Linkage analysis was performed on 15 BXD/Ty recombinant inbred (RI) strains to identify QTLs associated with copper and zinc regulation in the brain. BXD/Ty RI strains are derived from C57BL/6J and DBA/2J inbred strains. Animals were tested at an averageage of 120 days. Loci reaching LOD>2.8 are reported, and were compared to brain iron content QTL from a previous experiment by Jones et al (2003).
On mouse Chromosome 1, highly significant linkage to zinc in the prefrontal cortex in females mapped to 155.64 Mb (81 cM) with LOD=5.41. This locus is named Bczr1 (brain copper/zinc regulation 1). Bczr1 also shows suggestive linkage to zinc in the ventral midbrain in females (LOD=2.37). Potential candidate genes mapping near this region include Cacna1e (86 cM) and Kcnj10 (93.5 cM). Bczr1 colocalizes with previously identified QTL Vmbic1 at 81.6 cM and may represent the same locus.
On mouse Chromosome 8, significant linkage to zinc in the nucleus accumbens in females mapped to 55.72 Mb (31 cM) with LOD=3.59.This locus is named Bczr2 (brain copper/zinc regulation 2). Hpgd is a potential candidate genes mapping near Bczr2.
On mouse Chromosome 16, significant linkage to copper in the caudate-putamen in males mapped to 61.1 MB (40 cM) with LOD=3.69. This locusis named Bczr3 (brain copper/zinc regulation 3). Potential candidate genes mapping near Bczr3 include Epha6, Pros1, and Epha3.
On mouse Chromosome 17, linkage to copper and zinc in the prefrontal cortex in males mapped to 42.82 Mb near D17Mit49 (23.2 cM) with LOD= 3.79 and LOD=3.33, respectively. This locus is the same as Vmbic9 (ventral midbrain iron content 9), a QTL identified in the same set of BXD/Ty RI strains in a previous experiment. Males carrying DBA/2J-derived alleles at Vmbic9 exhibit on average 16% increased zinc concentration in the prefrontal cortex, 72% increased copper concentration in the prefrontal cortex, and 34% increased iron concentration in the caudate-putamen. Vmbic9 also shows linkage to zinc in the nucleus accumbens in males and females with LOD=2.28 and LOD=3.52, respectively. Males and females carrying DBA/2J-derived alleles at Vmbic9 exhibit on average 32% increased zinc concentration in the nucleus accumbens and 45% increased iron concentration in the ventral midbrain. The H2 locus (23 cM) maps near Vmbic9. Previously identified loci for seizure threshold susceptibility (McCall 1981; Plomin 1991) also map near Vmbic9.
Suggestive linkage to copper in the caudate-putamen and nucleus accumbens in females mapped to approximately 27 Mb on mouse Chromosome 12 (LOD=2.84 and LOD=2.35, respectively). Suggestive linkage to copper and zinc in the prefrontal cortex in males mapped to 20.71 Mb on mouse Chromosome 3 (LOD=3.15), 109.66 Mb on mouse Chromosome 13 (LOD=2.82), and 27.2 Mb on mouse Chromosome 17 (LOD=4.03).