The expanded GS on chromosome 4q32.1 included 137 unique SNPs spanning an intergenic region approximately 6–83 kb from the 5’ end of the protein-coding Neuropeptide Receptor 2 gene (NPY2R) gene, which is most highly expressed in brain tissues (Supplementary Figure 3, available online) (26). Five SNPs in the expanded GS (rs12641982:G, rs9999820:G, rs4467508, rs7671213:C, rs9990781:G) were statistically significantly associated with increased NPY2R expression in the hippocampus (effect size range = 0.42–0.44, P range = 3.0×10-6–7.7×10-6), including the top SNP from our single-SNP analysis (rs9999820:G) (Table 2) with an effect size of 0.44 and P value of 3.1×10-6 (26). In addition, we also observed that the SNPs in the expanded GS were statistically significantly enriched for Polycomb-repressed chromatin states in six human cell types, including H9-derived cultured neurons (P = 7.2×10-9) and ovarian cells (P = 5.6×10-8) (Table 4). Visualization of the expanded GS in brain and ovarian cell types revealed that the region of interest overlaps a distinctive repressive-state pattern that is strongest in the region surrounding NPY2R (Figure 3).
Polycomb-repressed chromatin state enrichment analysis for SNPs in the expanded genetic signal relative to the reference set of SNPs consisting of all the other SNPs from the original single-SNP analysis with PM-association P < .05 (“comparison SNP set”) (statistically significant enrichments only, among 127 human cell types with OR > 1 and P < .05)
| Epigenome identifier . | Epigenomes . | Expanded GS SNPs (n = 137)* . | Comparison SNPs (n = 33 074)† . | OR (95% CI) . | P‡ . |
|---|---|---|---|---|---|
| E061 | Foreskin melanocyte | 109 | 7652 | 12.93 (8.46 to 20.37) | 6.6×10-44 |
| E094 | Gastric | 10 | 215 | 12.03 (5.56 to 23.28) | 3.6×10-8 |
| E097 | Ovary | 33 | 2855 | 3.36 (2.19 to 5.02) | 5.6×10-8 |
| E010 | H9 derived neuron cultured cells | 55 | 6172 | 2.92 (2.04 to 4.17) | 7.2×10-9 |
| E119 | HMEC mammary epithelial | 29 | 3939 | 1.99 (1.27 to 3.02) | 2.1×10-3 |
| E095 | Left ventricle | 39 | 5640 | 1.94 (1.30 to 2.84) | 8.8×10-4 |
| Epigenome identifier . | Epigenomes . | Expanded GS SNPs (n = 137)* . | Comparison SNPs (n = 33 074)† . | OR (95% CI) . | P‡ . |
|---|---|---|---|---|---|
| E061 | Foreskin melanocyte | 109 | 7652 | 12.93 (8.46 to 20.37) | 6.6×10-44 |
| E094 | Gastric | 10 | 215 | 12.03 (5.56 to 23.28) | 3.6×10-8 |
| E097 | Ovary | 33 | 2855 | 3.36 (2.19 to 5.02) | 5.6×10-8 |
| E010 | H9 derived neuron cultured cells | 55 | 6172 | 2.92 (2.04 to 4.17) | 7.2×10-9 |
| E119 | HMEC mammary epithelial | 29 | 3939 | 1.99 (1.27 to 3.02) | 2.1×10-3 |
| E095 | Left ventricle | 39 | 5640 | 1.94 (1.30 to 2.84) | 8.8×10-4 |
Frequency of SNP overlap with ChromHMM Polycomb repressed state among 137 SNPs in the expanded GP in a given epigenome. CI = confidence interval; GS = genetic signal; OR = odds ratio; PM = premature menopause; SNP = single nucleotide polymorphism.
Frequency of SNP overlap with ChromHMM Polycomb repressed state among 33 074 nominally statistically significant GWAS SNPs (P < .05) in a given epigenome.
Two-sided Fisher exact test.
Polycomb-repressed chromatin state enrichment analysis for SNPs in the expanded genetic signal relative to the reference set of SNPs consisting of all the other SNPs from the original single-SNP analysis with PM-association P < .05 (“comparison SNP set”) (statistically significant enrichments only, among 127 human cell types with OR > 1 and P < .05)
| Epigenome identifier . | Epigenomes . | Expanded GS SNPs (n = 137)* . | Comparison SNPs (n = 33 074)† . | OR (95% CI) . | P‡ . |
|---|---|---|---|---|---|
| E061 | Foreskin melanocyte | 109 | 7652 | 12.93 (8.46 to 20.37) | 6.6×10-44 |
| E094 | Gastric | 10 | 215 | 12.03 (5.56 to 23.28) | 3.6×10-8 |
| E097 | Ovary | 33 | 2855 | 3.36 (2.19 to 5.02) | 5.6×10-8 |
| E010 | H9 derived neuron cultured cells | 55 | 6172 | 2.92 (2.04 to 4.17) | 7.2×10-9 |
| E119 | HMEC mammary epithelial | 29 | 3939 | 1.99 (1.27 to 3.02) | 2.1×10-3 |
| E095 | Left ventricle | 39 | 5640 | 1.94 (1.30 to 2.84) | 8.8×10-4 |
| Epigenome identifier . | Epigenomes . | Expanded GS SNPs (n = 137)* . | Comparison SNPs (n = 33 074)† . | OR (95% CI) . | P‡ . |
|---|---|---|---|---|---|
| E061 | Foreskin melanocyte | 109 | 7652 | 12.93 (8.46 to 20.37) | 6.6×10-44 |
| E094 | Gastric | 10 | 215 | 12.03 (5.56 to 23.28) | 3.6×10-8 |
| E097 | Ovary | 33 | 2855 | 3.36 (2.19 to 5.02) | 5.6×10-8 |
| E010 | H9 derived neuron cultured cells | 55 | 6172 | 2.92 (2.04 to 4.17) | 7.2×10-9 |
| E119 | HMEC mammary epithelial | 29 | 3939 | 1.99 (1.27 to 3.02) | 2.1×10-3 |
| E095 | Left ventricle | 39 | 5640 | 1.94 (1.30 to 2.84) | 8.8×10-4 |
Frequency of SNP overlap with ChromHMM Polycomb repressed state among 137 SNPs in the expanded GP in a given epigenome. CI = confidence interval; GS = genetic signal; OR = odds ratio; PM = premature menopause; SNP = single nucleotide polymorphism.
Frequency of SNP overlap with ChromHMM Polycomb repressed state among 33 074 nominally statistically significant GWAS SNPs (P < .05) in a given epigenome.
Two-sided Fisher exact test.
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