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<h1 id="title">Accelerated epigenetic aging in newborns with Down syndrome</h1>
<br>
<h3 id="author" class="author">
</h3>
<h5 id="author_extra" class="author_extra">
Keren Xu<sup>1</sup>
Shaobo Li<sup>1</sup>
Ivo S. Muskens<sup>1</sup>
Natalina Elliott<sup>2</sup>
Swe Swe Myint<sup>1</sup>
Priyatama Pandey<sup>1</sup>
Xiaomei Ma<sup>3</sup>
Catherine Metayer<sup>4</sup>
Beth A. Mueller<sup>5</sup>
Kyle M. Walsh<sup>6</sup>
Irene Roberts<sup>2</sup>
Steve Horvath<sup>7</sup>
Joseph L. Wiemels<sup>1</sup>
Adam J. de Smith<sup>1</sup>
</h5>
<p id="affiliation" class="affiliation">
<sup>1</sup> 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<br> <sup>2</sup> 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<br> <sup>3</sup> Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA<br> <sup>4</sup> School of Public Health, University of California, Berkeley, Berkeley, CA, USA<br> <sup>5</sup> Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA<br> <sup>6</sup> Department of Neurosurgery, Duke University, Durham, NC, USA<br> <sup>7</sup> Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA
</p>
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<div id="introduction" class="section level1">
<h1>Introduction</h1>
<p>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,<span class="citation"><sup>1</sup></span> but when this premature aging begins is unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth.</p>
</div>
<div id="methods" class="section level1">
<h1>Methods</h1>
<ul>
<li>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.<span class="citation"><sup>2</sup></span><br />
</li>
<li>We calculated epigenetic age (DNAmAge) using a published epigenetic clock (391 CpGs)<span class="citation"><sup>3</sup></span> and performed reference-based deconvolution of blood cell proportions using the “Identifying Optimal Libraries” algorithm.<span class="citation"><sup>4</sup></span><br />
</li>
<li><em>GATA1</em> was sequenced in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis.<br />
</li>
<li>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.<span class="citation"><sup>5</sup></span> 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 <em>GATA1</em>-positive DS newborns to address potential confounding. We tested for association between <em>GATA1</em> mutation variant allele frequency (VAF) and DNAmAge in DS newborns.</li>
</ul>
</div>
<div id="results" class="section level1">
<h1>Results</h1>
<ul>
<li>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 (<strong>Figure</strong>).<br />
</li>
<li>Blood cell proportions were significantly associated with DS status and DNAmAge, including strong correlation between nRBCs and DNAmAge (r=0.29, p=<span class="math inline">\(5.8*10^{-19}\)</span>).<br />
</li>
<li>Adjusting for cell proportions, DS was significantly associated with increased DNAmAge (beta=0.2419, p=<span class="math inline">\(6.42*10^{-22}\)</span>), with an age acceleration of 237 days (<strong>Table</strong>). This association remained after excluding high nRBC newborns and <em>GATA1</em>-positive DS newborns (beta=0.1285, p=<span class="math inline">\(3.18*10^{-11}\)</span>, age acceleration=127 days).<br />
</li>
<li>Among newborns with DS, <em>GATA1</em> mutations were associated with increased DNAmAge (p=<span class="math inline">\(6.65*10^{-12}\)</span>), with age acceleration of 115 days per 10% increase in VAF.</li>
</ul>
<table class="table lightable-paper" style="font-size: 120px; margin-left: auto; margin-right: auto;border-bottom: 0; font-family: Rasa; margin-left: auto; margin-right: auto;">
<thead>
<tr>
<th style="border-bottom:hidden;padding-bottom:0; padding-left:3px;padding-right:3px;text-align: center; font-weight: bold; font-size: 44px;" colspan="4">
<div style="border-bottom: 1px solid #ddd; padding-bottom: 5px; ">
Table. Linear regression comparing DNAmAge between DS and non-DS newborns.
</div>
</th>
</tr>
<tr>
<th style="text-align:left;">
term
</th>
<th style="text-align:left;">
estimate (95% CI)
</th>
<th style="text-align:left;">
p
</th>
<th style="text-align:left;">
obs
</th>
</tr>
</thead>
<tbody>
<tr>
<td style="text-align:left;">
Model 1
</td>
<td style="text-align:left;">
</td>
<td style="text-align:left;">
</td>
<td style="text-align:left;">
</td>
</tr>
<tr>
<td style="text-align:left;">
DS
</td>
<td style="text-align:left;">
0.3502 (0.3126,0.3878)
</td>
<td style="text-align:left;">
8.3e-63
</td>
<td style="text-align:left;">
835
</td>
</tr>
<tr>
<td style="text-align:left;">
Chronological age
</td>
<td style="text-align:left;">
0.0003 (-0.0006,0.0011)
</td>
<td style="text-align:left;">
0.527
</td>
<td style="text-align:left;">
835
</td>
</tr>
<tr>
<td style="text-align:left;">
Age accel. for DS
</td>
<td style="text-align:left;">
355.23 days
</td>
<td style="text-align:left;">
</td>
<td style="text-align:left;">
</td>
</tr>
<tr>
<td style="text-align:left;">
Model 2
</td>
<td style="text-align:left;">
</td>
<td style="text-align:left;">
</td>
<td style="text-align:left;">
</td>
</tr>
<tr>
<td style="text-align:left;">
DS
</td>
<td style="text-align:left;">
0.2419 (0.1940,0.2898)
</td>
<td style="text-align:left;">
6.42e-22
</td>
<td style="text-align:left;">
835
</td>
</tr>
<tr>
<td style="text-align:left;">
Chronological age
</td>
<td style="text-align:left;">
0.0008 (0.0001,0.0015)
</td>
<td style="text-align:left;">
0.0224
</td>
<td style="text-align:left;">
835
</td>
</tr>
<tr>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
Age accel. for DS
</td>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
236.89 days
</td>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
</td>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
</td>
</tr>
<tr>
<td style="text-align:left;">
Model 3
</td>
<td style="text-align:left;">
</td>
<td style="text-align:left;">
</td>
<td style="text-align:left;">
</td>
</tr>
<tr>
<td style="text-align:left;">
DS
</td>
<td style="text-align:left;">
0.1285 (0.0911,0.1658)
</td>
<td style="text-align:left;">
3.18e-11
</td>
<td style="text-align:left;">
768
</td>
</tr>
<tr>
<td style="text-align:left;">
Chronological age
</td>
<td style="text-align:left;">
0.0005 (0.0001,0.0009)
</td>
<td style="text-align:left;">
0.0238
</td>
<td style="text-align:left;">
768
</td>
</tr>
<tr>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
Age accel. for DS
</td>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
126.50 days
</td>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
</td>
<td style="text-align:left;font-weight: bold;color: #990000 !important;font-size: 60px;">
</td>
</tr>
</tbody>
<tfoot>
<tr>
<td style="padding: 0; " colspan="100%">
<span style="font-style: italic;">Note: </span>
</td>
</tr>
<tr>
<td style="padding: 0; " colspan="100%">
<sup></sup> 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 <em>GATA1</em> mutation.
</td>
</tr>
</tfoot>
</table>
</div>
<div id="conclusion" class="section level1">
<h1>Conclusion</h1>
<p>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.</p>
</div>
<div id="references" class="section level1">
<h1>References</h1>
<style>
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<div id="refs" class="references csl-bib-body">
<div id="ref-horvathAcceleratedEpigeneticAging2015" class="csl-entry">
<div class="csl-left-margin">1. </div><div class="csl-right-inline">Horvath S, Garagnani P, Bacalini MG, et al. Accelerated epigenetic aging in <span>Down</span> syndrome. <em>Aging Cell</em>. 2015;14(3):491–495. </div>
</div>
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<p><strong>Down syndrome</strong> is associated with <strong>increased DNAmAge</strong> in <strong>newborns</strong>, with an age acceleration of 237 days.<br><br> <img src="https://raw.githubusercontent.com/XUKEREN/ashg_EpigeneticClock/main/Figures/figure1.png" class="main_pic" style="width:100.0%" /></p>
<img src="https://raw.githubusercontent.com/XUKEREN/ashg_EpigeneticClock/main/Figures/KSOM_DeptofPopPublicHS_1lineWhtGold.png" class="main-img-right" style="width:28.0%" />
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