Locus for severity implicates CNS resilience in progression of multiple sclerosis.
Locus for severity implicates CNS resilience in progression of multiple sclerosis.
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DOI：
10.1038/s41586-023-06250-x
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发表时间：
2023-07
期刊：
影响因子：
64.8
通讯作者：
Baranzini, Sergio E.
中科院分区：
文献类型：
--
作者：
Harroud, Adil;Stridh, Pernilla J.;McCauley, Jacob H.;Saarela, Janna;van den Bosch, Aletta M. R.;Engelenburg, Hendrik;Beecham, Ashley;Alfredsson, Lars;Alikhani, Katayoun;Amezcua, Lilyana;Andlauer, Till F. M.;Ban, Maria;Barcellos, Lisa;Barizzone, Nadia;Berge, Tone;Berthele, Achim;Bittner, Stefan;Bos, Steffan;Briggs, Farren B. S.;Caillier, Stacy;Calabresi, Peter;Caputo, Domenico;Carmona-Burgos, David;Cavalla, Paola;Celius, Elisabeth;Cerono, Gabriel;Chinea, Angel;Chitnis, Tanuja;Clarelli, Ferdinando;Comabella, Manuel;Comi, Giancarlo;Cotsapas, Chris;Cree, Bruce C. A.;D'Alfonso, Sandra;Dardiotis, Efthimios;De Jager, Philip;Delgado, Silvia;Dubois, Benedicte;Engel, Sinah;Esposito, Federica;Fabis-Pedrini, Marzena;Filippi, Massimo;Fitzgerald, Kathryn;Gasperi, Christiane;Gomez, Lissette;Gomez, Refujia;Hadjigeorgiou, Georgios;Hamann, Joerg;Held, Friederike;Henry, Roland;Hillert, Jan;Huang, Jesse;Huitinga, Inge;Islam, Talat;Isobe, Noriko;Jagodic, Maja;Kermode, Allan L.;Khalil, Michael;Kilpatrick, Trevor;Konidari, Ioanna;Kreft, Karim;Lechner-Scott, Jeannette;Leone, Maurizio;Luessi, Felix;Malhotra, Sunny;Manouchehrinia, Ali;Manrique, Clara;Martinelli-Boneschi, Filippo;Martinez, Andrea;Martinez-Maldonado, Viviana;Mascia, Elisabetta;Metz, Luanne;Midaglia, Luciana;Montalban, Xavier;Oksenberg, Jorge;Olsson, Tomas;Oturai, Annette;Paakkonen, Kimmo;Parnell, Grant P.;Patsopoulos, Nikolaos;Pericak-Vance, Margaret;Piehl, Fredrik;Rubio, Justin;Santaniello, Adam;Santoro, Silvia;Schaefer, Catherine;Sellebjerg, Finn;Shams, Hengameh;Shchetynsky, Klementy;Silva, Claudia;Siokas, Vasileios;Sondergaard, Helle;Sorosina, Melissa;Taylor, Bruce;Vandebergh, Marijne;Vasileiou, Elena;Vecchio, Domizia;Voortman, Margarete;Weiner, Howard;Wever, Dennis;Yong, V. Wee;Hafler, David;Stewart, Graeme;Compston, Alastair;Zipp, Frauke;Harbo, Hanne;Hemmer, Bernhard;Goris, An;Smolders, Joost;Hauser, Stephen;Kockum, Ingrid;Sawcer, Stephen;Baranzini, Sergio;Jonsdottir, Ingileif;Blanco, Yolanda;Llufriu, Sara;Madireddy, Lohith;Saiz, Albert;Villoslada, Pablo;Stefansson, Kari;Harbo, Hanne F.;Hemmer, Bernhard;Goris, An;Kockum, Ingrid;Sawcer, Stephen J.;Baranzini, Sergio E.
多发性硬化症（MS）是中枢神经系统（CNS）的自身免疫性疾病，其导致大多数受影响者的显著神经变性，并且是年轻成人中慢性神经功能障碍的常见原因。为了深入了解决定进展的机制，我们对12，584例与年龄相关的MS严重程度评分进行了全基因组关联研究，并在另外9，805例病例中复制了我们的发现。我们发现DYSF-ZNF 638基因座中的rs 10191329显著相关（P=3.6×10−9），风险等位基因缩短了需要助行器的中位时间长达3.7年，并增加了脑干和脑组织皮质病理学。我们还确定了DNM 3-PIGC基因座中与rs 149097173的暗示性关联（P=2.3×10−7），并在CNS组织中表达显著富集。孟德尔随机化分析表明，较高的教育程度的保护作用。与免疫驱动的易感性相反，这些发现表明CNS恢复力和神经认知储备在确定MS结局中的关键作用。
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults. To provide insight into the mechanisms determining progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus (P=3.6×10−9), the risk allele shortening the median time to require a walking aid by up to 3.7 years and increasing brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus (P=2.3×10−7) and significant enrichment for expression in CNS tissues. Mendelian randomization analyses indicated a protective role for higher educational attainment. In contrast to immune-driven susceptibility, these findings indicate a key role of CNS resilience and neurocognitive reserve in determining outcome in MS.
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影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Finucane HK;Reshef YA;Anttila V;Slowikowski K;Gusev A;Byrnes A;Gazal S;Loh PR;Lareau C;Shoresh N;Genovese G;Saunders A;Macosko E;Pollack S;Brainstorm Consortium;Perry JRB;Buenrostro JD;Bernstein BE;Raychaudhuri S;McCarroll S;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
3.5
作者：
D'hooghe, M. B.;Haentjens, P.;Nagels, G.
通讯作者：
Nagels, G.