Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Lavinia Paternoster, Marie Standl, Chih-Mei Chen, Adaikalavan Ramasamy, Klaus Bønnelykke, Liesbeth Duijts, Manuel A Ferreira, Alexessander Couto Alves, Jacob P Thyssen, Eva Albrecht, Hansjörg Baurecht, Bjarke Feenstra, Patrick M A Sleiman, Pirro Hysi, Nicole M Warrington, Ivan Curjuric, Ronny Myhre, John A Curtin, Maria M Groen-Blokhuis, Marjan Kerkhof, Annika Sääf, Andre Franke, David Ellinghaus, Regina Fölster-Holst, Emmanouil Dermitzakis, Stephen B Montgomery, Holger Prokisch, Katharina Heim, Anna-Liisa Hartikainen, Anneli Pouta, Juha Pekkanen, Alexandra I F Blakemore, Jessica L Buxton, Marika Kaakinen, David L Duffy, Pamela A Madden, Andrew C Heath, Grant W Montgomery, Philip J Thompson, Melanie C Matheson, Peter Le Souëf, Australian Asthma Genetics Consortium (AAGC), Beate St Pourcain, George Davey Smith, John Henderson, John P Kemp, Nicholas J Timpson, Panos Deloukas, Susan M Ring, H-Erich Wichmann, Martina Müller-Nurasyid, Natalija Novak, Norman Klopp, Elke Rodríguez, Wendy McArdle, Allan Linneberg, Torkil Menné, Ellen A Nohr, Albert Hofman, André G Uitterlinden, Cornélia M van Duijn, Fernando Rivadeneira, Johan C de Jongste, Ralf J P van der Valk, Matthias Wjst, Rain Jogi, Frank Geller, Heather A Boyd, Jeffrey C Murray, Cecilia Kim, Frank Mentch, Michael March, Massimo Mangino, Tim D Spector, Veronique Bataille, Craig E Pennell, Patrick G Holt, Peter Sly, Carla M T Tiesler, Elisabeth Thiering, Thomas Illig, Medea Imboden, Wenche Nystad, Angela Simpson, Jouke-Jan Hottenga, Dirkje Postma, Gerard H Koppelman, Henriette A Smit, Cilla Söderhäll, Bo Chawes, Eskil Kreiner-Møller, Hans Bisgaard, Erik Melén, Dorret I Boomsma, Adnan Custovic, Bo Jacobsson, Nicole M Probst-Hensch, Lyle J Palmer, Daniel Glass, Hakon Hakonarson, Mads Melbye, Deborah L Jarvis, Vincent W V Jaddoe, Christian Gieger, Genetics of Overweight Young Adults (GOYA) Consortium, David P Strachan, Nicholas G Martin, Marjo-Riitta Jarvelin, Joachim Heinrich, David M Evans, Stephan Weidinger, EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium, Lavinia Paternoster, Marie Standl, Chih-Mei Chen, Adaikalavan Ramasamy, Klaus Bønnelykke, Liesbeth Duijts, Manuel A Ferreira, Alexessander Couto Alves, Jacob P Thyssen, Eva Albrecht, Hansjörg Baurecht, Bjarke Feenstra, Patrick M A Sleiman, Pirro Hysi, Nicole M Warrington, Ivan Curjuric, Ronny Myhre, John A Curtin, Maria M Groen-Blokhuis, Marjan Kerkhof, Annika Sääf, Andre Franke, David Ellinghaus, Regina Fölster-Holst, Emmanouil Dermitzakis, Stephen B Montgomery, Holger Prokisch, Katharina Heim, Anna-Liisa Hartikainen, Anneli Pouta, Juha Pekkanen, Alexandra I F Blakemore, Jessica L Buxton, Marika Kaakinen, David L Duffy, Pamela A Madden, Andrew C Heath, Grant W Montgomery, Philip J Thompson, Melanie C Matheson, Peter Le Souëf, Australian Asthma Genetics Consortium (AAGC), Beate St Pourcain, George Davey Smith, John Henderson, John P Kemp, Nicholas J Timpson, Panos Deloukas, Susan M Ring, H-Erich Wichmann, Martina Müller-Nurasyid, Natalija Novak, Norman Klopp, Elke Rodríguez, Wendy McArdle, Allan Linneberg, Torkil Menné, Ellen A Nohr, Albert Hofman, André G Uitterlinden, Cornélia M van Duijn, Fernando Rivadeneira, Johan C de Jongste, Ralf J P van der Valk, Matthias Wjst, Rain Jogi, Frank Geller, Heather A Boyd, Jeffrey C Murray, Cecilia Kim, Frank Mentch, Michael March, Massimo Mangino, Tim D Spector, Veronique Bataille, Craig E Pennell, Patrick G Holt, Peter Sly, Carla M T Tiesler, Elisabeth Thiering, Thomas Illig, Medea Imboden, Wenche Nystad, Angela Simpson, Jouke-Jan Hottenga, Dirkje Postma, Gerard H Koppelman, Henriette A Smit, Cilla Söderhäll, Bo Chawes, Eskil Kreiner-Møller, Hans Bisgaard, Erik Melén, Dorret I Boomsma, Adnan Custovic, Bo Jacobsson, Nicole M Probst-Hensch, Lyle J Palmer, Daniel Glass, Hakon Hakonarson, Mads Melbye, Deborah L Jarvis, Vincent W V Jaddoe, Christian Gieger, Genetics of Overweight Young Adults (GOYA) Consortium, David P Strachan, Nicholas G Martin, Marjo-Riitta Jarvelin, Joachim Heinrich, David M Evans, Stephan Weidinger, EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium

Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Figures

Figure 1. Manhattan plot for the discovery…
Figure 1. Manhattan plot for the discovery genome-wide association meta-analysis of atopic dermatitis
after excluding all SNPs MAF−5 are shown in red.
Figure 2. Forest plots for the association…
Figure 2. Forest plots for the association of (a) rs479844, (b) rs2164983 and (c) rs2894772 with atopic dermatitis
All OR are reported with the minor allele (shown in brackets) as the effect allele. *MoBa imputation quality score was ‘info’ from PLINK. GENR=Generation R. rs2164983 was not included in the HapMap release 21 and so was missing for some discovery cohorts. Black points indicate the Odds Ratios (ORs) and the horizontal lines represent the 95% confidence intervals (CIs) for each study. Arrows are used to show where a CI extends beyond the range of the plot. The sizes of the red and blue boxes indicate the relative weight of each study (using inverse variance weighting). Blue boxes indicate SNPs that were imputed and red boxes indicate SNPs on the genome-wide genotyping chip for the discovery cohorts and either on the genome-wide genotyping chip or individually genotyped for the replication cohorts. Only Health2006, KORA/GENEVA and NFBC86’ underwent individual SNP genotyping. The subtotals (for discovery and replication) and overall ORs and CIs are indicated by the centre and range of the diamonds.
Figure 2. Forest plots for the association…
Figure 2. Forest plots for the association of (a) rs479844, (b) rs2164983 and (c) rs2894772 with atopic dermatitis
All OR are reported with the minor allele (shown in brackets) as the effect allele. *MoBa imputation quality score was ‘info’ from PLINK. GENR=Generation R. rs2164983 was not included in the HapMap release 21 and so was missing for some discovery cohorts. Black points indicate the Odds Ratios (ORs) and the horizontal lines represent the 95% confidence intervals (CIs) for each study. Arrows are used to show where a CI extends beyond the range of the plot. The sizes of the red and blue boxes indicate the relative weight of each study (using inverse variance weighting). Blue boxes indicate SNPs that were imputed and red boxes indicate SNPs on the genome-wide genotyping chip for the discovery cohorts and either on the genome-wide genotyping chip or individually genotyped for the replication cohorts. Only Health2006, KORA/GENEVA and NFBC86’ underwent individual SNP genotyping. The subtotals (for discovery and replication) and overall ORs and CIs are indicated by the centre and range of the diamonds.
Figure 2. Forest plots for the association…
Figure 2. Forest plots for the association of (a) rs479844, (b) rs2164983 and (c) rs2894772 with atopic dermatitis
All OR are reported with the minor allele (shown in brackets) as the effect allele. *MoBa imputation quality score was ‘info’ from PLINK. GENR=Generation R. rs2164983 was not included in the HapMap release 21 and so was missing for some discovery cohorts. Black points indicate the Odds Ratios (ORs) and the horizontal lines represent the 95% confidence intervals (CIs) for each study. Arrows are used to show where a CI extends beyond the range of the plot. The sizes of the red and blue boxes indicate the relative weight of each study (using inverse variance weighting). Blue boxes indicate SNPs that were imputed and red boxes indicate SNPs on the genome-wide genotyping chip for the discovery cohorts and either on the genome-wide genotyping chip or individually genotyped for the replication cohorts. Only Health2006, KORA/GENEVA and NFBC86’ underwent individual SNP genotyping. The subtotals (for discovery and replication) and overall ORs and CIs are indicated by the centre and range of the diamonds.

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Source: PubMed

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