LETTERS Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology Manuel A Ferreira1,38 , Judith M Vonk2,38, Hansjörg Baurecht3,38, Ingo Marenholz4,5,38, Chao Tian6,38, Joshua D Hoffman7,38, Quinta Helmer8,38, Annika Tillander9,38, Vilhelmina Ullemar9,38, Jenny van Dongen8,38, Yi Lu9,38, Franz Rüschendorf4,38 , Jorge Esparza-Gordillo4,5,37, Chris W Medway10, Edward Mountjoy10 , Kimberley Burrows10, Oliver Hummel4, Sarah Grosche4,5, Ben M Brumpton10–12, John S Witte13, Jouke-Jan Hottenga8, Gonneke Willemsen8, Jie Zheng10, Elke Rodríguez3, Melanie Hotze3, Andre Franke14 , Joana A Revez1, Jonathan Beesley1, Melanie C Matheson15, Shyamali C Dharmage15, Lisa M Bain1, Lars G Fritsche11, Maiken E Gabrielsen11, Brunilda Balliu16, 23andMe Research Team17, AAGC collaborators17, BIOS consortium17, LifeLines Cohort Study17, Jonas B Nielsen18,19 , Wei Zhou19, Kristian Hveem11,20, Arnulf Langhammer20, Oddgeir L Holmen11, Mari Løset11,21, Gonçalo R Abecasis11,22, Cristen J Willer11,18,19,22 , Andreas Arnold23, Georg Homuth24, Carsten O Schmidt25, Philip J Thompson26, Nicholas G Martin1, David L Duffy1, Natalija Novak27, Holger Schulz28,29, Stefan Karrasch28–30, Christian Gieger31, Konstantin Strauch32, Ronald B Melles33, David A Hinds6, Norbert Hübner4,39, Stephan Weidinger3,39, Patrik K E Magnusson9,39, Rick Jansen34,39 , Eric Jorgenson33,39 , Young-Ae Lee4,5,39, Dorret I Boomsma8,39, Catarina Almqvist9,35,39 , Robert Karlsson9,39 , Gerard H Koppelman36,39 & Lavinia Paternoster10,39 Asthma, hay fever (or allergic rhinitis) and eczema (or atopic having suffered from asthma and/or hay fever and/or eczema with dermatitis) often coexist in the same individuals1, partly 180,709 controls who reported not suffering from any of these diseases because of a shared genetic origin2–4. To identify shared risk (Supplementary Table 2), all of European ancestry. Meta-analysis variants, we performed a genome-wide association study of results from the 13 contributing studies (Supplementary Fig. 2) (GWAS; n = 360,838) of a broad allergic disease phenotype identified 99 genomic regions (loci) located >1 Mb apart containing at that considers the presence of any one of these three diseases. least one genetic variant associated with allergic disease at a genome- We identified 136 independent risk variants (P < 3 × 10−8), wide significance threshold of 3 × 10−8 (Fig. 1 and Supplementary including 73 not previously reported, which implicate 132 Table 3). On the basis of approximate conditional analysis5, 136 nearby genes in allergic disease pathophysiology. Disease- Nature America, Inc., part of Springer Nature. All rights reserved. genetic variants in these 99 loci had a statistically independent asso- 7 specific effects were detected for only six variants, confirming ciation with disease risk (Supplementary Table 4). Henceforth, we that most represent shared risk factors. Tissue-specific refer to these as ‘sentinel risk variants’, which either represent or are 201 © heritability and biological process enrichment analyses suggest in linkage disequilibrium (LD) with a causal functional variant. These that shared risk variants influence lymphocyte-mediated included 86 (in 50 loci) located <1 Mb from risk variants reported immunity. Six target genes provide an opportunity for drug in previous GWAS of allergic disease (Supplementary Table 5). Of repositioning, while for 36 genes CpG methylation was found note, 23 of these 86 sentinel variants were in low LD (r2 < 0.05) with to influence transcription independently of genetic effects. the previously reported risk variants, indicating that they represent Asthma, hay fever and eczema partly coexist because they new associations in these loci. The remaining 50 sentinel variants share many genetic risk variants that dysregulate the expression (in 49 loci) were located >1 Mb from previously reported associa- of immune-related genes. tions (Supplementary Table 6), of which 17 were in low LD with nearby variants reported for other diseases or traits (Supplementary The analytical approach used in our study is summarized in Table 7). Eighteen loci had multiple independent association sig- Supplementary Figure 1. We tested for association with allergic nals (Supplementary Table 3). Altogether, we identified 73 (50 + disease 8,307,659 genetic variants that passed quality control filters 23) genetic associations with allergic disease that are new, a sub- (Supplementary Table 1), comparing 180,129 cases who reported stantial increment over the 89 associations reported previously (Supplementary Fig. 3 and Supplementary Table 8). A full list of affiliations appears at the end of the paper. As expected from a study design that maximized power to identify 6 Received 13 June; accepted 6 October; published online 30 October 2017; shared risk variants , we found that 130 of the 136 sentinel variants doi:10.1038/ng.3985 had similar allele frequencies in case-only association analyses that NATURE GEnETICS ADVANCE ONLINE PUBLICATION LETTERS compared three non-overlapping groups of adults: those who reported three individual diseases. The six variants with evidence for stronger suffering from asthma only (n = 12,268), hay fever only (n = 33,305) effects in one allergic disease when compared to the other two were or eczema only (n = 6,276) (Supplementary Table 9). There was thus located in five known allergy risk loci (for example, FLG and GSDMB; no evidence that these 130 variants have differential effects on the Fig. 2). On the other hand, many sentinel variants (26, or 19%) were 50 known loci 49 new loci STMN3 1 1 1 11 C22orf46, PMM1, NHP2L1, CCDC134, PHF5A, CSDC2,MEI1 [ZNF217] 0 1 X 1 0 [SIK1] [NFATC2] 0 1 1 0 [RUNX1] 22 GNGT2 1 1 21 1 0 SLC7A10-[]-CEBPA ORMDL3, CCR7, RP11-94L15.2, ZPBP2, GSDMB 7 4 20 1 1 PIGN CLEC16A-[]-RMI2, RMI2-[]--LITAF 0 2 19 1 1 DYNAP AAGAB 1 1 18 1 2 MAP3K14-AS1, SPATA32 RP11-554D20.1 1 1 1 0 [STAT5B] 17 [RAD51B] 0 1 1 1 ALOX15 FOXA1-[]--TTC6 0 1 16 1 2 IQGAP1, CRTC3 NFKBIA, PPP2R3C, KIAA0391, FAM177A1 4 1 1 2 RTF1, ITPKA 15 PITPNM2, OGFOD2, ARL6IP4, ABCB9, SBNO1 10 1 1 0 RCOR1-[]-TRAF3 NAB2, STAT6, SUOX, RPS26, PA2G4, MYL6B, ERBB3 8 2 14 1 0 JDP2-[]-BATF KIRREL3-AS3---[]--ETS1 0 1 1 0 PIBF1-[]-KLF5 DDX6-[]-CXCR5 0 1 13 1 0 [FOXO1] WNT11--[]-LRRC32 0 3 1 1 SPPL3 OVOL1, SNX32, RP11-770G2.5, EFEMP2 4 1 12 1 1 SH2B3 ACTR1A, TMEM180, ARL3 3 1 1 1 AQP5 [ZNF365] 0 1 11 1 1 HDAC7 GATA3---[]---SFTA1P, GATA3--[]SFTA1P 0 6 1 2 PPP2R1B, SIK2 IL2RA 1 2 10 1 0 SESN3--[]-FAM76B C9orf114-[]-LRRC8A 0 1 1 1 FBXW2 ERMP1 1 3 1 1 GSAP [MYC] 0 1 9 1 0 C7orf72-[]-IKZF1 MIR5708--[]--ZBTB10 0 1 1 1 JAZF1 ITGB8--[]-ABCB5, [ITGB8] 0 2 8 1 0 RNASET2-[]-MIR3939 [BACH2] 0 1 1 0 [ARID1B] HLA-C, MCCD1P1, HLA-DQA1, GPANK1, PRRC2A 5 7 1 1 TNFAIP3 HDAC3, NDFIP1 2 2 7 1 0 [PTPRK] SLC22A4, SLC22A5, C5orf56, IL13 4 3 1 0 [ATG5] CAMK4, SLC25A46, TSLP, CTC-551A13.2, WDR36 5 4 6 1 2 RGS14, RAB24 PTGER4 1 1 1 0 MIR3142-[]-MIR146A IL7R 1 1 1 0 [TNFAIP8] FAM105A 1 1 5 1 0 [MANBA] KIAA1109 1 2 1 0 STX18--[]-MSX1 TLR1 1 1 FBXO45-[]-CEP19 0 1 1 1 RASA2 4 RP11-132N15.2, RP11-132N15.1, BCL6 3 4 1 4 SLC15A2, EAF2, IQCB1, DC86 [GLB1] 0 1 1 1 SENP7 [D2HGDH] 0 1 1 0 LINC00870--[]-RYBP Nature America, Inc., part of Springer Nature. All rights reserved. 3 1 1 INPP5D 7 BOLL, RFTN2, MARS2, PLCL1 4 1 MFSD9, IL18R1, IL1RL1, IL18RAP 4 2 1 0 CCL20-[]-DAW1 201 [LINC00299] 0 1 1 1 ARHGAP15 © TNFSF18--[]-TNFSF4,FASLG-[]--TNFSF18 0 2 1 0 [IL1B] 2 CD247 1 1 2 0 BCL2L11--[]--ANAPC1 USF1, F11R, PPOX, ADAMTS4, B4GALT3, FCER1G 7 1 1 0 [LOC339807] IL6R 1 1 1 0 [ITPKB] THEM4, FLG 2 3 1 0 SFPQ-[]-ZMYM4 1 RPRD2, C1orf54, TARS2 3 1 1 1 RUNX3 RP5-1115A15.1, RERE 2 1 1 1 TNFRSF14 s 21 18 15 12 9 6 3 0 s –log10 (P value) target genes target genes Target genes Target genes n n sentinel variant sentinel variant n n Figure 1 Loci containing genetic risk variants independently associated with the risk of allergic disease at P < 3 × 10−8. The 136 sentinel risk variants were located in 50 previously reported (86 variants) and 49 new (50 variants) risk loci. The numbers of plausible target genes of sentinel risk variants identified for each locus are shown, with target gene names listed in blue font. For loci with many target genes, only a selection is listed. When no target gene was identified (black font), brackets are used to indicate the location of the sentinel risk variant relative to the nearest gene(s). Specifically, when the risk variant was intergenic (indicated by “gene1-[]-gene2”), the two closest genes (upstream and downstream) are shown; the distance to each gene is proportional to the number of dashes shown. Otherwise, when the risk variant was located within a gene, the respective gene name is shown in brackets (“[gene]”). The red vertical line in the Manhattan plot shows the genome-wide significance threshold used (P = 3 × 10−8). aDVANCE ONLINE PUBLICATION NATURE GEnETICS LETTERS rs61816761[A] (chr. 1: 152 Mb) rs12123821[T] (chr. 1: 152 Mb) rs12470864[A] (chr. 2: 103 Mb) also associated with the age at which symptoms of any allergic dis- [FLG] RPTN-[]-HRNR IL1RL2-[]-IL18R1 ease first developed (n = 35,972; Supplementary Table 10), with the Asthma Asthma Asthma allele associated with a higher disease risk always being associated with earlier age of onset (Supplementary Fig. 4). For 18 of these 1.03 1.05 1.07 1.01 26 variants, the effect on age of onset was not significantly different 1.26 1.18 between individual diseases (Supplementary Table 10), suggesting 1.32 1.16 Eczema Hay fever Eczema Hay fever Eczema 1.07Hay fever that these variants influence the age at which symptoms first develop for all three diseases.