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

Author:

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

Abstract

AbstractMegabase-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.

Publisher

Springer Science and Business Media LLC

Subject

Genetics

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