Mar 29, 2019 The Japanese twist on gene variants

A five-year program is filling in the information gap about disease-causing genetic variations within the Japanese population

The amount of variation in an individual’s genome depends on their ethnic background,
which highlights the need for a Japanese database of genetic and clinical information

© Jose Luis Pelaez Inc/DigitalVision/Getty

Clinical molecular geneticists are undertaking a multi-million-dollar project to collect and verify data on genetic variations found within the Japanese population. The project aims to facilitate disease diagnosis and to help direct clinicians to possible treatments.

Although 99.9 per cent of individual human genomes are identical, there is still a considerable amount of variation within our genes. Some variations will have no negative consequences on human health and are simply what makes each individual unique. But other variations can cause disease.

Globally, researchers have invested considerable time and resources into identifying disease-causing genetic variations. Collating this information is difficult and resource-intensive but necessary.

In 2012/13, the United States’ National Institutes of Health launched ClinVar, a publicly available archive of data on the relationships between human genetic variations and how they manifest in the form of disease. “We use ClinVar, but the amount of variation depends on ethnic background,” says clinical molecular geneticist Kenjiro Kosaki of Japan’s Keio University. “The variants seen in the US or in Caucasians can be different from those seen in Asians,” he explains. A Japanese alternative was needed.

In 2016, Kosaki and a large team of clinical molecular geneticists from across Japan, with funding from the Japan Agency for Medical Research and Development (AMED), launched a five-year Program for an Integrated Database of Clinical and Genomic Information.

Aiming to improve the infrastructure that can facilitate the sharing of clinical and genomic information, the program will accelerate research and development and promote genomic medicine in a clinical setting. The research will help clarify the relationship between genomic information and the clinical characteristics of diseases. It is also developing accessible databases that archive this data for clinical and research purposes.

Aiming to improve the infrastructure that can facilitate the sharing of clinical and genomic information

A database for genetic variants

Kosaki and colleagues at Keio University are developing, for example, the Japanese pathogenic variant database (DPV). A small number of uniquely skilled scientists, called variant scientists, sift through1 tens of thousands of studies and case reports conducted in Japan to identify data on disease-causing genetic mutations discovered within the population.

Kosaki describes one extensive study2 that was conducted in Japan on phenylketonuria, a rare genetic condition in which an amino acid called phenylalanine builds up, damaging the nervous system. Kosaki’s team found that the Japanese study had identified more than 60 genetic variants related to the disease in the Japanese population. About 40 of those genetic variants had been published in the ClinVar database, but another 20 were not. “So, we need to fill the gap,” he says.

“While that process is painstaking, it needs to be done,” says Kosaki. “Another issue is that it is possible that variances that seemed to be pathogenic several years ago can turn out to be completely normal as the information from the healthy populations grows. So, this needs to be excluded from the pathogenic database and this kind of process currently takes a lot of human effort.”

Diagnosis and treatment

Clinicians can use the database for patient diagnosis. When a patient’s genomic information is run through it, their variants are compared to those in the database. “If there is a hit, you can make a diagnosis immediately,” says Kosaki.

The database can also be a useful therapeutic tool, as it includes some information on treatable genetic mutations.

Kosaki and his team published a study in 2015, for example, that found that a novel overgrowth syndrome in two Japanese patients was caused by a mutation that over-activates a gene called platelet-derived growth factor receptor B (PDGFRB). A Belgian group that read Kosaki's study found that the anti-leukemic drug imatinib can target this gene, turning it off, with a positive therapeutic effect on patients with the syndrome. “This drug can now be used for other rare diseases that we have identified,” says Kosaki. “This use of a known safe drug for other diseases is called drug repositioning, and hopefully the database we are developing can facilitate many drugs to be repositioned for different diseases.”

The data currently being developed in Japan could also be relevant to populations in other Asian countries

The information that is processed through the DPV is eventually incorporated into the Medical Genomics Japan Variant Database (MGeND) managed by Kyoto University researchers. This database collates data from collaborating institutions on genomic variations and their clinical characteristics to improve the diagnosis of cancers, rare diseases, infectious diseases, dementia, and hearing loss.

The data currently being developed in Japan could also be relevant to populations in other Asian countries, such as Taiwan, Korea and China, says Kosaki.

As more variant scientists are trained by the program, Kosaki expects a market for this profession will grow in the country, particularly within commercial genetic testing companies.

Although only established three years ago, the Program for an Integrated Database of Clinical and Genomic Information is already creating an impact, and Japanese clinical molecular geneticists are continuing the laborious concerted efforts required to take the results of their research from the lab and into the clinic.


  1. Suzuki, H. Kurosawa, K., Fukuda, K., Iijima, K., Sumazaki, R. et al.  Japanese pathogenic variant database: DPV. Translational Science of Rare Diseases 3, 133–137 (2018). Article
  2. Okano, Y., Kudo, S., Nishi, Y., Sakaguchi, T. & Aso, K. Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan. Journal of Human Genetics 56, 306–312 (2011). Article

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