Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells.
Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells.
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DOI：
10.1038/s41586-020-2786-7
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Sankaran VG
中科院分区：
文献类型：
--
作者：
Bao EL;Nandakumar SK;Liao X;Bick AG;Karjalainen J;Tabaka M;Gan OI;Havulinna AS;Kiiskinen TTJ;Lareau CA;de Lapuente Portilla AL;Li B;Emdin C;Codd V;Nelson CP;Walker CJ;Churchhouse C;de la Chapelle A;Klein DE;Nilsson B;Wilson PWF;Cho K;Pyarajan S;Gaziano JM;Samani NJ;FinnGen;23andMe Research Team;Regev A;Palotie A;Neale BM;Dick JE;Natarajan P;O'Donnell CJ;Daly MJ;Milyavsky M;Kathiresan S;Sankaran VG
骨髓增生性肿瘤（MPN）是以成熟骨髓细胞的过度产生为特征的血癌，其由造血干细胞（HSC）中获得体细胞驱动突变引起。流行病学研究表明，癌症的遗传率是已知最高的。然而，只有一组有限的遗传风险位点已被确定，和潜在的生物学机制，导致MPN收购仍然无法解释。在这里，我们进行了一项大规模的全基因组关联研究（3，797例病例和1，152，977例对照），以确定17个MPN风险位点（p < 5.0 × 10−8），其中7个以前从未报道过。我们发现MPN风险和几个造血性状之间共享的遗传结构跨越不同的谱系，富集映射到HSC中可访问的染色质的风险变体，以及增加的MPN风险与较长的白细胞端粒长度和其他克隆造血状态的关联，共同暗示HSC功能和自我更新。基因定位鉴定了HSC生物学的调节剂，靶向变体-功能测定表明CHEK 2和GFI 1B在改变HSC功能以赋予疾病风险中的可能作用。总的来说，我们证明了人类遗传学研究的力量，通过调节HSC功能阐明了以前不受重视的遗传性MPN风险机制。
Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells, which result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs). Epidemiologic studies indicate a substantial disease heritability that is among the highest known for cancers. However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, we conducted a large-scale genome-wide association study (3,797 cases and 1,152,977 controls) to identify 17 MPN risk loci (p < 5.0 × 10−8), seven of which have not been previously reported. We find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, an enrichment for risk variants mapping to accessible chromatin in HSCs, and associations of increased MPN risk with longer leukocyte telomere length and other clonal hematopoietic states, collectively implicating HSC function and self-renewal. Gene mapping identifies modulators of HSC biology and targeted variant-to-function assays suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for inherited MPN risk through modulation of HSC function.
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影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
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：
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：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
82.9
作者：
Chen, Jiahao;Kao, Yun-Ruei;Steidl, Ulrich
通讯作者：
Steidl, Ulrich