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3.24E-05
6.25E-01
7.59E-01
Pathway analysis
Of all SNP-by-ETS interactions included in the identification analysis in the LifeLines study, p-values of 165,298 interactions were mapped to 15,243 genes and 231 gene sets/pathways. Pathway analysis showed one significant (FDR p-value < 0.05) and two suggestively enriched pathways (FDR p-value < 0.25) (Table 3). The most significant, i.e. the apoptosis pathway, includes 71 genes of which 54 were present in the identification analysis and 23 were significantly associated with the outcome (Table 4). The two suggestively associated pathways were the p38 MAPK pathway (Table 5) and tumor necrosis factor (TNF) pathway (Table 6), with 16 genes and 9 genes from the SNP-by-ETS exposure interaction analysis that were significantly associated with the outcome, respectively. [ Table Omitted - see PDF ]
Table 3
Significantly (FDR p-value <0.05) and suggestively (FDR p-value <0.25) enriched pathways based on genome-wide interaction SNP-by-ETS exposure p-values within 100 kb of the gene using i-GSEA-4-GWAS [15]
Pathway/Gene set name
Description
FDR corrected p-value
Significant genes/ Selected genes/All genes
Apoptosis
Apoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis.
0.003
22/54/71
P38 MAPK pathway
The Rho family GTPases activate the p38 MAPKs under environmental stress or in the presence of pro-inflammatory cytokines.
0.063
16/33/40
Tumor Necrosis Factor pathway
Tumor necrosis factor is a pro-inflammatory cytokine that activates NF-kB and c-Jun.
0.081
9/22/29
[ Table Omitted - see PDF ]
Table 4
Genes significantly enriched in the apoptosis pathway. Effect estimates (Bint in mL FEV1) and p-values from the SNP-by-ETS exposure interaction analysis in LifeLines are given
Significant genes in the Apoptosis pathway
Pathway analysis
SNP-by-ETS exposure interaction
Gene Name
SNP
-log(P-value)
Bint FEV1 (ml)
P-value
APAF1
rs12581724
4.23
?111
5.88E-05
MYC
rs7829529
3.00
109
1.00E-03
IRF2
rs3775574
2.74
?47
1.81E-03
BNIP3L
rs3808578
2.63
?70
2.35E-03
CASP9
rs4645983
2.52
?52
3.00E-03
BCL2L11
rs1877330
2.47
85
3.40E-03
JUN
rs2716129
2.45
?43
3.52E-03
MAP2K4
rs2013868
2.11
?51
7.73E-03
TNFRSF10B
rs11784599
1.91
?48
1.24E-02
MAPK10
rs7688651
1.86
38
1.39E-02
FAS
rs1926189
1.75
54
1.76E-02
GZMB
rs1957519
1.75
?62
1.79E-02
NFKBIE
rs513688
1.72
37
1.91E-02
TNFRSF1B
rs235214
1.67
50
2.14E-02
BCL2L1
rs6060870
1.64
42
2.29E-02
FADD
rs10751209
1.57
?33
2.71E-02
BAK1
rs210138
1.55
42
2.80E-02
BCL2
rs1801018
1.50
32
3.17E-02
CASP8
rs3769823
1.47
35