Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing

Yasminka Jakubek Swartzlander; Ying Zhou; Adrienne Stilp; Jason Bacon; Justin W. Wong; Zuhal Ozcan; Donna Arnett; Kathleen Barnes; Joshua C. Bis; Eric Boerwinkle; Jennifer A. Brody; April P. Carson; Daniel I. Chasman; Jiawen Chen; Michael Cho; Matthew P. Conomos; Nancy Cox; Margaret F. Doyle; Myriam Fornage; Xiuqing Guo; Sharon L.R. Kardia; Joshua P. Lewis; Ruth J.F. Loos; Xiaolong Ma; Mitchell J. Machiela; Taralynn M. Mack; Rasika A. Mathias; Braxton D. Mitchell; Josyf C. Mychaleckyj; Kari North; Nathan Pankratz; Patricia A. Peyser; Michael H. Preuss; Bruce Psaty; Laura M. Raffield; Ramachandran S. Vasan; Susan Redline; Stephen S. Rich; Jerome I. Rotter; Edwin K. Silverman; Jennifer A. Smith; Aaron P. Smith; Margaret Taub; Kent D. Taylor; Jeong Yun; Yun Li; Pinkal Desai; Alexander G. Bick; Alexander P. Reiner; Paul Scheet; Paul L. Auer

doi:10.1038/s41588-023-01553-1

Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing

Yasminka Jakubek Swartzlander, Ying Zhou, Adrienne Stilp, Jason Bacon, Justin W. Wong, Zuhal Ozcan, Donna Arnett, Kathleen Barnes, Joshua C. Bis, Eric Boerwinkle, Jennifer A. Brody, April P. Carson, Daniel I. Chasman, Jiawen Chen, Michael Cho, Matthew P. Conomos, Nancy Cox, Margaret F. Doyle, Myriam Fornage, Xiuqing GuoSharon L.R. Kardia, Joshua P. Lewis, Ruth J.F. Loos, Xiaolong Ma, Mitchell J. Machiela, Taralynn M. Mack, Rasika A. Mathias, Braxton D. Mitchell, Josyf C. Mychaleckyj, Kari North, Nathan Pankratz, Patricia A. Peyser, Michael H. Preuss, Bruce Psaty, Laura M. Raffield, Ramachandran S. Vasan, Susan Redline, Stephen S. Rich, Jerome I. Rotter, Edwin K. Silverman, Jennifer A. Smith, Aaron P. Smith, Margaret Taub, Kent D. Taylor, Jeong Yun, Yun Li, Pinkal Desai, Alexander G. Bick, Alexander P. Reiner, Paul Scheet, Paul L. Auer

Epidemiology

Research output: Contribution to journal › Article › peer-review

Abstract

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

Original language	English (US)
Pages (from-to)	1912-1919
Number of pages	8
Journal	Nature Genetics
Volume	55
Issue number	11
DOIs	https://doi.org/10.1038/s41588-023-01553-1
State	Published - Nov 2023

ASJC Scopus subject areas

Genetics

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Jakubek Swartzlander, Y., Zhou, Y., Stilp, A., Bacon, J., Wong, J. W., Ozcan, Z., Arnett, D., Barnes, K., Bis, J. C., Boerwinkle, E., Brody, J. A., Carson, A. P., Chasman, D. I., Chen, J., Cho, M., Conomos, M. P., Cox, N., Doyle, M. F., Fornage, M., ... Auer, P. L. (2023). Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. Nature Genetics, 55(11), 1912-1919. https://doi.org/10.1038/s41588-023-01553-1

Jakubek Swartzlander, Y, Zhou, Y, Stilp, A, Bacon, J, Wong, JW, Ozcan, Z, Arnett, D, Barnes, K, Bis, JC, Boerwinkle, E, Brody, JA, Carson, AP, Chasman, DI, Chen, J, Cho, M, Conomos, MP, Cox, N, Doyle, MF, Fornage, M, Guo, X, Kardia, SLR, Lewis, JP, Loos, RJF, Ma, X, Machiela, MJ, Mack, TM, Mathias, RA, Mitchell, BD, Mychaleckyj, JC, North, K, Pankratz, N, Peyser, PA, Preuss, MH, Psaty, B, Raffield, LM, Vasan, RS, Redline, S, Rich, SS, Rotter, JI, Silverman, EK, Smith, JA, Smith, AP, Taub, M, Taylor, KD, Yun, J, Li, Y, Desai, P, Bick, AG, Reiner, AP, Scheet, P & Auer, PL 2023, 'Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing', Nature Genetics, vol. 55, no. 11, pp. 1912-1919. https://doi.org/10.1038/s41588-023-01553-1

@article{c4b47f2dbc084ded998efe8972e47185,

title = "Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing",

abstract = "Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.",

author = "{Jakubek Swartzlander}, Yasminka and Ying Zhou and Adrienne Stilp and Jason Bacon and Wong, {Justin W.} and Zuhal Ozcan and Donna Arnett and Kathleen Barnes and Bis, {Joshua C.} and Eric Boerwinkle and Brody, {Jennifer A.} and Carson, {April P.} and Chasman, {Daniel I.} and Jiawen Chen and Michael Cho and Conomos, {Matthew P.} and Nancy Cox and Doyle, {Margaret F.} and Myriam Fornage and Xiuqing Guo and Kardia, {Sharon L.R.} and Lewis, {Joshua P.} and Loos, {Ruth J.F.} and Xiaolong Ma and Machiela, {Mitchell J.} and Mack, {Taralynn M.} and Mathias, {Rasika A.} and Mitchell, {Braxton D.} and Mychaleckyj, {Josyf C.} and Kari North and Nathan Pankratz and Peyser, {Patricia A.} and Preuss, {Michael H.} and Bruce Psaty and Raffield, {Laura M.} and Vasan, {Ramachandran S.} and Susan Redline and Rich, {Stephen S.} and Rotter, {Jerome I.} and Silverman, {Edwin K.} and Smith, {Jennifer A.} and Smith, {Aaron P.} and Margaret Taub and Taylor, {Kent D.} and Jeong Yun and Yun Li and Pinkal Desai and Bick, {Alexander G.} and Reiner, {Alexander P.} and Paul Scheet and Auer, {Paul L.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

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doi = "10.1038/s41588-023-01553-1",

language = "English (US)",

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T1 - Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing

AU - Jakubek Swartzlander, Yasminka

AU - Zhou, Ying

AU - Stilp, Adrienne

AU - Bacon, Jason

AU - Wong, Justin W.

AU - Ozcan, Zuhal

AU - Arnett, Donna

AU - Barnes, Kathleen

AU - Bis, Joshua C.

AU - Boerwinkle, Eric

AU - Brody, Jennifer A.

AU - Carson, April P.

AU - Chasman, Daniel I.

AU - Chen, Jiawen

AU - Cho, Michael

AU - Conomos, Matthew P.

AU - Cox, Nancy

AU - Doyle, Margaret F.

AU - Fornage, Myriam

AU - Guo, Xiuqing

AU - Kardia, Sharon L.R.

AU - Lewis, Joshua P.

AU - Loos, Ruth J.F.

AU - Ma, Xiaolong

AU - Machiela, Mitchell J.

AU - Mack, Taralynn M.

AU - Mathias, Rasika A.

AU - Mitchell, Braxton D.

AU - Mychaleckyj, Josyf C.

AU - North, Kari

AU - Pankratz, Nathan

AU - Peyser, Patricia A.

AU - Preuss, Michael H.

AU - Psaty, Bruce

AU - Raffield, Laura M.

AU - Vasan, Ramachandran S.

AU - Redline, Susan

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Silverman, Edwin K.

AU - Smith, Jennifer A.

AU - Smith, Aaron P.

AU - Taub, Margaret

AU - Taylor, Kent D.

AU - Yun, Jeong

AU - Li, Yun

AU - Desai, Pinkal

AU - Bick, Alexander G.

AU - Reiner, Alexander P.

AU - Scheet, Paul

AU - Auer, Paul L.

PY - 2023/11

Y1 - 2023/11

N2 - Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

AB - Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

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SP - 1912

EP - 1919

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing

Abstract

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