Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications

Leslie C. Jones, John L. Beard, Byron C. Jones

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Fe, Cu, and Zn are of widespread neurobiological importance, but must be regulated closely as too much or too little of these metals can have adverse effects on brain function. Recent evidence from nutritional models notes that the hippocampus is particularly vulnerable to Fe and Zn deficiencies. We recently performed a quantitative trait loci (QTL) analysis as a preliminary step in identifying genes that contribute to natural variation in hippocampal Fe, Cu, and Zn content. We used ICP-MS to measure the concentrations of these metals in 120-day-old mice from 30 strains of the BXD/TY panel. The BXD/Ty recombinant inbred strain panel is well-suited for complex trait analysis, as all strains are genotyped with a dense marker set and have been phenotyped extensively for neurobehavioral traits and hippocampal gene expression. We observed a wide-range of hippocampal Fe, Cu, and Zn concentrations across the BXD strains. These concentrations were related to systemic Fe status, but not to Fe, Cu, and Zn elsewhere in the brain. The three metals also showed strong covariance, suggestive of overlap in their regulatory pathways. We identified two QTL, on chromosomes 14 and 9, most strongly associated with Cu but also suggestively associated with Fe (chr. 14) and Zn (chr. 9). We also performed genetic correlational analyses with existing data on these strains and revealed associations with cognitive, anxiety-related, and alcohol-related phenotypes. Covariance of these metals with gene expression is also discussed. This work shows that hippocampal Fe, Cu, and Zn are under polygenic influence and that trace metal regulation is associated with hippocampus-related behaviors. Future work will elucidate the genes underlying the two QTL identified, to aid in identifying homologous genetic variants in human populations, which may underlie altered trace metal homeostasis and related neurological disease.

Original languageEnglish (US)
Pages (from-to)398-410
Number of pages13
JournalHippocampus
Volume18
Issue number4
DOIs
StatePublished - Apr 22 2008

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Zinc
Copper
Hippocampus
Iron
Metals
Quantitative Trait Loci
Gene Expression
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 9
Brain
Genes
Homeostasis
Anxiety
Alcohols
Phenotype
Population

All Science Journal Classification (ASJC) codes

  • Cognitive Neuroscience

Cite this

Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications. / Jones, Leslie C.; Beard, John L.; Jones, Byron C.

In: Hippocampus, Vol. 18, No. 4, 22.04.2008, p. 398-410.

Research output: Contribution to journalArticle

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