Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms

被引：146

作者：

Baurecht, Hansjoerg ^{[1
]}

Hotze, Melanie ^{[1
]}

Brand, Stephan ^{[2
]}

Buening, Carsten ^{[3
]}

Cormican, Paul ^{[4
,5
]}

Corvin, Aiden ^{[4
,5
]}

Ellinghaus, David ^{[6
]}

Ellinghaus, Eva ^{[6
]}

Esparza-Gordillo, Jorge ^{[7
,8
]}

Foelster-Holst, Regina ^{[1
]}

Franke, Andre ^{[6
]}

Gieger, Christian ^{[9
,10
,11
]}

Hubner, Norbert ^{[7
]}

Illig, Thomas ^{[10
,12
]}

Irvine, Alan D. ^{[13
,14
,15
]}

Kabesch, Michael ^{[16
]}

Lee, Young A. E. ^{[7
,8
]}

Lieb, Wolfgang ^{[17
,18
]}

Marenholz, Ingo ^{[7
,8
]}

McLean, W. H. Irwin ^{[19
,20
]}

Morris, Derek W. ^{[4
,5
,21
,22
]}

Mrowietz, Ulrich ^{[1
]}

Nair, Rajan ^{[23
]}

Noethen, Markus M. ^{[24
,25
]}

Novak, Natalija ^{[26
]}

O'Regan, Grainne M. ^{[13
]}

Schreiber, Stefan ^{[6
,27
]}

Smith, Catherine ^{[28
]}

Strauch, Konstantin ^{[9
,29
]}

Stuart, Philip E. ^{[23
]}

Trembath, Richard ^{[30
]}

Tsoi, Lam C. ^{[31
]}

Weichenthal, Michael ^{[1
]}

Barker, Jonathan ^{[28
]}

Elder, James T. ^{[23
,32
]}

Weidinger, Stephan ^{[1
]}

Cordell, Heather J. ^{[33
]}

Brown, Sara J. ^{[34
]}

机构：

[1] Univ Hosp Schleswig Holstein, Dept Dermatol Allergol & Venereol, D-24105 Kiel, Germany

[2] Univ Munich, Dept Med Grosshadern 2, D-81377 Munich, Germany

[3] Charite, Dept Gastroenterol Hepatol & Endocrinol, D-10117 Berlin, Germany

[4] Univ Dublin Trinity Coll, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 2, Ireland

[5] Univ Dublin Trinity Coll, Inst Mol Med, Dublin 2, Ireland

[6] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[7] Max Delbruck Ctr MDC Mol Med, D-13092 Berlin, Germany

[8] Charite, Pediat Allergy Expt & Clin Res Ctr, D-10117 Berlin, Germany

[9] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany

[10] German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany

[11] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany

[12] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany

[13] Our Ladys Childrens Hosp, Dept Paediat Dermatol, Dublin 12, Ireland

[14] Natl Childrens Res Ctr, Dublin 12, Ireland

[15] Univ Dublin Trinity Coll, Dept Clin Med, Dublin 2, Ireland

[16] Univ Childrens Hosp Regensburg KUNO, Dept Pediat Pneumol & Allergy, D-93042 Regensburg, Germany

[17] Univ Hosp Schleswig Holstein, Inst Epidemiol, D-24105 Kiel, Germany

[18] Univ Hosp Schleswig Holstein, PopGen Biobank, D-24105 Kiel, Germany

[19] Univ Dundee, Coll Life Sci, Dundee DD1 5EH, Scotland

[20] Univ Dundee, Coll Med, Dundee DD1 5EH, Scotland

[21] Natl Univ Ireland, Sch Psychol, Cognit Genet & Therapy Grp, Galway, Ireland

[22] Natl Univ Ireland, Discipline Biochem, Galway, Ireland

[23] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA

[24] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany

[25] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany

[26] Univ Bonn, Med Ctr, Dept Dermatol & Allergy, D-53105 Bonn, Germany

[27] Univ Med Ctr Schleswig Holstein, Dept Internal Med, D-24105 Kiel, Germany

[28] Kings Coll London, St Johns Inst Dermatol, Div Genet & Mol Med, London SE1 9RT, England

[29] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-80539 Munich, Germany

[30] Queen Mary Univ London, Barts & London Sch Med & Dent, London E1 4NS, England

[31] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA

[32] Ann Arbor Vet Affairs Hosp, Ann Arbor, MI 48105 USA

[33] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[34] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2015年 / 96卷 / 01期

基金：

英国惠康基金;

关键词：

CLASSICAL HLA ALLELES; ANALYSIS IDENTIFIES 3; OF-FUNCTION VARIANTS; CD8(+) T-CELLS; SUSCEPTIBILITY LOCI; CELLULAR ACTIVATOR; ASSOCIATION; FILAGGRIN; DISEASE; DIFFERENTIATION;

D O I：

10.1016/j.ajhg.2014.12.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.

引用

页码：104 / 120

页数：17

共 66 条

[1] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[2] Deletion of Late Cornified Envelope 3B and 3C Genes Is Not Associated with Atopic Dermatitis [J].

Bergboer, Judith G. M. ;

Zeeuwen, Patrick L. J. M. ;

Irvine, Alan D. ;

Weidinger, Stephan ;

Giardina, Emiliano ;

Novelli, Giuseppe ;

Den Heijer, Martin ;

Rodriguez, Elke ;

Illig, Thomas ;

Riveira-Munoz, Eva ;

Campbell, Linda E. ;

Tyson, Jess ;

Dannhauser, Emma N. ;

O'Regan, Grainne M. ;

Galli, Elena ;

Klopp, Norman ;

Koppelman, Gerard H. ;

Novak, Natalija ;

Estivill, Xavier ;

McLean, W. H. Irwin ;

Postma, Dirkje S. ;

Armour, John A. L. ;

Schalkwijk, Joost .

JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2010, 130 (08) :2057-2061

[3] A Subset-Based Approach Improves Power and Interpretation for the Combined Analysis of Genetic Association Studies of Heterogeneous Traits [J].

Bhattacharjee, Samsiddhi ;

Rajaraman, Preetha ;

Jacobs, Kevin B. ;

Wheeler, William A. ;

Melin, Beatrice S. ;

Hartge, Patricia ;

Yeager, Meredith ;

Chung, Charles C. ;

Chanock, Stephen J. ;

Chatterjee, Nilanjan .

AMERICAN JOURNAL OF HUMAN GENETICS, 2012, 90 (05) :821-835

[4] Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci [J].

Cookson, WOCM ;

Ubhi, B ;

Lawrence, R ;

Abecasis, GR ;

Walley, AJ ;

Cox, HE ;

Coleman, R ;

Leaves, NI ;

Trembath, RC ;

Moffatt, MF ;

Harper, JI .

NATURE GENETICS, 2001, 27 (04) :372-373

[5] Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis [J].

de Cid, Rafael ;

Riveira-Munoz, Eva ;

Zeeuwen, Patrick L. J. M. ;

Robarge, Jason ;

Liao, Wilson ;

Dannhauser, Emma N. ;

Giardina, Emiliano ;

Stuart, Philip E. ;

Nair, Rajan ;

Helms, Cynthia ;

Escaramis, Georgia ;

Ballana, Ester ;

Martin-Ezquerra, Gemma ;

den Heijer, Martin ;

Kamsteeg, Marijke ;

Joosten, Irma ;

Eichler, Evan E. ;

Lazaro, Conxi ;

Pujol, Ramon M. ;

Armengol, Lluis ;

Abecasis, Goncalo ;

Elder, James T. ;

Novelli, Giuseppe ;

Armour, John A. L. ;

Kwok, Pui-Yan ;

Bowcock, Anne ;

Schalkwijk, Joost ;

Estivill, Xavier .

NATURE GENETICS, 2009, 41 (02) :211-215

[6] Investigating International Time Trends in the Incidence and Prevalence of Atopic Eczema 1990-2010: A Systematic Review of Epidemiological Studies [J].

Deckers, Ivette A. G. ;

McLean, Susannah ;

Linssen, Sanne ;

Mommers, Monique ;

van Schayck, C. P. ;

Sheikh, Aziz .

PLOS ONE, 2012, 7 (07)

[7] Nonallergic comorbidities of atopic eczema: an overview of systematic reviews [J].

Deckert, S. ;

Kopkow, C. ;

Schmitt, J. .

ALLERGY, 2014, 69 (01) :37-45

[8]

Delaneau O, 2012, NAT METHODS, V9, P179, DOI [10.1038/NMETH.1785, 10.1038/nmeth.1785]

[9] HLA*IMP-an integrated framework for imputing classical HLA alleles from SNP genotypes [J].

Dilthey, Alexander T. ;

Moutsianas, Loukas ;

Leslie, Stephen ;

McVean, Gil .

BIOINFORMATICS, 2011, 27 (07) :968-972

[10] Molecular Dissection of Psoriasis: Integrating Genetics and Biology [J].

Elder, James T. ;

Bruce, Allen T. ;

Gudjonsson, Johann E. ;

Johnston, Andrew ;

Stuart, Philip E. ;

Tejasvi, Trilokraj ;

Voorhees, John J. ;

Abecasis, Goncalo R. ;

Nair, Rajan P. .

JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2010, 130 (05) :1213-1226

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