Lightnews — Scholar-powered news

Rosa Ma @rosaxma.bsky.social · Nov 25

@sdconley.bsky.social,
@gtca.bsky.social, @mayayayas.bsky.social, @613weilin.bsky.social, @soumyakundu.bsky.social, @laurenduan.bsky.social, @randersson.bsky.social, @jamesrpriestmd.bsky.social, @axelvisel.bsky.social, @anshulkundaje.bsky.social, @caseygifford.bsky.social, @jamespirruccello.com

1 4

Rosa Ma @rosaxma.bsky.social · Nov 25

This work is the result of a major collaboration across many labs and institutions. A huge thanks to all authors, especially my advisor, @jengreitz.bsky.social.

1 3

Rosa Ma @rosaxma.bsky.social · Nov 25

We believe this will be a transformative resource for understanding cardiac development, interpreting genetic variants associated with heart disease, and discovering targets for cell-type specific therapies.

1 2

Rosa Ma @rosaxma.bsky.social · Nov 25

We are excited to share this regulatory map of the human fetal heart with the community (data available here: https://www.synapse.org/Synapse:syn63997960).

1 4

Rosa Ma @rosaxma.bsky.social · Nov 25

Together, our results implicate new enhancers, genes, and cell types in the genetic etiology of CHD and suggest a more expansive view of the cell types instrumental in genetic risk for CHD, beyond the working cardiomyocyte.

1 3

Rosa Ma @rosaxma.bsky.social · Nov 25

Here, we illustrated a regulatory pathway connecting common and rare variants associated with heart valve development. This provides a model in which common genetic variation tunes the severity or form of CHD, potentially explaining the varying severities of heart defects in CHD patients carrying th

1 4

Rosa Ma @rosaxma.bsky.social · Nov 25

3. Intriguingly, both rare variants associated with CHD and common variants associated with quantitative valve traits and acquired valve diseases converged on similar genes and pathways in VICs, suggesting a possible polygenic contribution to CHD.

1 1 4

Rosa Ma @rosaxma.bsky.social · Nov 25

For example, we found enhancers with spatially specific activity in either the outflow tract or interventricular septum. This suggests a means by which noncoding genetic variants can affect specific aspects of heart structure.

1 3

Rosa Ma @rosaxma.bsky.social · Nov 25

We identified candidate noncoding variants, target genes, and cell types for >700 GWAS signals associated with 45 cardiac diseases and traits. Many of these variants overlap enhancers accessible only in specific cell types.

1 1 5

Rosa Ma @rosaxma.bsky.social · Nov 25

2. Certain noncoding variants impact enhancers with activities highly specific to particular subanatomic structures in the heart, illuminating how such variants can impact specific aspects of heart structure and function.

1 4

Rosa Ma @rosaxma.bsky.social · Nov 25

VICs and cardiac fibroblasts were strongly implicated in multiple CHD subtypes. This suggests that heart defects may arise from issues beyond the working myocardium, motivating the development of appropriate cell and animal models to study the contributions of these cell types to CHD.

1 5

Rosa Ma @rosaxma.bsky.social · Nov 25

1. Unexpectedly, genes carrying rare coding variants associated with CHD were most strongly enriched in valvular interstitial cells (VICs) and cardiac fibroblasts.

1 5

Rosa Ma @rosaxma.bsky.social · Nov 25

By applying these gene regulation maps of 90 cardiac cell types to interpret the functions of coding and noncoding variants associated with CHD, we uncovered the following new principles for how genetic variants affect heart development and disease:

1 4

Rosa Ma @rosaxma.bsky.social · Nov 25

Next, we created the most comprehensive gene regulation map of healthy heart development to date! The unprecedented depth of our dataset allowed us to apply state-of-the-art computational models (scE2G, BPNet) to infer relationships between variants, genes and regulatory elements.

1 4

Rosa Ma @rosaxma.bsky.social · Nov 25

First, we collected single-cell multiomic data from 734K single cells from 41 fetal hearts spanning post-conception weeks 6 to 22 and annotated them to over 90 different cell types and cell states, including rare and clinically relevant ones like cardiac conduction cells.

1 1 3

Rosa Ma @rosaxma.bsky.social · Nov 25

What cell types drive congenital heart defects (CHD)?

Some new answers in our latest preprint, where we explored:
1). Key cell types contributing to CHD genetics
2). Impact of noncoding variants on CHD risk

https://www.medrxiv.org/content/10.1101/2024.11.20.24317557v1

1 20 59

Rosa Ma @rosaxma.bsky.social · Nov 25

We are excited to share this regulatory map of the human fetal heart with the community (data available here: https://www.synapse.org/Synapse:syn63997960). We believe this will be a transformative resource for understanding cardiac development, interpreting genetic variants associated with heart dis

Rosa Ma @rosaxma.bsky.social · Nov 25

Together, our results implicate new enhancers, genes, and cell types in the genetic etiology of CHD and suggest a more expansive view of the cell types instrumental in genetic risk for CHD, beyond the working cardiomyocyte.

1

Rosa Ma @rosaxma.bsky.social · Nov 25

Here, we illustrated a regulatory pathway connecting common and rare variants associated with heart valve development. This provides a model in which common genetic variation tunes the severity or form of CHD, potentially explaining the varying severities of heart defects in CHD patients carrying th

1

Rosa Ma @rosaxma.bsky.social · Nov 25

3. Intriguingly, both rare variants associated with CHD and common variants associated with quantitative valve traits and acquired valve diseases converged on similar genes and pathways in VICs, suggesting a possible polygenic contribution to CHD.

1

Rosa Ma @rosaxma.bsky.social · Nov 25

For example, we found enhancers with spatially specific activity in either the outflow tract or interventricular septum. This suggests a means by which noncoding genetic variants can affect specific aspects of heart structure.

1

Rosa Ma @rosaxma.bsky.social · Nov 25

We identified candidate noncoding variants, target genes, and cell types for >700 GWAS signals associated with 45 cardiac diseases and traits. Many of these variants overlap enhancers accessible only in specific cell types.

1

Rosa Ma @rosaxma.bsky.social · Nov 25

2. Certain noncoding variants impact enhancers with activities highly specific to particular subanatomic structures in the heart, illuminating how such variants can impact specific aspects of heart structure and function.

1

Rosa Ma @rosaxma.bsky.social · Nov 25

VICs and cardiac fibroblasts were strongly implicated in multiple CHD subtypes. This suggests that heart defects may arise from issues beyond the working myocardium, motivating the development of appropriate cell and animal models to study the contributions of these cell types to CHD.

1

Rosa Ma @rosaxma.bsky.social · Nov 25

1. Unexpectedly, genes carrying rare coding variants associated with CHD were most strongly enriched in valvular interstitial cells (VICs) and cardiac fibroblasts.

1