Researchers use multi-ancestry comparison to refine risk factors for
coronary artery disease

Date:
October 6, 2020
Source:
RIKEN
Summary:
Researchers have used a combination of genome-wide association
analysis - - or GWAS -- and a trans-ancestry comparison of different
GWAS studies, to come up with a more accurate predictor of coronary
artery disease based on genetic factors.



FULL STORY ==========================================================================
An international group led by researchers from the RIKEN Center for
Integrative Medical Sciences have used a combination of genome-wide
association analysis - - or GWAS -- and a trans-ancestry comparison of different GWAS studies, to come up with a more accurate predictor of
coronary artery disease based on genetic factors.


==========================================================================
It is known that coronary artery disease -- the world's leading cause
of death -- is highly heritable, and in some cases, most notably the
PCSK9 gene, the knowledge of genetic associations has contributed to the development of therapies. Genetic Risk Scores based on genetic information
can accurately predict the onset of disease in individuals. However,
studies so far have focused primarily on European populations, and it
is not clear whether the results apply to other ancestry populations.

In the present study, published in Nature Genetics, the team performed two important tasks. First, they looked at the genetics of the disease in a Japanese population, by comparing the genome sequences of 25,892 coronary artery disease patients in the Biobank Japan and 142,336 controls,
constituting the largest GWAS project on coronary artery disease in
a non-European population. Using a reference panel they developed to
estimate the genotypes of the individuals, they identified 48 genetic
loci associated with a susceptibility to coronary artery disease,
eight of which were previously unknown. In particular, they found one
genetic variant in the RNF213 gene, which is known to be associated with
a cerebrovascular disease known as moyamoya disease, which had never
been identified in GWAS studies with European cohorts.

Thanks to these results, they were able to build a reference panel for
the Japanese population, which could be used to gauge the risk of even
variants found in a very small percentage of the population. "We found
one variant in the LDLR gene," says Kaoru Ito, one of the authors of
the study, "which is not very common, but it has an important effect on cholesterol metabolism, and Japanese people with this rare mutation raises
the likelihood of developing coronary artery disease five-fold." The
group also discovered mutations specific to the Japanese population that
can reduce the livelihood of coronary artery disease. The group's next
step was to combine the results of the 170,000 Japanese subjects with two
other datasets from European populations (approximately 180,000 from the CARDIoGRAMplusC4D study and 300,000 from the UK Biobank, to create one
of the world's largest trans-ethnic GWAS in coronary artery disease with
a total of more than 600,000 individuals. Doing this, they identified 35
new loci associated with disease, and one of them was in the HMGCR gene,
which is the target of statin drugs.

A very positive result of the study was that the group was able to use
the combined GWAs to create a genetic risk score that outperformed the
results of GSCs crafted either According to Ito, "This is exciting,
as it means that even when there are different frequency of variants
in different populations, we can combine GWAS studies from different
ancestries and use this to create a risk score that is more accurate than
any of the individual ones, and this means that integrating existing
data is a good way to develop GRSs in non-European populations." He
continues, "We hope that our study will help lead to the development of
GRSs optimized for Japanese people, which could be used effectively in
the future of precision medicine based on genetic information."

========================================================================== Story Source: Materials provided by RIKEN. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Satoshi Koyama, Kaoru Ito, Chikashi Terao, Masato Akiyama, Momoko
Horikoshi, Yukihide Momozawa, Hiroshi Matsunaga, Hirotaka Ieki,
Kouichi Ozaki, Yoshihiro Onouchi, Atsushi Takahashi, Seitaro Nomura,
Hiroyuki Morita, Hiroshi Akazawa, Changhoon Kim, Jeong-sun Seo,
Koichiro Higasa, Motoki Iwasaki, Taiki Yamaji, Norie Sawada,
Shoichiro Tsugane, Teruhide Koyama, Hiroaki Ikezaki, Naoyuki
Takashima, Keitaro Tanaka, Kokichi Arisawa, Kiyonori Kuriki,
Mariko Naito, Kenji Wakai, Shinichiro Suna, Yasuhiko Sakata,
Hiroshi Sato, Masatsugu Hori, Yasushi Sakata, Koichi Matsuda,
Yoshinori Murakami, Hiroyuki Aburatani, Michiaki Kubo, Fumihiko
Matsuda, Yoichiro Kamatani, Issei Komuro. Population-specific and
trans- ancestry genome-wide analyses identify distinct and shared
genetic risk loci for coronary artery disease. Nature Genetics,
2020; DOI: 10.1038/ s41588-020-0705-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201006094543.htm

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