Biology subjects

Bimschleger, H. V.

Publications and source records attributed to Bimschleger, H. V..

3 recordsLinked to original sources

bioRxiv2024

Genome-Wide Association Study in Outbred Heterogeneous Stock Rats Identifies Multiple Loci for the Incentive Salience of Reward Cues.

Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues; both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1,645 genetically diverse heterogeneous stock (HS) rats. We tested HS rats in a Pavlovian conditioned approach task, in which we characterized the individual responses to food-associated stimuli ("cues"). Rats exhibited either cue-directed "sign-tracking" behavior or food-cup directed "goal-tracking" behavior. We then used the conditioned reinforcement procedure to determine whether rats would perform a novel operant response for unrewarded presentations of the cue. We found that these measures were moderately heritable (SNP heritability, h2 = .189-.215). GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits we examined. Interval sizes of these QTLs varied widely. 7 traits shared a QTL on chromosome 1 that contained a few genes (e.g. Tenm4, Mir708) that have been associated with substance use disorders and other mental health traits in humans. Other candidate genes (e.g. Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on other behavioral measures in HS rats and found that regions containing QTLs on chromosome 1 were also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive salience and provide further support for a relationship between attribution of incentive salience and drug abuse-related traits.

neuroscience↗

bioRxiv2023

Exponential increase in QTL detection with increased sample size.

Power analyses are often used to determine the number of animals required for a genome wide association analysis (GWAS). These analyses are typically intended to estimate the sample size needed for at least one locus to exceed a genome-wide significance threshold. A related question that is less commonly considered is the number of significant loci that will be discovered with a given sample size. We used simulations based on a real dataset that consisted of 3,173 male and female adult N/NIH heterogeneous stock (HS) rats to explore the relationship between sample size and the number of significant loci discovered. Our simulations examined the number of loci identified in sub-samples of the full dataset. The sub-sampling analysis was conducted for four traits with low (0.15 {+/-} 0.03), medium (0.31 {+/-} 0.03 and 0.36 {+/-} 0.03) and high (0.46 {+/-} 0.03) SNP-based heritabilities. For each trait, we sub-sampled the data 100 times at different sample sizes (500, 1,000, 1,500, 2,000, and 2,500). We observed an exponential increase in the number of significant loci with larger sample sizes. Our results are consistent with similar observations in human GWAS and imply that future rodent GWAS should use sample sizes that are significantly larger than those needed to obtain a single significant result.

genetics↗

bioRxiv2019

Adapting genotyping-by-sequencing and variant calling for heterogeneous stock rats

The heterogeneous stock (HS) is an outbred rat population derived from eight inbred rat strains. HS rats are ideally suited for genome wide association studies; however, only a few genotyping microarrays have ever been designed for rats and none of them are currently in production. To address the need for an efficient and cost effective method of genotyping HS rats, we have adapted genotype-by-sequencing (GBS) to obtain genotype information at large numbers of single nucleotide polymorphisms (SNPs). In this paper, we have outlined the laboratory and computational steps we took to optimize double digest genotype-by-sequencing (ddGBS) for use in rats. We also evaluate multiple existing computational tools and explain the workflow we have used to call and impute over 3.7 million SNPs. We also compared various rat genetic maps, which are necessary for imputation, including a recently developed map specific to the HS. Using our approach, we obtained concordance rates of 99% with data obtained using data from a genotyping array. The principles and computational pipeline that we describe could easily be adapted for use in other species for which reliable reference genome sets are available.

genetics↗