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epigenetic_age.Rmd
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epigenetic_age.Rmd
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---
title: Accelerated epigenetic aging in newborns with Down syndrome
author:
- name: Keren Xu
affil: 1
- name: Shaobo Li
affil: 1
- name: Ivo S. Muskens
affil: 1
- name: Natalina Elliott
affil: 2
- name: Swe Swe Myint
affil: 1
- name: Priyatama Pandey
affil: 1
- name: Xiaomei Ma
affil: 3
- name: Catherine Metayer
affil: 4
- name: Beth A. Mueller
affil: 5
- name: Kyle M. Walsh
affil: 6
- name: Irene Roberts
affil: 2
- name: Steve Horvath
affil: 7
- name: Joseph L. Wiemels
affil: 1
- name: Adam J. de Smith
affil: 1
affiliation:
- num: 1
address: Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
- num: 2
address: Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University and BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, UK
- num: 3
address: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
- num: 4
address: School of Public Health, University of California, Berkeley, Berkeley, CA, USA
- num: 5
address: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- num: 6
address: Department of Neurosurgery, Duke University, Durham, NC, USA
- num: 7
address: Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA
main_findings:
- "**Down syndrome** is associated with **increased DNAmAge** in **newborns**, with an age acceleration of 237 days."
- '{.main_pic width=100%}'
logoright_name: '{.main-img-right width=28%}'
output:
posterdown::posterdown_betterland:
self_contained: false
pandoc_args: --mathjax
highlight: haddock
number_sections: false
bibliography: reference.bib
poster_height: "32in"
poster_width: "56.88in"
title_textsize: "100pt"
authorextra_textsize: "35pt"
affiliation_textsize: "25pt"
sectitle_textsize: "60pt"
sectitle2_textsize: "40pt"
primary_colour: '#990000'
accent_colour: "#000000"
secondary_colour: "#990000"
body_bgcol: "#ffffff"
body_textsize: "48px"
body_textcol: "#000000"
main_fontfamily: "Rasa"
affiliation_textcol: "#000000"
main_width: 0.45
column_padding: "10mm"
main_textsize: "175px"
caption_textzie: "80pt"
reference_textsize: "32px"
csl: blood.csl
---
```{css, echo = F}
tbody tr:nth-child(odd){
background-color: #FFFFFF;
}
tbody tr:nth-of-type(4n+1) td {
background: #eacccc;
}
tfoot {
font-size: 80%;
}
```
```{r, include=FALSE}
knitr::opts_chunk$set(results = 'asis',
echo = FALSE,
warning = FALSE,
tidy = FALSE,
message = FALSE,
fig.align = 'center',
out.width = "100%")
options(knitr.table.format = "html")
```
# Introduction
Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer’s disease and premature aging of skin, hair, and immune and endocrine systems. Accelerated epigenetic aging was found in blood and brain tissue of adults with DS [@horvathAcceleratedEpigeneticAging2015], but when this premature aging begins is unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth.
# Methods
- Dried bloodspots were obtained from 347 newborns with DS and 567 newborns without DS from California or Washington. DNA was isolated, bisulfite-converted, and assayed on Illumina MethylationEPIC DNA methylation (DNAm) arrays [@muskensGenomewideImpactTrisomy2021].
- We calculated epigenetic age (DNAmAge) using a published epigenetic clock (391 CpGs) [@horvathEpigeneticClockSkin2018] and performed reference-based deconvolution of blood cell proportions using the "Identifying Optimal Libraries" algorithm [@koestlerImprovingCellMixture2016].
- *GATA1* was sequenced in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis.
- We compared DNAmAge between DS and non-DS newborns using linear regression adjusting for chronological age from conception (gestational age plus age at blood sampling), sex, batch, blood cell proportions, and genetic ancestry using EPISTRUCTURE [@rahmaniGenomewideMethylationData2017]. Age acceleration was calculated as the deviation from expected DNAmAge based on its linear association with chronological age in non-DS newborns. We repeated analyses excluding 61 newborns (60 DS) exceeding mean+1SD for nucleated red blood cell (nRBC) proportions and 30 *GATA1*-positive DS newborns to address potential confounding. We tested for association between *GATA1* mutation variant allele frequency (VAF) and DNAmAge in DS newborns.
# Results
- Mean chronological age from conception was 269 days in DS and 276 in non-DS newborns. Chronological age was significantly positively correlated with DNAmAge in both DS and non-DS newborns (**Figure**).
- Blood cell proportions were significantly associated with DS status and DNAmAge, including strong correlation between nRBCs and DNAmAge (r=0.29, p=$5.8*10^{-19}$).
- Adjusting for cell proportions, DS was significantly associated with increased DNAmAge (beta=0.2419, p=$6.42*10^{-22}$), with an age acceleration of 237 days (**Table**). This association remained after excluding high nRBC newborns and *GATA1*-positive DS newborns (beta=0.1285, p=$3.18*10^{-11}$, age acceleration=127 days).
- Among newborns with DS, *GATA1* mutations were associated with increased DNAmAge (p=$6.65*10^{-12}$), with age acceleration of 115 days per 10% increase in VAF.
```{r, regressiontable}
library(tidyverse)
library(kableExtra)
dt <- data.table::fread("tb.csv")
dt <- dt %>% mutate(p=ifelse(is.na(p), "", p), obs = ifelse(is.na(obs), "", obs))
kbl(dt, align = "l", booktabs = T, linesep = "") %>%
kable_styling(full_width = T, position = "center",font_size = 120) %>%
footnote(general = "Model 1 adjusted for sex, 9 EPISTRUCTURE PCs, and batch; Model 2 additionally adjusted for blood cell proportions; Model 3 is model 2 excluding high nRBC subjects and subjects with *GATA1* mutation. "
) %>% add_header_above(c("Table. Linear regression comparing DNAmAge between DS and non-DS newborns." = 4), bold = T, font_size = 44) %>%
row_spec(c(8,12), font_size = 60, color = "#990000", bold = T) %>% kable_paper(html_font = "Rasa")
```
# Conclusion
Our results support that accelerated aging in blood in DS begins prenatally, with implications for the pathophysiology of immunosenescence and other aging-related traits in DS.
# References
<style>
.table>tbody>tr>td{
padding: 1px;
}
</style>