Nature Genetics international large-scale research has revealed dozens of new genes linked to heart disease

Over the past 15 years, scientists have found that more than 200 sites in the human genome are associated with the risk of coronary artery disease, which is the leading cause
of death worldwide.
Still, researchers don't yet fully understand how these genomic variants alter the function of proteins, cells, or tissues to cause disease — knowledge that could inform the development of new therapies
.

In a large-scale study, scientists from the International CARDIoGRAMplusC4D Alliance compiled and analyzed DNA data from more than 1 million people, including more than 200,000 people with
coronary artery disease.
The researchers identified 68 new genomic regions, or sites, associated with an increased risk of CAD, bringing the total to more than 250
.
They also developed a comprehensive method that combined eight different lines of evidence and used it to systematically identify 220 potential causal genes that underlie
relevant loci.
They validated the role of one of these putative disease-causing genes through genome editing and cell-based experiments, demonstrating the power
of their approach in revealing how specific genes are involved in CAD development.

Dr.
Brooke Wolford, a postdoctoral researcher in the Department of Computational Medicine and Bioinformatics at the University of Michigan School of Medicine, said, "This project is an example of team science, with six equally contributing first authors, representing multiple cohorts and broad analytical expertise
.
"

The work, published in Nature Genetics, provides a more complete picture of the genetic roots of CAD, outlines a list of genes and genetic variants for future research, and presents an analytical framework for identifying causal genes that can be used to enhance research
on other diseases involving genome-wide association studies (GWAS).
The researchers openly shared their findings on the Cardiovascular Disease Knowledge Portal, a joint development
by scientists at MIT's Broad Institute and Harvard University.

With the emergence of large biobanks and cohorts over the past few years, the research community has been able to mine larger and larger datasets
of genetic associations of diseases.
In the current study, the researchers hope to expand the search for genetic links to heart disease and show that their approach can reveal the functional implications
of disease-associated locus.
In the new study, the combined scientists collected genetic and medical data on 1 million people of European ancestry from the UK Biobank, the CARDIoGRAMplusC4D Consortium, prospective cohorts, hospital biobanks and clinical trials, including nearly 200,000 people with
coronary artery disease.
They performed a GWAS meta-analysis of the entire dataset, scanning each person's genome for DNA sites to identify genetic variants
that are more likely to be found in people with the disease.
They found 241 sites associated with CAD risk in the genome, including 30 sites
that had never been associated with CAD.
Most of the new genomic loci were associated with very small changes in CAD risk, suggesting that few, if any, common genetic variants that had a significant impact on CAD risk by studying people of predominantly European ancestry were yet to be discovered, and to improve their discovery power, the researchers combined their large dataset with data from tens of thousands of individuals of East Asian descent from the Japan Biobank, including 29,000 CAD patients
.
The joint analysis revealed an additional 38 genomic loci
associated with CAD risk.

The team wanted to go one step further and not only find these GWAS "hits," but also link them to nearby genes that cause CAD, when they are destroyed
.
There are multiple ways to determine which gene near GWAS may play a causal role in the disease, so the researchers decided to pioneer an innovative, systematic approach that combined evidence from 8 of them
.
Some of these methods look for the closest or potentially most damaging variation, while others look for genes
known to be altered in patients.
The researchers applied their framework to all 279 CAD-associated genomic loci to systematically search for disease-causing genes
in a consistent manner.
Those genes that are prioritized by 3 or more of the 8 measurement methods are considered highly likely causal genes
for GWAS hits.
The team confirmed one of the disease-causing genes, MYO9B, through genome editing and cell-based experiments, and he found that it appeared to regulate the risk of
coronary heart disease by regulating vascular cell movement.

To explore the potential clinical application of their findings, the researchers generated a new polygenic risk score that incorporates more than 2 million variants in the genome and predicts the risk of
sporadic and recurrent CAD.
The score is based on personal data approximately three times the CAD risk score
.
While the team's score better predicts an individual's risk of developing new-onset and recurrent CAD, this improvement is surprisingly limited
given the large increase in GWAS sample size.
This suggests that more ancestral diversity and advances in polygenic scoring methods may be more likely to lead to substantial improvements
in polygenic risk score performance compared to increasing single-ancestor GWAS.
The team hopes that other researchers will use their findings to further explore the effects of
possible disease-causing genes on function.

Adam Butterworth, co-senior author of the study and professor of molecular epidemiology at the University of Cambridge, said: "We have demonstrated that a systematic, disease-specific approach can effectively pinpoint the true genetic roots of disease and provide clearer insights into disease mechanisms, which is essential to translate statistical insights into biological significance and ultimately find innovative therapies
to treat dangerous diseases such as coronary artery disease.
" Future GWAS are more inclusive of populations of different ancestry than those confined to participants of European ancestry and may yield more insights
.
”

Krishna Aragam, a cardiologist at Massachusetts General Hospital and co-first author of the study and a scientist at the Broad Institute's Cardiovascular Disease Initiative, said: "The current era of discovery in genetics is not just about discovery, but also about asking about the connection
between each discovered genetic locus and related diseases 。 This collaborative effort represents a significant advance in the field of coronary artery disease genetics, and we hope that our approach will encourage groups working on GWAS studies of other traits and diseases to systematically interrogate genetic loci with several orthogonal lines of evidence, and provide a wide range of resources for others to inquire about
.
" Such research does not end with the publication of the list of genes – on the contrary, they pave the way
for new mechanistic studies.
”