Quantitative Trait Loci for Brain Morphology and Complex Behavior: Neurogenetics in Cognitive Neuroscience.

摘要

A growing area of cognitive neuroscience research is an exploratory, whole-genome approach to associating measurable phenotypes with genetic variation, in an effort to identify the basic biological causes of observable phenotypes. Most human whole-genome studies of interest to cognitive neuroscience, at present, investigate neuropsychiatric disorders---particularly wherein cognitive dysfunction is a defining feature---including schizophrenia, obsessive-compulsive disorder, and attention deficit-hyperactivity disorder. The data generated by human studies are augmented by animal studies of translational phenotypes with proven clinical value. A series of exploratory whole-genome mapping studies of phenotypes with translational clinical implications were conducted in a fixed genetic reference population of mice, the BXD recombinant inbred panel. Quantitative trait loci were mapped for neocortex (chr. 11, p0.05), noncortical brain (chr. 19, p0.05), and corpus callosum volume. (chr. 2, p.005). Reduced cortical volume and white mater anomies have been reported in clinical populations, particularly attention deficit-hyperactivity disorder (ADHD). White matter anomalies are common to several neuropsychiatric syndromes, including autism and schizophrenia. A potential translational phenotype related to cognitive control was tested in a mutant mouse related to ADHD and ADHD treatment: reversal learning in heterozygous norepinephrine transporter (NET) knockout mice, a genetic analogue of an ADHD treatment (atomoxetine, a selective NET inhibitor). As predicted by known effects of atomoxetine on reversal learning in rats, NET mutants have better reversal learning performance (p0.05), which subsequently validated our mouse version of reversal learning task as a useful translational endophenotype for ADHD. Finally, a genome-wide QTL mapping study of the reversal learning phenotype was conducted, and novel locus was mapped to chromosome 10 (p0.05). Subsequent informatics analyses were conducted to a filter the genes near the QTL and positional candidates were advanced. Syn3 was prioritized as one of the top two candidates by statistical analysis alone, and is a particularly promising candidate given that the protein affiliates with synaptic vesicles and is known to modulate inhibitory neural circuitry.