New preprint!
10% of women lose one X chromosome in a fraction of leukocytes. What’s the cause/consequence?
We leveraged genetic data from 904,524 women and show germline variants predispose to mLOX and shape the magnitude of clonal expansion.
Hi - I will give a seminar about our recently published Nature paper on “mosaic X chromosome loss” at the PQG working group NEXT TUESDAY!
Welcome to Join the talk and discussion in person!!
⏰Time: 1-2 PM, Tuesday, Oct 22
🏠Location: Biostats Conference Room (2-426), Harvard
Happy to have my work recognized by
@FinnGen_FI
and share the prize with
@mpreeve
!
Together, we are learning more about female genetics!!
🏄♀️🏄♀️🏄♀️
This year, the FinnGen publication prize goes to:
🎉
@mpreeve
for her Am J Hum Genet publication & 🎉
@Aoxing2
for her Nature publication
Warm congratulations!
The prize is awarded thanks to the BioFinland Award granted to FinnGen in 2019 by the Finnish Bioindustries.
T1D and other autoimmune diseases (AIDs) co-occur in families. How parental AIDs impact T1D risk in offspring and how much of the familial risk is explained by HLA and non-HLA variants? 👩🏻🦱🧔🏻♂️👶🏻
Find out more from this thread 🧵 and our new preprint ⬇️!
Thanks
@JaraCarcel
for the kind invitation & organization!! 💡💡💡
Looking forward to talking about sex chromosomes and sex differences with "The Biological Sex Differences in Stroke Working Group" from
@StrokeGenetics
!!
🧬🧬🧬
🚨 Exciting event! The Biological Sex Differences in Stroke Working Group from
@StrokeGenetics
is hosting a talk by Dr. Aoxing Liu (
@Aoxing2
) on her study, "Genetic Drivers and Cellular Selection of Female Mosaic X Chromosome Loss," recently published in
@Nature
. 🧬✨
Kudos to our amazing collaborators!!! Mosaic X loss is such a fantastic and mysterious phenotype! This project would be impossible without your continuous support (💖💯🌟) during the last two years!!!
A preprint detailing our investigation of germline contributors to mosaic loss of the X chromosome (
#mLOX
) in 900K females is online! Check out this 🧵 by
@Aoxing2
summarizing our findings. Kudos to our amazing collaborators!
#NCI_ITEB
@NCIEpiTraining
1/10
Why do women develop mosaic loss of X (mLOX)?
Detectable age-related mLOX develops in females only if the mutant haematopoietic stem cell survives X loss and the loss confers a proliferative advantage, resulting in a mosaic of normal cells and cells with X loss.
4/10
Which X chromosome copy is lost?
We identified 44 independent chromosome X germline variants for which one allele is preferentially lost. Most of these variants were associated with blood cell phenotypes.
3/10
Are genetic drivers of mLOX shared with mosaic loss of the Y chromosome (mLOY) in men?
Only a small fraction of associations were shared between mLOX and mLOY (genetic correlation=0.3), suggesting partially different biological processes.
6/10
What are the clinical consequences of mLOX?
Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Associations with leukemia risk remained when ruling out the effects of other types of clonal hematopoiesis.
5/10
Can we predict which X chromosome is retained in expanded clones?
A differential polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile.
(6) What are clinical consequences of mLOX?
Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Associations with overall leukemia risk remained when ruling out the effects of other types of clonal hematopoiesis.
2/10
What role do germline mutations play?
Studying 880K women of European or East Asian ancestry, we identified 56 common variants and FBXO10 missense variants influencing mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition, and autoimmunity.
(3) Are genetic drivers of mLOX shared with mosaic loss of the Y chromosome (mLOY) in men?
Only a small fraction of associations were shared between mLOX and mLOY (rg=0.30), suggesting different biological processes. Interestingly, some HLA signals showed inverse associations.
2/5
University of Oxford press release:
FIMM’s news story:
Leverhulme Centre for Demographic Science news:
The BBC interview ratio (listen from 16:55):
3/5
It's a four year journey:
We started by applying about 20 registers from different 🇫🇮 & 🇸🇪 data agencies, went through endless data QC, tried our best to fully use large sample size!
We also learned how sensitive this topic is with 58 pages of peer-reviewed information! 🧐
Is the genetic of disease susceptibility and progression shared?
We look at this question within a global biobank collaboration across 10 major diseases 💁
(5) Can we predict which X chromosome is retained in expanded clones?
A differential polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile.
(1) Why do women develop mLOX?
Detectable age-related mosaic loss of X (mLOX) develops in females only if the mutant haematopoietic stem cell (HSC) survives mLOX and the mutation confers a proliferative advantage, resulting in a mosaic of normal cells and cells with X loss.
(4) Which X chromosome copy is lost?
We identified 44 independent chromosome X germline variants for which one allele is preferentially lost. Most of these variants were associated with blood cell phenotypes.
(2) What role do germline mutations play?
Studying 900K women of European or East Asian ancestry, we identified 49 common variants and FBXO10 missense variants influencing mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition, and autoimmunity.
@MartinKolk
@andganna
@melindacmills
Hello, Martin, thanks for your interest in our work. We estimated N of children unborn related to disease diagnoses in the observational period by combining relative risk (converted from OR), disease prevalence, and parity. Please see table S8-9 in appendix p30-33.
@ShihchengGuo
Hello,
@ShihchengGuo
, great question!!
As commented by
@SafiaDanovi
in the Nature Genetics Research Highlights () - "This study provides an important stepping stone for future investigations of mLOX and its role in female health and disease."
In other