Table 3.

Genome-Wide Association Study Data Pathways Significantly Associated with Consortium Lung Phenotype (KNoRMA)

Pathway		Genes (n)	Corrected P Value*	Genes with Gene-Level P Value <0.10 (Ordered by P Value)
Identifier	Name
Analyses included all available pathways†
KEGG pathways, n = 338 tested
00510	N-glycan biosynthesis	48	0.019	ALG12, MAN1C1, MGAT5B, MGAT4C, MGAT4A, TUSC3, ALG14, MAN1A1, MAN2A1, GANAB, DPM3, ALG6
05168	Herpes simplex virus infection	173	0.030	HLA-DQA1, HLA-DQB1, HLA-DRB1, PVRL2, PVRL1, PER2, CCL2, TLR2, SRSF2, TYK2, CCL5, POLR2A, IFNA6, TP53, C3, IFNA13, IFNA1, EIF2AK2, LTA, TNF, IFNA2, IFNA5, MCRS1, TBPL1, IFNA14, TLR3, IFNA8, TAF5, HLA-B, IFNA17, PPP1CC, HLA-DOB, TAP1, TAP2, MAPK9, HCFC2, ALYREF, TBPL2
00601	Glycosphingolipid biosynthesis lacto and neolacto series	24	0.030	ST3GAL6, B3GALT5, FUT3, FUT5, FUT6, FUT2, B3GALT2, GCNT2, ST3GAL3, FUT4
05310	Asthma	23	0.102	HLA-DQA1, HLA-DQB1, HLA-DRB1, FCER1A, IL13, IL4, TNF, CCL11, HLA-DOB, PRG2
04650	Natural killer cell–mediated cytotoxicity	123	0.120	FCGR3B, ICAM1, PRKCB, KRAS, VAV2, VAV3, IFNA6, VAV1, PIK3R2, TNFSF10, IFNA13, IFNA1, NCR3, TNF, RAC2, IFNA2, IFNA5, HCST, TYROBP, PRF1, IFNA14, LCP2, IFNA8, MAPK3, HLA-B, IFNA17, PIK3R3, ULBP3, FCGR3A, RAET1L, RAF1
GO cellular component pathways, n = 516 tested
0044448	Cell cortex part	114	0.057	EXOC3, CAPZA2, GYS2, TCHP, CAPZB, PCLO, EXOC4, CORO1A, MYH2, SPTAN1, EXOC7, TRPV4, SPTBN4, EXOC3L2, SPTBN2, SPTA1, CDH1, LLGL1, ANK1, GYPC, PRKCZ, CALD1
0009898	Cytoplasmic side of plasma membrane	152	0.114	FRK, TNK2, GNA12, ACP1, KRAS, TYK2, LDLRAP1, PTK6, LYN, GNAO1, NPHS2, GNG5, GNG7, RASA1, GNA14, CABP1, HTRA2, TEC, SRMS, SPTA1, PTPN7, CDH1, ALOX15, GNAI3
0098562‡
GO biological pathways, n = 4,670 tested
0032770	Positive regulation of monooxygenase activity	25	0.024	AGTR2, APOE, KRAS, TNF, CALM1, POR, TERF2
0051000‡
2000027	Regulation of organ morphogenesis	165	0.029	AGTR2, MET, POU5F1, FOXP2, HNF1B, CNTF, SFRP2, SIX4, SMAD4, SNAI2, SOX17, MSX1, IFT88, MMP20, HGF, DMRT3, CTHRC1, SFRP1, FGFR2, CAV3, XBP1, SIX1, EDNRA, GPC3, TNF, WNT9B, ZNRF3, CDH1, EDN1, FGF1, POR, TBX5
0042311	Vasodilation	67	0.058	AGTR2, APOE, MRVI1, NPR1, SMTNL1, ADCYAP1, CFTR, NPPB, UTS2B, ADORA1, MKKS, P2RY2, HMOX1, BDKRB2, NOS1
0035150‡
0050880‡
0003018‡
0001711	Endodermal cell fate commitment	16	0.098	POU5F1, HNF1B, SOX17, CDC73, EOMES
0042659‡
0031960	Response to corticosteroid	140	0.139	AGTR2, TRH, S100B, KRAS, AQP1, CCL2, ALPL, ADCYAP1, GHRHR, SCGB1A1, STAR, BMP6, CASP9, SPARC, TNF, CALM1, ALDH3A1, GBA, TPH2, EDN1, SSTR3, ACADS, SLC18A2
GO molecular function pathways, n = 910 tested
0044548	S100 protein binding	10	0.123	S100B, AHNAK, S100A1, ATP2A2, FGF1
0032794	GTPase-activating protein binding	11	0.144	PLCD1, TSC1, GNAO1, FMNL3, CDH1, GNAI3
CF-relevant custom pathways, n = 72 tested
	Goblet cell relevant	37	0.001	MUC4, TFF2, CFTR, FUT6, GALNT12, SCGB1A1, ERN2, B4GALNT2, ST6GALNAC1, XBP1, MUC1, GCNT3, FUT4
	Ciliary trafficking	157	0.006	RAB8B, TBC1D7, PTCH1, EFHC1, ARFGEF2, IFT88, TTC26, IFT74, KIF19, RAB4A, RP1, VMA21, GLI3, IFT122, TRAF3IP1, TRPV1, COPG2, DNAH2, MKKS, OFD1, HSPB11, ODF2, IFT81, SSTR3, PACS1, ARHGEF1, KLC3, PCM1, GLI2, SCLT1
	Mucin Calu3	12	0.024	MUC4, MUC20, MUC1
	MCF7 hypoxia (down)	162	0.054	OSTM1, ADAT1, CORO1A, SNRNP40, GAS2L1, SPAG1, POLR3K, RAB35, EEF1E1, GPATCH2, CALM1, ADORA1, KPNA1, PPIF, GDPD3, SLCO3A1, GYG1, PIK3R3, ARHGDIA
	HIF1si (up)/MCF7 hypoxia (down)‡
	Asthma-COPD (up)	36	0.059	CEP72, FAM110C, CD44, TMEM200A, S100A16, CSTA, GCNT3, IGF2BP3, CEACAM5, CDC42EP5
	EHF positive correlation	154	0.092	MUC20, SLC44A4, SH3YL1, RAB25, LCN2, LIMA1, FUT3, STAP2, CTNND1, CEACAM6, FUT6, PTK6, CHMP4C, SH2D3A, SPAG1, PIGR, ST6GALNAC1, S100A14, MYH14, RIPK4, FUT2, SPINT2, CDH1, C10orf99, YAP1, CEACAM5, CGN, CDC42EP5, SLC44A3
	COPD (up)	50	0.099	MUC4, CFB, NR4A1, LCN2, ARNTL2, FUT3, IRAK3, MTNR1A, GCNT3, IGF2BP3, CEACAM5
	Airway epithelium T-helper type 2	92	0.115	CEP72, SCGB2A1, TFF3, FAM110C, CD44, TMEM200A, S100A16, CSTA, GCNT3, ITLN1, IGF2BP3, ALOX15, CEACAM5, CDC42EP5, SLC18A2, SLC22A16
CFTR interactome pathways§, n = 11 tested
	loT1hr dCF; Table E7, 484 genes	466	0.055	LMNA, PRDX1, AHNAK, LIMA1, CAPZB, PDCD6, MCM6, CFTR, ACLY, STAU1, CLPTM1, PPP6R1, SDHA, MYH2, RDX, XRCC5, STRBP, SPTAN1, TPM1, TUBB6, ACSL4, TP53, RBBP4, C3, POLR2E, CNN2, UBR4, MYH13, MOV10, PPP1R12A, RPLP0, MMS19, YTHDF3, SAE1, CSTA, MYH14, SNX27
	loT6hr dCF; Table E8, 618 genes	592	0.059	LMNB2, ICAM1, LMNA, PRDX1, AHNAK, LIMA1, CAPZB, PDCD6, MCM6, THADA, STAU1, CLPTM1, EXOC4, PPP6R1, SDHA, MYH2, RDX, XRCC5, STRBP, SPTAN1, TPM1, TUBB6, ACSL4, TP53, RBBP4, C3, POLR2E, SLC35E1, UBR4, SLC27A3, MYH13, MOV10, PPP1R12A, RPLP0, DARS, MMS19, NUP155, SAE1, MSN, MYH14, SNX27
	Core CFTR interactome; Table E1, 638 genes	620	0.088	CAPZA2, LMNB2, HSPA1B, BLMH, HSPA1A, ICAM1, LMNA, PRDX1, AHNAK, LIMA1, CAPZB, MCM6, THADA, RGPD2, COG6, CFTR, ACLY, STAU1, SORCS1, CLPTM1, EXOC4, SDHA, MYH2, RDX, XRCC5, STRBP, SPTAN1, TPM1, TUBB6, EXOC7, ACSL4, TP53, RBBP4, C3, POLR2E, CNN2, YTHDF2, UBR4, MYH13, MOV10, PPP1R12A, RPLP0, DARS, MMS19, YTHDF3, SAE1, RAC2, CSTA, MSN, MYH14, SNX27
	SAHA dCF‡; Table E11, 681 genes
MetaMiner cystic fibrosis–specific pathways (GeneGo)‖, n = 36 tested
	Cytokine production by Th17 cells in CF	41	0.090	ICAM1, CFTR, RELB, IL12RB1, CXCL1, IL8, RORC, CXCL6
HLA-specific pathways, n = 2 tested
	Class I and class II	18	0.095	HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-B, HLA-DOB, PSMB8, PSMB9, TAP1, TAP2
	Class II	8	0.146	HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DOB
Analyses confined to pathways significant for differential expression in nasal scrape samples¶, n = 37 tested
KEGG pathways
05168	Herpes simplex virus infection	173	0.008	HLA-DQA1, HLA-DQB1, HLA-DRB1, PVRL2, PVRL1, PER2, CCL2, TLR2, SRSF2, TYK2, CCL5, POLR2A, IFNA6, TP53, C3, IFNA13, IFNA1, EIF2AK2, LTA, TNF, IFNA2, IFNA5, MCRS1, TBPL1, IFNA14, TLR3, IFNA8, TAF5, HLA-B, IFNA17, PPP1CC, HLA-DOB, TAP1, TAP2, MAPK9, HCFC2, ALYREF, TBPL2
05164	Influenza A virus	165	0.080	HSPA1B, HLA-DQA1, HLA-DQB1, HLA-DRB1, HSPA1A, HSPA1L, PABPN1L, ICAM1, PRKCB, CCL2, TYK2, CCL5, IFNA6, PIK3R2, TNFSF10, IFNA13, IFNA1, CASP9, EIF2AK2, TNF, IFNA2, IFNA5, IFNA14, TLR3, KPNA1, IFNA8, MAPK3, IFNA17, DDX39B, PIK3R3, HLA-DOB, MAPK9, RAF1

Definition of abbreviations: CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; COPD = chronic obstructive pulmonary disease; dCF = Phe508del; EHF = ETS homologous factor; GO = Gene Ontology Consortium; GTPase = GTP (guanosine triphosphate) enzyme; HIF1si = HIF-1α siRNA; HLA = human leukocyte antigen; KEGG = Kyoto Encyclopedia of Genes and Genomes database; KNoRMA = Kulich Normal Residual Mortality Adjusted; SAHA = suberoylanilide hydroxamic acid.

Default parameters with 1,000 simulations were used, and pathways were limited to those that contained at least 10 but less than or equal to 200 genes. GeneSetScan uses mapping of genotyped single-nucleotide polymorphisms to 50 kb upstream and downstream of protein-coding genes based on ENSEMBL version 82 annotation and maps genes to annotated pathways and gene sets. CF relevant custom pathways were developed (46) using human gene counterparts (Table E8). See Table E3 for gene Online Mendelian Inheritance in Man catalogue numbers.

^*Multiple comparison corrected P values.

^†Gene level P values were calculated using family-wise error rate (all single-nucleotide polymorphisms, genes, and pathways tested) as provided by GeneSetScan. Pathways are listed if corrected P value is less than 0.15.

^‡These pathways are statistically significant and carry robust overlap of genes with first-listed pathway; see Table E5, tab F, for complete listing of pathway genes.

^§For gene sets containing more than 200 genes, genes with P < 0.05 are listed; see Table E5, tab F, for complete list of pathway genes.

^‖MetaMiner CF-specific pathways represent a version of the Thomson Reuters (formerly GeneGo) MetaDiscovery suite that is enriched with content specific for CF.

^¶Pathways listed in Table 2 were evaluated for association with genotype.