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000285361 1001_ $$00000-0003-2615-4916$$aGrover, Sandeep$$b0
000285361 245__ $$aFirst genome-wide association study reveals immune-mediated aetiopathology in idiopathic achalasia.
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000285361 520__ $$aIdiopathic achalasia (IA) is characterised by the degeneration of neurons in the myenteric plexus leading to an irreversible impaired oesophageal function. Although immune-mediated mechanisms have been proposed, the underlying aetiopathology of IA remains poorly understood.This study aimed to uncover the genetic risk architecture of IA.We carried out the first genome-wide association study (GWAS) on 4602 European patients with IA and 10 766 ethnically-matched controls.A single nucleotide polymorphism (SNP) in HLA-DQB1 leading to an 8-amino acid insertion on the protein level conferred strongest IA risk (PQGPPPAG: p=3.27×10-68, OR=2.45). Conditional analyses within the HLA locus revealed a complex genetic risk architecture. Three additional amino acid positions showed independent IA association (Omnibus p<5×10-8). These refer to positions 41 and 130 in HLA-DQα1, position 45 in HLA-DQβ1 and position 86 in HLA-DRβ1. Together, these findings highlight the pivotal role of class II HLA genetic variation in IA pathogenesis. Outside HLA, three independent variants showed IA association (p<5×10-8). One leads to an amino acid substitution with functional effect in PTPN22. Another risk variant leads to a downregulated expression of TNFSF8, TNFSF15 and TNC in immune cells. The third risk SNP is located near ZNF365, but the exact underlying cellular mechanism remains unknown. Beyond the single marker level, polygenic risk scores revealed that patients with IA can be stratified based on their genetic risk. In addition, IA shows a shared aetiopathology with Crohn's disease (rg=0.335). Integrating GWAS and single-cell RNA-sequencing data from the myenteric plexus showed that the memory T-cell type FOS+Tc4+CD8+ plays a central role in IA development (p=2.50×10-19).This GWAS led to the identification of SNPs, cellular mechanisms and cell types that are involved in IA aetiopathology.
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000285361 650_7 $$2Other$$aACHALASIA
000285361 650_7 $$2Other$$aGENETIC POLYMORPHISMS
000285361 650_7 $$2Other$$aGENETICS
000285361 650_7 $$2Other$$aHLA CLASS II ALLELES
000285361 650_7 $$2Other$$aRNA EXPRESSION
000285361 7001_ $$aGockel, Ines$$b1
000285361 7001_ $$aLatiano, Anna$$b2
000285361 7001_ $$aMokrowiecka, Anna$$b3
000285361 7001_ $$aDasmeh, Pouria$$b4
000285361 7001_ $$aWouters, Mira M$$b5
000285361 7001_ $$aVackova, Zuzana$$b6
000285361 7001_ $$aHaas, Stephan L$$b7
000285361 7001_ $$aTriantafyllou, Tania$$b8
000285361 7001_ $$aKreuser, Nicole$$b9
000285361 7001_ $$aTrautmann, Jessica$$b10
000285361 7001_ $$aNiebisch, Stefan$$b11
000285361 7001_ $$aHess, Timo$$b12
000285361 7001_ $$aThieme, Rene$$b13
000285361 7001_ $$aBigge, Jessica$$b14
000285361 7001_ $$aLouis, Hubert$$b15
000285361 7001_ $$aQuertinmont, Eric$$b16
000285361 7001_ $$aMeirhaeghe, Aline$$b17
000285361 7001_ $$aMuntaner, Manon$$b18
000285361 7001_ $$aAmouyel, Philippe$$b19
000285361 7001_ $$00000-0001-8220-9155$$aGourcerol, Guillaume$$b20
000285361 7001_ $$aBruley des Varannes, Stanislas$$b21
000285361 7001_ $$aMion, Francois$$b22
000285361 7001_ $$aVieth, Michael$$b23
000285361 7001_ $$aScarmeas, Nikolaos$$b24
000285361 7001_ $$aPalmieri, Orazio$$b25
000285361 7001_ $$aTavano, Francesca$$b26
000285361 7001_ $$00000-0003-0867-5873$$aDe Giorgio, Roberto$$b27
000285361 7001_ $$aGalimberti, Daniela$$b28
000285361 7001_ $$aArighi, Andrea$$b29
000285361 7001_ $$aArosio, Beatrice$$b30
000285361 7001_ $$aBruno, Marco$$b31
000285361 7001_ $$aWasielica-Berger, Justyna$$b32
000285361 7001_ $$aGawron-Kiszka, Magdalena$$b33
000285361 7001_ $$aJaniak, Maria$$b34
000285361 7001_ $$aSiepsiak, Magdalena$$b35
000285361 7001_ $$aAdrych, Krystian$$b36
000285361 7001_ $$aMarek, Tomasz$$b37
000285361 7001_ $$aDabrowski, Andrzej$$b38
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000285361 7001_ $$aGietka, Piotr$$b40
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000285361 7001_ $$aPérez de la Serna, Julio$$b42
000285361 7001_ $$aMartínez, Laisy Zacarías$$b43
000285361 7001_ $$aGiedraitis, Vilmantas$$b44
000285361 7001_ $$aKilander, Lena$$b45
000285361 7001_ $$aFratiglioni, Laura$$b46
000285361 7001_ $$aReal, Luis Miguel$$b47
000285361 7001_ $$aSpicak, Julius$$b48
000285361 7001_ $$00000-0002-3206-6704$$aTack, Jan$$b49
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000285361 7001_ $$aIngelsson, Martin$$b52
000285361 7001_ $$aGraff, Caroline$$b53
000285361 7001_ $$aRuiz, Agustín$$b54
000285361 7001_ $$aLambert, Jean-Charles$$b55
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000285361 7001_ $$aEckardt, Alexander J$$b57
000285361 7001_ $$aMüller, Michaela$$b58
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000285361 7001_ $$aWissinowski, Thaddäus T$$b60
000285361 7001_ $$00000-0002-5884-1115$$aKeller, Jutta$$b61
000285361 7001_ $$aBruns, Christiane Josephine$$b62
000285361 7001_ $$aGerges, Christian$$b63
000285361 7001_ $$aNeuhaus, Horst$$b64
000285361 7001_ $$00000-0003-2270-2495$$aRösch, Thomas$$b65
000285361 7001_ $$00000-0002-0055-958X$$aSiegmund, Britta$$b66
000285361 7001_ $$aSchumacher, Brigitte$$b67
000285361 7001_ $$00000-0001-8581-0974$$aVenerito, Marino$$b68
000285361 7001_ $$aRuiz de León, Antonio$$b69
000285361 7001_ $$aRosati, Riccardo$$b70
000285361 7001_ $$aAnnese, Vito$$b71
000285361 7001_ $$aFumagalli, Uberto$$b72
000285361 7001_ $$00000-0003-4187-1059$$aLaghi, Luigi$$b73
000285361 7001_ $$aUrcelay, Elena$$b74
000285361 7001_ $$aVavasseur, Fabienne$$b75
000285361 7001_ $$00000-0002-7798-7638$$aRoman, Sabine$$b76
000285361 7001_ $$00000-0002-5434-0540$$aZhou, Pinghong$$b77
000285361 7001_ $$00000-0002-9108-8786$$aLi, Quanlin$$b78
000285361 7001_ $$aLiu, Zuqiang$$b79
000285361 7001_ $$aRahden, Burkhard H A von$$b80
000285361 7001_ $$aTheodorou, Dimitris$$b81
000285361 7001_ $$aMalecka-Wojciesko, Ewa$$b82
000285361 7001_ $$aMaj, Carlo$$b83
000285361 7001_ $$aVigo, Ana G$$b84
000285361 7001_ $$00000-0002-1415-4719$$aMartinek, Jan$$b85
000285361 7001_ $$00000-0001-8267-5797$$aBoeckxstaens, Guy$$b86
000285361 7001_ $$aSchumacher, Johannes$$b87
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