Approximately 40% of protein-coding genes in the nematode Caenorhabditis elegans (C. elegans) are orthologous to human protein-coding genes, making this animal a useful model organism. The characteristics of this model organism include its simple structure, detailed basic biological description, and ease of culturing and freezing. In older years, researchers have used forward genetics to isolate mutants, examine their phenotypes, and clone the causal gene, revealing gene functions. By the end of the 20th century, researchers began to use various experimental techniques developed in the C. elegans community, including transgenic analyses by green fluorescent protein (GFP) expression and RNA interference, and this facilitated gene function analyses. These techniques are now used regularly in mammalian experiments. The C. elegans genome was sequenced for the first time as a multicellular organism, and the technologies used were then transferred to human genome sequencing.

We used C. elegans genome sequences and developed efficient techniques to isolate deletion mutants in a genome-wide manner using reverse genetics. We introduced deletions in the C. elegans genome by treating the animals with trimethylpsoralen (TMP) and ultraviolet light, and then screened for mutants using PCR. Next-generation sequencing was used to isolate the deletion mutants more efficiently. Current research has revealed that our laboratory has achieved a higher number and quality of deletion mutants than that of other laboratories worldwide. Furthermore, only our laboratory has effectively isolated deletion mutants for approximately half of the total genes. Through the National Bioresource Project funded by MEXT (Ministry of Education, Culture, Sports, Science and Technology), Japan, we have been distributing these deletion mutants to laboratories worldwide. Thus, in the past 20 years, gene function analyses of C. elegans have progressed notably. This information is useful for understanding the functions of human disease-causing genes. We hope that the knowledge gained from these activities will benefit research on the treatment of human diseases.

Intracranial aneurysms (IA) cause subarachnoid hemorrhage (SAH), which has high mortality and morbidity rates when rupture occurs. The success of genome-wide association studies (GWASs) followed by phenotypic confirmation in transgenic mice has supported the implication of genetic factors in the formation of IA. For example, a Sox17-deficient mouse model was established based on previous GWAS findings, confirming the development of IA resulting in SAH following Sox17 deficiency. The most recent international GWAS identified over half of the disease heritability of IA, including 17 risk loci using more than ten thousand patients. The remaining proportion of heritability, the so-called missing heritability, can be explained by the effects of rare variants detected by next-generation sequencing (NGS). In this review, we discuss the current knowledge regarding genetic factors associated with IAs provided by GWAS and rare variant analysis using NGS.

Spinal muscular atrophy (SMA) is a lower motor neuron disease characterized by muscle atrophy and progressive muscle weakness due to the degeneration and loss of anterior horn cells of the spinal cord. For a long time, it was a disease that received only care in hospitals and at home as a disease without cure. SMA is caused by the deletion or mutation of the survival of motor neuron 1 (SMN1) gene, therefore only a small amount of functional full-length survival motor protein (SMN) protein is produced from the SMN2 gene. There are three disease-modifying therapies that increase the production of the SMN protein: nusinersen, a nucleic acid drug with an exon inclusion mechanism; risdipram, a small molecule-drug with a similar mechanism; and onasemnogene abeparvovec, an adeno-associated virus 9 vector containing the SMN gene. Each drug was listed on the national health insulance (NHI) drug price based on the success of global clinical trials in which the author acted as the principal investigator. With the development of these effective therapeutic agents, early diagnosis and early treatment are essential. By administering the drug before the symptoms appear, it is possible to suppress or reduce the symptoms of SMA, and newborn screening at a nationwide level is expected to realized.

Genome wide association study (GWAS) is a type of genetic analysis that looks for association between a particular disease or trait and single nucleotide polymorphism (SNP). The polygenic risk score is the sum of the number of risk alleles weighted the GWAS-estimated effect sizes of each SNP on a disease. Researchers have been exploring the use of polygenic risk score (PRS) to predict disease risk and personalize treatment plans, an approach known as precision medicine. Our study was the first to demonstrate that a PRS based on GWAS data for rheumatoid arthritis (RA) onset can also predict joint damage progression. In particular, we found that the PRS is more accurate for predicting joint damage progression in young-onset patients with RA. To facilitate large-scale validation of our findings, we developed an artificial intelligence-based joint damage scoring system. This system will enable us to further investigate the relationship between PRS and disease severity in a larger, more diverse population. Further research is needed to refine the PRS construction method, particularly in terms of identifying the most informative SNPs and optimizing the weighting scheme for risk alleles.

Maturity-onset diabetes of the young (MODY) is the most prevalent form of early onset diabetes patients with caused by a single gene disorder.

The number of patients with MODY in Japan is estimated to be more than 12,000. MODY1, MODY2, and MODY3 are the most prevalent types of MODY, and are good indications for precision medicine, which results in improved prognosis and medical cost-effectiveness associated with MODY. We have provided a basis for genetic diagnosis and treatment of MODY using precision medicine. Improving the quality of life in patients with MODY by promoting the use of of precision medicine is an urgent task in Japan.

As medical science advances, the implementation of medical genetics is required in all areas of medicine. Genetic information has the following characteristics: 1) it does not change throughout a person's life, 2) it can predict the incidence of diseases, 3) it can affect blood relatives, and 4) it has inherent ambiguity. Therefore, care must be taken in handling this information. The Department of Medical Genetics specializes in handling genetic information. The Institute of Medical Genetics was established at Tokyo Women's Medical University in 2004. The important roles of our institute can be summarized as 1) providing genetic counseling; 2) providing accurate diagnosis and appropriate testing for hereditary diseases and congenital syndromes, including cancer; and 3) serving as a hub for routine management and medical care for people with hereditary diseases or congenital syndromes. Secondary findings may be found as a result of comprehensive genomic analyses, such as whole-genome sequencing and whole-exon sequencing. Genetic counseling is the process of helping people understand and adjust to the medical, psychological, and familial implications of a disease with genetic involvement. Thus, it is necessary for all physicians to have genetic counseling as part of their standard knowledge. Furthermore, medical geneticists and genetic counselors provide appropriate genetic counseling in a team setting for clients in the Department of Medical Genetics.