Abstract
Although the search for quantitative trait loci for behaviour remains a considerable challenge, the complicated genetic architecture of quantitative traits is beginning to be understood. The current project utilised heterogeneous stock (HS) male mice (n = 580) to investigate the genetic basis for brain weights, activity, anxiety and cognitive phenotypes. We identified 126 single nucleotide polymorphisms (SNPs) in genes involved in regulation of neurotransmitter systems, nerve growth/death and gene expression, and subsequently investigated their associations with changes in behaviour and/or brain weights in our sample. We found significant associations between four SNP-phenotype pairs, after controlling for multiple testing. Specificity protein 2 (Sp2, rs3708840), tryptophan hydroxylase 1 (Tph1, rs262731280) and serotonin receptor 3A (Htr3a, rs50670893) were associated with activity/anxiety behaviours, and microtubule-associated protein 2 (Map2, rs13475902) was associated with cognitive performance. All these genes except for Tph1 were expressed in the brain above the array median, and remained significantly associated with relevant behaviours after controlling for the family structure. Additionally, we found evidence for a correlation between Htr3a expression and activity. We discuss our findings in the light of the advantages and limitations of currently available mouse genetic tools, suggesting further directions for association studies in rodents.
Highlights
IntroductionThe HS mice have a number of advantages in genetic research, including some the highest resolution mapping of QTLs (of up to 1Mb7) offered by mouse genetic models[8,9]
High levels of recombination[6]
We investigated the association between behavioural tests that provide indices of these functions and a series of single nucleotide polymorphisms (SNPs) in candidate genes involved in major neurotransmitter systems (glutamate (Glu), serotonin (5HT), dopamine (DA), acetylcholine (Ach), GABA, noradrenaline (NA), and the endocannabinoid system), neuronal growth/death and gene expression (Table S1)
Summary
The HS mice have a number of advantages in genetic research, including some the highest resolution mapping of QTLs (of up to 1Mb7) offered by mouse genetic models[8,9]. Using HS mice we aimed to identify the genetic underpinnings of behavioural domains affected in a number of psychiatric disorders, namely anxiety, activity and cognitive phenotypes. The list of genes we investigated was by no means exhaustive, nominating a more limited number of loci from across a range of biological pathways offered us a better scope to identify the molecular background of the phenotypes we were interested in than narrower, more in-depth search. We discuss the validity of HS as a tool for genetic research, and suggest further directions for genetic association studies in mice
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