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@ARTICLE{Liu:295920,
author = {A. Liu and G. Genovese and Y. Zhao and M. Pirinen and S. M.
Zekavat and K. A. Kentistou and Z. Yang and K. Yu and C.
Vlasschaert and X. Liu and D. W. Brown and G. Hudjashov and
B. R. Gorman and J. Dennis and W. Zhou and Y. Momozawa and
S. Pyarajan and V. Tuzov and F.-D. Pajuste and M. Aavikko
and T. P. Sipilä and A. Ghazal and W.-Y. Huang and N. D.
Freedman and L. Song and E. J. Gardner and V. G. Sankaran
and A. Palotie and H. M. Ollila and T. Tukiainen and S. J.
Chanock and R. Mägi and P. Natarajan and M. J. Daly and A.
Bick and S. A. McCarroll and C. Terao and P.-R. Loh and A.
Ganna and J. R. B. Perry and M. J. Machiela},
collaboration = {FinnGen and E. B. R. Team and B. C. A. Consortium and M. V.
Program},
othercontributors = {A. Metspalu and T. Esko and M. Nelis and L. Milani and T.
U. Ahearn and I. L. Andrulis and H. Anton-Culver and A. C.
Antoniou and A. B. de Gonzalez and N. V. Bogdanova and S. E.
Bojesen and M. K. Bolla and H. Brenner$^*$ and J.
Chang-Claude$^*$ and G. Chenevix-Trench and S. V. Colonna
and F. J. Couch and A. Cox and K. Czene and M. B. Daly and
P. Devilee and T. Dörk and A. M. Dunning and M. Dwek and D.
F. Easton and D. M. Eccles and P. A. Fasching and O.
Fletcher and M. Gago-Dominguez and M. García-Closas and M.
S. Goldberg and A. González-Neira and P. Guénel and C. A.
Haiman and P. Hall and U. Hamann$^*$ and A. Hollestelle and
R. Hoppe and J. L. Hopper and A. Jakubowska and H.
Jernström and E. M. John and R. Kaaks$^*$ and E. K.
Khusnutdinova and C. M. Kitahara and P. Kraft and V. N.
Kristensen and D. Lambrechts and A. Lindblom and A.
Mannermaa and U. Menon and K. Michailidou and R. A. Murphy
and H. Nevanlinna and N. Obi and K. Offit and P. Peterlongo
and P. D. P. Pharoah and D. Plaseska-Karanfilska and G.
Rennert and A. Romero and E. Saloustros and M. K. Schmidt
and R. K. Schmutzler and J. Stone and R. M. Tamimi and L. R.
Teras and M. B. Terry and M. A. Troester and C. M. Vachon
and Q. Wang and C. R. Weinberg and R. Winqvist and A. Wolk},
title = {{G}enetic drivers and cellular selection of female mosaic
{X} chromosome loss.},
journal = {Nature},
volume = {631},
number = {8019},
issn = {0028-0836},
address = {London [u.a.]},
publisher = {Nature Publ. Group},
reportid = {DKFZ-2024-02733},
pages = {134 - 141},
year = {2024},
abstract = {Mosaic loss of the X chromosome (mLOX) is the most common
clonal somatic alteration in leukocytes of female
individuals1,2, but little is known about its genetic
determinants or phenotypic consequences. Here, to address
this, we used data from 883,574 female participants across 8
biobanks; $12\%$ of participants exhibited detectable mLOX
in approximately $2\%$ of leukocytes. Female participants
with mLOX had an increased risk of myeloid and lymphoid
leukaemias. Genetic analyses identified 56 common variants
associated with mLOX, implicating genes with roles in
chromosomal missegregation, cancer predisposition and
autoimmune diseases. Exome-sequence analyses identified rare
missense variants in FBXO10 that confer a twofold increased
risk of mLOX. Only a small fraction of associations was
shared with mosaic Y chromosome loss, suggesting that
distinct biological processes drive formation and clonal
expansion of sex chromosome missegregation. Allelic shift
analyses identified X chromosome alleles that are
preferentially retained in mLOX, demonstrating variation at
many loci under cellular selection. A polygenic score
including 44 allelic shift loci correctly inferred the
retained X chromosomes in $80.7\%$ of mLOX cases in the top
decile. Our results support a model in which germline
variants predispose female individuals to acquiring mLOX,
with the allelic content of the X chromosome possibly
shaping the magnitude of clonal expansion.},
keywords = {Adult / Female / Humans / Male / Middle Aged / Alleles /
Aneuploidy / Autoimmune Diseases: genetics / Biological
Specimen Banks / Chromosome Segregation: genetics /
Chromosomes, Human, X: genetics / Chromosomes, Human, Y:
genetics / Clone Cells: metabolism / Clone Cells: pathology
/ Exome: genetics / F-Box Proteins: genetics / Genetic
Predisposition to Disease: genetics / Germ-Line Mutation /
Leukemia: genetics / Leukocytes: metabolism / Models,
Genetic / Mosaicism / Multifactorial Inheritance: genetics /
Mutation, Missense: genetics / F-Box Proteins (NLM
Chemicals) / FBXO10 protein, human (NLM Chemicals)},
cin = {C070 / C120 / HD01 / C020 / B072},
ddc = {500},
cid = {I:(DE-He78)C070-20160331 / I:(DE-He78)C120-20160331 /
I:(DE-He78)HD01-20160331 / I:(DE-He78)C020-20160331 /
I:(DE-He78)B072-20160331},
pnm = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
pid = {G:(DE-HGF)POF4-313},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38867047},
doi = {10.1038/s41586-024-07533-7},
url = {https://inrepo02.dkfz.de/record/295920},
}