Shared and distinct genetic etiologies for different types of clonal hematopoiesis.
Shared and distinct genetic etiologies for different types of clonal hematopoiesis.
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DOI：
10.1038/s41467-023-41315-5
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发表时间：
2023-09-08
影响因子：
16.6
通讯作者：
Machiela, Mitchell J.
中科院分区：
文献类型：
--
作者：
Brown, Derek W.;Cato, Liam D.;Zhao, Yajie;Nandakumar, Satish K.;Bao, Erik L.;Gardner, Eugene J.;Hubbard, Aubrey K.;Depaulis, Alexander;Rehling, Thomas;Song, Lei;Yu, Kai;Chanock, Stephen J.;Perry, John R. B.;Sankaran, Vijay G.;Machiela, Mitchell J.
克隆性造血（CH）-突变造血克隆的年龄相关扩增-可以在频率和细胞适应性方面因CH类型而异（例如，驱动基因的突变（CHIP）、染色体区段的获得/丢失和拷贝中性丢失（mCA）以及性染色体的丢失）。共现的CH提出了关于它们的起源、选择和影响的问题。我们整合了多达482，378名英国生物库参与者的序列和基因型阵列数据，以证明CH类型之间的共享遗传结构。我们的分析表明，不同类型的CH之间的细胞进化权衡，LOY发生在已建立的CHIP基因携带突变的个体中的发生率较低。我们观察到CHIP和mCA同时出现，在TET 2、DNMT 3A和JAK 2处重叠，其中CHIP先于mCA采集。此外，携带重叠CH的个体将来发生淋巴和骨髓恶性肿瘤的风险较高。最后，我们利用CH性状的共享遗传结构来确定与白血病风险相关的15个新基因座。克隆造血（CH）的类型在频率和适应性上不同。这些发现揭示了共享的遗传结构，表明CH类型之间的进化权衡，并详细说明了具有重叠类型CH的个体中白血病风险的升高。
Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk. Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH.
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影响因子：
64.8
作者：
Bick AG;Weinstock JS;Nandakumar SK;Fulco CP;Bao EL;Zekavat SM;Szeto MD;Liao X;Leventhal MJ;Nasser J;Chang K;Laurie C;Burugula BB;Gibson CJ;Lin AE;Taub MA;Aguet F;Ardlie K;Mitchell BD;Barnes KC;Moscati A;Fornage M;Redline S;Psaty BM;Silverman EK;Weiss ST;Palmer ND;Vasan RS;Burchard EG;Kardia SLR;He J;Kaplan RC;Smith NL;Arnett DK;Schwartz DA;Correa A;de Andrade M;Guo X;Konkle BA;Custer B;Peralta JM;Gui H;Meyers DA;McGarvey ST;Chen IY;Shoemaker MB;Peyser PA;Broome JG;Gogarten SM;Wang FF;Wong Q;Montasser ME;Daya M;Kenny EE;North KE;Launer LJ;Cade BE;Bis JC;Cho MH;Lasky-Su J;Bowden DW;Cupples LA;Mak ACY;Becker LC;Smith JA;Kelly TN;Aslibekyan S;Heckbert SR;Tiwari HK;Yang IV;Heit JA;Lubitz SA;Johnsen JM;Curran JE;Wenzel SE;Weeks DE;Rao DC;Darbar D;Moon JY;Tracy RP;Buth EJ;Rafaels N;Loos RJF;Durda P;Liu Y;Hou L;Lee J;Kachroo P;Freedman BI;Levy D;Bielak LF;Hixson JE;Floyd JS;Whitsel EA;Ellinor PT;Irvin MR;Fingerlin TE;Raffield LM;Armasu SM;Wheeler MM;Sabino EC;Blangero J;Williams LK;Levy BD;Sheu WH;Roden DM;Boerwinkle E;Manson JE;Mathias RA;Desai P;Taylor KD;Johnson AD;NHLBI Trans-Omics for Precision Medicine Consortium;Auer PL;Kooperberg C;Laurie CC;Blackwell TW;Smith AV;Zhao H;Lange E;Lange L;Rich SS;Rotter JI;Wilson JG;Scheet P;Kitzman JO;Lander ES;Engreitz JM;Ebert BL;Reiner AP;Jaiswal S;Abecasis G;Sankaran VG;Kathiresan S;Natarajan P
通讯作者：
Natarajan P
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
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.