Inherited causes of clonal haematopoiesis in 97,691 whole genomes

被引：434

作者：

Bick, Alexander G. ^{[1
,2
,118
]}

Weinstock, Joshua S. ^{[4
]}

Nandakumar, Satish K. ^{[2
,5
,6
]}

Fulco, Charles P. ^{[2
,7
]}

Bao, Erik L. ^{[2
,5
,6
,8
]}

Zekavat, Seyedeh M. ^{[2
,9
]}

Szeto, Mindy D. ^{[10
,11
]}

Liao, Xiaotian ^{[2
,5
,6
]}

Leventhal, Matthew J. ^{[2
]}

Nasser, Joseph ^{[2
]}

Chang, Kyle ^{[12
]}

Laurie, Cecelia

Burugula, Bala Bharathi ^{[13
]}

Gibson, Christopher J. ^{[14
]}

Lin, Amy E. ^{[15
]}

Taub, Margaret A. ^{[16
]}

Aguet, Francois ^{[2
]}

Ardlie, Kristin ^{[2
]}

Mitchell, Braxton D. ^{[17
,18
,19
]}

Barnes, Kathleen C. ^{[10
]}

Moscati, Arden ^{[20
]}

Fornage, Myriam ^{[21
,22
]}

Redline, Susan ^{[3
,23
,24
]}

Psaty, Bruce M. ^{[25
,26
,27
,28
]}

Silverman, Edwin K. ^{[3
,29
]}

Weiss, Scott T. ^{[3
,29
]}

Palmer, Nicholette D. ^{[30
]}

Vasan, Ramachandran S. ^{[31
,32
]}

Burchard, Esteban G. ^{[33
,34
]}

Kardia, Sharon L. R. ^{[35
]}

He, Jiang ^{[36
,37
]}

Kaplan, Robert C. ^{[38
,39
]}

Smith, Nicholas L. ^{[26
,28
,40
]}

Arnett, Donna K. ^{[41
]}

Schwartz, David A. ^{[42
]}

Correa, Adolfo ^{[43
,44
]}

de Andrade, Mariza ^{[45
]}

Guo, Xiuqing ^{[46
]}

Konkle, Barbara A. ^{[47
,48
]}

Custer, Brian ^{[49
,50
]}

Peralta, Juan M. ^{[51
,52
]}

Gui, Hongsheng ^{[53
]}

Meyers, Deborah A. ^{[54
]}

McGarvey, Stephen T. ^{[55
,56
]}

Chen, Ida Yii-Der ^{[57
]}

Shoemaker, M. Benjamin ^{[58
]}

Peyser, Patricia A. ^{[35
]}

Broome, Jai G.

Gogarten, Stephanie M.

Wang, Fei Fei

机构：

[1] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

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

[5] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA

[6] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[7] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[8] Harvard Med Sch, Hlth Sci & Technol Program, Boston, MA 02115 USA

[9] Yale Sch Med, New Haven, CT USA

[10] Univ Colorado Anschutz Med Campus, Dept Med, Div Biomed Informat & Personalized Med, Aurora, CO USA

[11] Univ Colorado Anschutz Med Campus, Med Scientist Training Program, Aurora, CO USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[13] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[14] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[15] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA

[16] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

[17] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[18] Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA

[19] Univ Colorado, Sch Med, Colorado Ctr Personalized Med, Aurora, CO USA

[20] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[21] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[22] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA

[23] Brigham & Womens Hosp, Dept Med, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA

[24] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[25] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[26] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[27] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[28] Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA

[29] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[30] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC 27101 USA

[31] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA

[32] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA

[33] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[34] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[35] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[36] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA

[37] Tulane Univ, Translat Sci Inst, New Orleans, LA 70118 USA

[38] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA

[39] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[40] Seattle Epidemiol Informat & Res Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA

[41] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA

[42] Univ Colorado, Dept Med, Aurora, CO USA

[43] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA

[44] Univ Mississippi, Med Ctr, Dept Populat Hlth Sci, Jackson, MS 39216 USA

[45] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[46] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA

[47] Bloodworks Northwest, Seattle, WA USA

[48] Univ Washington, Dept Med, Seattle, WA USA

[49] Vitalant Res Inst, San Francisco, CA USA

[50] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA USA

来源：

NATURE | 2020年 / 586卷 / 7831期

关键词：

SOMATIC MUTATIONS; JAK2; HAPLOTYPE; VARIANTS; COMMON; RISK; AGE; SUSCEPTIBILITY; PREDISPOSE; EXPANSION; BREAST;

D O I：

10.1038/s41586-020-2819-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown(1). The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer(2-4) and coronary heart disease(5)-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)(6). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

引用

页码：763 / +

页数：21

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