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Aberrant activation...
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Weinstock, Joshua SUniversity of Michigan
(author)
Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
- Article/chapterEnglish2023
Publisher, publication year, extent ...
Numbers
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LIBRIS-ID:oai:gup.ub.gu.se/325109
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https://gup.ub.gu.se/publication/325109URI
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https://doi.org/10.1038/s41586-023-05806-1DOI
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https://lup.lub.lu.se/record/51babf53-932c-4d12-9728-7617d858c9b0URI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, butthis effect was not seen inclones withdriver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimentalknockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Smith, J.G.Gothenburg University,Göteborgs universitet,University of Gothenburg,Lund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Heart Failure and Mechanical Support,Forskargrupper vid Lunds universitet,Molecular Epidemiology and Cardiology,Cardiovascular Epigenetics,WCMM- Wallenberg center för molekylär medicinsk forskning,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Skåne University Hospital,Sahlgrenska University Hospital,Stanford University School of Medicine,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xsmigu
(author)
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Burugula, Bala BharathiBloodworks Northwest Research Institute,Skåne University Hospital,Lund University
(author)
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Uddin, Md Mesbah
(author)
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Jahn, Nikolaus
(author)
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Belk, Julia A
(author)
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Bouzid, Hind
(author)
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Daniel, Bence
(author)
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Miao, Zhuang
(author)
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Ly, Nghi
(author)
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Mack, Taralynn M
(author)
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Luna, Sofia E
(author)
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Prothro, Katherine P
(author)
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Mitchell, Shaneice R
(author)
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Laurie, Cecelia A
(author)
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Broome, Jai G
(author)
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Taylor, Kent D
(author)
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Guo, Xiuqing
(author)
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Sinner, Moritz F
(author)
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von Falkenhausen, Aenne S
(author)
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Kääb, Stefan
(author)
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Shuldiner, Alan R
(author)
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O'Connell, Jeffrey R
(author)
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Lewis, Joshua P
(author)
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Boerwinkle, Eric
(author)
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Barnes, Kathleen C
(author)
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Chami, Nathalie
(author)
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Kenny, Eimear E
(author)
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Loos, Ruth J F
(author)
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Fornage, Myriam
(author)
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Hou, Lifang
(author)
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Lloyd-Jones, Donald M
(author)
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Redline, Susan
(author)
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Cade, Brian E
(author)
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Psaty, Bruce M
(author)
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Bis, Joshua C
(author)
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Brody, Jennifer A
(author)
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Silverman, Edwin K
(author)
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Yun, Jeong H
(author)
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Qiao, Dandi
(author)
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Palmer, Nicholette D
(author)
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Freedman, Barry I
(author)
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Bowden, Donald W
(author)
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Cho, Michael H
(author)
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DeMeo, Dawn L
(author)
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Vasan, Ramachandran S
(author)
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Yanek, Lisa R
(author)
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Becker, Lewis C
(author)
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Kardia, Sharon L R
(author)
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Peyser, Patricia A
(author)
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He, Jiang
(author)
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Rienstra, Michiel
(author)
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Van der Harst, Pim
(author)
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Kaplan, Robert
(author)
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Heckbert, Susan R
(author)
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Smith, Nicholas L
(author)
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Wiggins, Kerri L
(author)
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Arnett, Donna K
(author)
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Irvin, Marguerite R
(author)
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Tiwari, Hemant
(author)
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Cutler, Michael J
(author)
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Knight, Stacey
(author)
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Muhlestein, J Brent
(author)
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Correa, Adolfo
(author)
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Raffield, Laura M
(author)
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Gao, Yan
(author)
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de Andrade, Mariza
(author)
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Rotter, Jerome I
(author)
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Rich, Stephen S
(author)
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Tracy, Russell P
(author)
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Konkle, Barbara A
(author)
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Johnsen, Jill MBloodworks Northwest Research Institute,Skåne University Hospital,Lund University
(author)
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Wheeler, Marsha M
(author)
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Smith, J. Gustav,1982Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xsmigu
(author)
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Melander, O.Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-ome
(author)
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Nilsson, P.M.Lund University,Lunds universitet,Internmedicin - epidemiologi,Forskargrupper vid Lunds universitet,Internal Medicine - Epidemiology,Lund University Research Groups(Swepub:lu)medf-pni
(author)
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Custer, Brian S
(author)
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Duggirala, Ravindranath
(author)
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Curran, Joanne E
(author)
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Blangero, John
(author)
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McGarvey, Stephen
(author)
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Williams, L Keoki
(author)
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Xiao, Shujie
(author)
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Yang, Mao
(author)
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Gu, C Charles
(author)
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Chen, Yii-Der Ida
(author)
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Lee, Wen-Jane
(author)
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Marcus, Gregory M
(author)
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Kane, John P
(author)
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Pullinger, Clive R
(author)
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Shoemaker, M Benjamin
(author)
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Darbar, Dawood
(author)
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Roden, Dan M
(author)
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Albert, Christine
(author)
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Kooperberg, Charles
(author)
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Zhou, Ying
(author)
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Manson, JoAnn E
(author)
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Desai, Pinkal
(author)
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Johnson, Andrew D
(author)
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Mathias, Rasika A
(author)
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Blackwell, Thomas W
(author)
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Abecasis, Goncalo R
(author)
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Smith, Albert V
(author)
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Kang, Hyun M
(author)
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Satpathy, Ansuman T
(author)
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Natarajan, Pradeep
(author)
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Kitzman, Jacob O
(author)
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Whitsel, Eric A
(author)
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Reiner, Alexander P
(author)
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Bick, Alexander G
(author)
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Jaiswal, Siddhartha
(author)
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University of MichiganKardiologi
(creator_code:org_t)
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In:Nature616:7958, s. 755-7631476-4687
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Weinstock, Joshu ...
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Smith, J.G.
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Burugula, Bala B ...
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Uddin, Md Mesbah
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Jahn, Nikolaus
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Belk, Julia A
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show more...
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Bouzid, Hind
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Daniel, Bence
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Miao, Zhuang
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Ly, Nghi
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Mack, Taralynn M
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Luna, Sofia E
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Prothro, Katheri ...
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Mitchell, Shanei ...
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Laurie, Cecelia ...
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Broome, Jai G
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Taylor, Kent D
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Guo, Xiuqing
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Sinner, Moritz F
-
von Falkenhausen ...
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Kääb, Stefan
-
Shuldiner, Alan ...
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O'Connell, Jeffr ...
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Lewis, Joshua P
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Boerwinkle, Eric
-
Barnes, Kathleen ...
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Chami, Nathalie
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Kenny, Eimear E
-
Loos, Ruth J F
-
Fornage, Myriam
-
Hou, Lifang
-
Lloyd-Jones, Don ...
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Redline, Susan
-
Cade, Brian E
-
Psaty, Bruce M
-
Bis, Joshua C
-
Brody, Jennifer ...
-
Silverman, Edwin ...
-
Yun, Jeong H
-
Qiao, Dandi
-
Palmer, Nicholet ...
-
Freedman, Barry ...
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Bowden, Donald W
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Cho, Michael H
-
DeMeo, Dawn L
-
Vasan, Ramachand ...
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Yanek, Lisa R
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Becker, Lewis C
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Kardia, Sharon L ...
-
Peyser, Patricia ...
-
He, Jiang
-
Rienstra, Michie ...
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Van der Harst, P ...
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Kaplan, Robert
-
Heckbert, Susan ...
-
Smith, Nicholas ...
-
Wiggins, Kerri L
-
Arnett, Donna K
-
Irvin, Marguerit ...
-
Tiwari, Hemant
-
Cutler, Michael ...
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Knight, Stacey
-
Muhlestein, J Br ...
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Correa, Adolfo
-
Raffield, Laura ...
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Gao, Yan
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de Andrade, Mari ...
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Rotter, Jerome I
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Rich, Stephen S
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Tracy, Russell P
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Konkle, Barbara ...
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Johnsen, Jill M
-
Wheeler, Marsha ...
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Smith, J. Gustav ...
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Melander, O.
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Nilsson, P.M.
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Custer, Brian S
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Duggirala, Ravin ...
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Curran, Joanne E
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Blangero, John
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McGarvey, Stephe ...
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Williams, L Keok ...
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Xiao, Shujie
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Yang, Mao
-
Gu, C Charles
-
Chen, Yii-Der Id ...
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Lee, Wen-Jane
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Marcus, Gregory ...
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Kane, John P
-
Pullinger, Clive ...
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Shoemaker, M Ben ...
-
Darbar, Dawood
-
Roden, Dan M
-
Albert, Christin ...
-
Kooperberg, Char ...
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Zhou, Ying
-
Manson, JoAnn E
-
Desai, Pinkal
-
Johnson, Andrew ...
-
Mathias, Rasika ...
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Blackwell, Thoma ...
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Abecasis, Goncal ...
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Smith, Albert V
-
Kang, Hyun M
-
Satpathy, Ansuma ...
-
Natarajan, Prade ...
-
Kitzman, Jacob O
-
Whitsel, Eric A
-
Reiner, Alexande ...
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Bick, Alexander ...
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Jaiswal, Siddhar ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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Nature
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University of Gothenburg
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Lund University