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Chunk #24 — Discussion

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Hemizygous Deletion on Chromosome 3p26.1 Is Associated with Heavy Smoking among African American Subjects in the COPDGene Study.
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There are no published studies of polymorphic CNVs influencing quantitative measures of smoking behaviors directly in either racial group, but linkage analysis studies from “The Nicotine Addiction Genetics linkage project” showed this chromosome 3p26-25 region was linked to depression with a multiponint LOD score of 4.14 in heavy smoker families, highlighting the need for further investigation into this genomic region [37, 38]. Here, we explored the effects of common deletions/amplifications on pack-years and reported number of cigarettes per day. Only the smaller African American sub-group achieved genome-wide significance, perhaps because they have more hemizygous deletion carriers (117) on chr3p26.1 compared to NHW (where there was only 3 hemizygous deletion carriers and one duplication carrier). The nearest gene to our most strongly associated CNV component on chromosome 3p26.1 deletion region is GRM7, which is involved with glutamate receptor activation. Several previous GWAS studies of nicotine dependence-related phenotypes have reported associations to markers in GRM7 [39–42]. Examining gene expression levels of GRM7 in the GTEx portal (http://www.gtexportal.org/home/gene/GRM7) showed higher expression in different parts of brain including the cortex, hypothalamus and hippocampus (S7