participants and completed at a significantly higher rate (77.5 %) than voice diaries (67.7 %). Facilitators included opportunities for self-reflection and cathartic sharing, monetary compensation, relationships with study staff, and daily reminders. Barriers included being busy or not having privacy at the time of reminders, forgetting, and falling asleep. Participants also described barriers and facilitators unique to each modality. Overall, both modalities were feasible and acceptable for use with our sample of HIV-infected MSM.