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is a reliable retinal ganglion cell (RGC) marker in adult mouse eyes and if Chrna6 expression can be used to track progressive loss of RGCs, such as is observed in the DBA/2J glaucoma model. METHODS: Data sets derived from the BXD strains were used to extract gene expression signatures for RGCs. Pooled retinas from DBA/2J or C57BL/6J cases at 1-3 months, 12 months, and 16-17 months were prepared for gene-array and RT-PCR analysis. Globes were fixed in paraformaldehyde and sectioned for immunofluorescence with antibodies against Chrna6. RESULTS: Chrna6 has a cellular expression signature for RGCs with high correlation to Thy1 (r = 0.65), a recognized RGC marker. Immunofluorescence experiments confirm that in the young and adult mouse retina, Chrna6 is preferentially expressed by RGCs. We further show that C3H/HeJ retinas, which lack photoreceptors, also express Chrna6 in the RGC layer. Gene expression array analyses, confirmed by RT-PCR, show progressive loss of Chrna6 expression in retinas of the DBA/2J glaucomatous mouse retinas. CONCLUSIONS: Quantitative trait locus analysis provides support for Chrna6 as a RGC marker. Chrna6 expression decreases with death of RGCs in glaucomatous DBA/2J mice and after optic nerve crush injury, further supporting Chrna6 as a reliable RGC marker. High expression of RGC Chrna6 in the absence of photoreceptors is suggestive that Chrna6 expression by RGCs is independent of photoreceptor-derived stimuli.

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ide polymorphisms (SNPs) in the CHRNB3-CHRNA6 gene cluster with ND in a Chinese Han population (N = 5,055). We found nominally significant associations for all tested SNPs with ND measured by the Fagerström Test for Nicotine Dependence score; of these, 11 SNPs remained significant after Bonferroni correction for multiple tests (p = 9 × 10-4~2 × 10-3). Further conditional analysis indicated that no other SNP was significantly associated with ND independent of the most-highly significant SNP, rs6474414. Also, our haplotype-based association analysis indicated that each haplotype block was significantly associated with ND (p < 0.01). Further, we provide the first evidence of the genetic interaction of these two genes in affecting ND in this sample with an empirical p-value of 0.0015. Finally, our meta-analysis of samples with Asian and European origins for five SNPs in CHRNB3 showed significant associations with ND, with p-values ranging from 6.86 × 10-14 for rs13280604 to 6.50 × 10-8 for rs4950. This represents the first study showing that CHRNB3/A6 are highly associated with ND in a large Chinese Han sample.

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involved in generalized addiction pathways. Using genotypic data from a GWAS of the Study of Addiction: Genetics and Environment (SAGE) dataset, we tested for association of CHRNB3-A6 SNPs with DSM-5 cocaine use disorder. Multiple SNPs in the region were significantly associated with increased risk of cocaine use disorder. Inclusion of the most significant SNP as a covariate in a linear regression model provided evidence for an additional independent signal within this locus for cocaine use disorder. These results suggest that the CHRNB3-A6 locus contains multiple variants affecting risk for vulnerability to cocaine and nicotine dependence as well as bipolar disorder, suggesting that they have pleiotropic effects.