Han Chinese people comprise nearly 20% of the global population but remain under-represented in genetic studies ^1,2 , so there is an urgent need for large-scale cohorts to advance precision medicine. Here we present the Taiwan Precision Medicine Initiative (TPMI), established by Academia Sinica in collaboration with 16 major medical centres around Taiwan, which has recruited 565,390 participants who consent to provide DNA samples for genetic profiling and grant access to their electronic medical records (EMRs) for research. EMR access is both retrospective and prospective, allowing longitudinal studies. Genetic profiling is done with population-optimized arrays of single-nucleotide polymorphisms for people of Han Chinese ancestry, which enable genome-wide association ^3,4 , phenome-wide association ^5,6 and polygenic risk score ^7,8 studies to be performed to evaluate common disease risk and pharmacogenetic response. Participants also agreed to be re-contacted for future research and receive personalized genetic risk profiles with health management recommendations. The TPMI has established the TPMI Data Access Platform, a central database and analysis platform that both safeguards the security of the data and facilitates academic research. As a large cohort of individuals with non-European ancestry that merges genetic profiles with EMR data and enables longitudinal follow-up, TPMI provides a unique resource that could be used to validate genetic risk prediction models, perform clinical trials of risk-based health management and inform health policies. Ultimately, the TPMI cohort will contribute to global genetic research and serve as a model for population-based precision medicine.

Background: ADH1B rs1229984 and ALDH2 rs671 are the specifically prevalent functional variants in the East Asians. These variants, which result in a dramatic change in enzyme activity, are highly associated with alcohol‐related disorders and cancer. Previous studies focusing on the additive and synergic effects of the variants are few and inconsistent. The aim of the research was to evaluate the associations of ADH1B rs1229984 and ALDH2 rs671 with the risks of alcohol‐related disorder and cancer.Methods: This cohort study enrolled 42,665 participants from the Taiwan Precision Medicine Initiative database, including 19,522 and 20,534, ADH1B and ALDH2 carriers, respectively. The associations between the two variants and cancer risk were analyzed by univariable and multivariable logistic regression.Results: Compared with the noncarriers, the ADH1B rs1229984 variant had a stronger effect on alcohol‐related disorders and was related to an increased risk of alcohol‐related cancers. The CC genotype of ADH1B rs1229984 was significantly associated with cancer of the larynx, pharynx, and nasal cavities [odds ratio (OR) = 1.56, p = 0.0009], cancer of the pancreas (OR = 1.66, p = 0.018), and cancer of the esophagus (OR = 4.10, p < 0.001). Participants who carried the rs1229984 TC/CC and rs671 GG genotypes were at higher risk of esophageal cancer (OR = 3.02, p < 0.001). The risk of esophageal cancer was increased by 381% (OR = 4.81, p < 0.001) in those carrying the rs1229984 TC/CC and rs671 GA/AA genotypes.Conclusion: rs1229984 and rs671 are common and functionally important genetic variants in the Taiwanese population. Our findings provide strong evidence of additive and synergic risks of ADH1B and ALDH2 variants for alcohol‐related disorders and cancer. The results suggested that are reduction in alcohol consumption should be advised as a preventive measure for high‐risk patients carrying ADH1B rs1229984 C or the ALDH2 rs671 A allele.

Predicting complex disease risks on the basis of individual genomic profiles is an advancing field in human genetics^1,2. However, most genetic studies have focused on populations of European ancestry, creating a global imbalance in precision medicine and underscoring the need for genomic research in non-European groups^3,4. The Taiwan Precision Medicine Initiative recruited more than half a million Taiwanese residents, providing a large dataset of genetic profiles and electronic medical record data for people with Han Chinese ancestry. Using extensive phenotypic data, we conducted comprehensive genomic analyses across the medical phenome with individuals genetically similar to Han Chinese reference populations. These analyses identified population-specific genetic risk variants and new findings for various complex traits. We developed polygenic risk scores, demonstrating strong predictive performance for conditions such as cardiometabolic diseases, autoimmune disorders, cancers and infectious diseases. We observed consistent findings in an independent dataset, Taiwan Biobank, and among people of East Asian ancestry in the UK Biobank and the All of Us Project. The identified genetic risks accounted for up to 10.3% of the overall health variation in the Taiwan Precision Medicine Initiative cohort. Our approach of characterizing the phenome-wide genomic landscape, developing population-specific risk-prediction models, assessing their performance and identifying the genetic effect on health serves as a model for similar studies in other diverse study populations.

Background: Esophageal cancer has extreme worldwide demographic and histologic variations in occurrence; thus, understanding the pathogenesis of esophageal cancer must be region- or country-based. We examined the incidence and tumor stage at diagnosis of esophageal cancer in relation to patients’ socioeconomic status (SES) in Taiwan. Method: This retrospective cohort study used data from Taiwan’s National Health Insurance Research Database and Taiwan Cancer Registry collected between January 2008 and December 2014. The records of 40- to 79-year-old patients diagnosed with esophageal cancer were retrieved. The distribution of the crude incidence rates of esophageal cancer by occupation and income variables was studied retrospectively. Cox proportional hazard model was used to adjust for potential confounders and compare the esophageal cancer incidence among four independent variables: age, gender, occupation, and income. Logistic regression analysis was applied to find the power of the independent variables on the odds ratio of late-stage presentation. Results: The analysis included 7763 subjects. Esophageal squamous cell carcinoma (ESCC) was the predominant histological type (96.6%) and 94.4% of patients were male. The peak affected age for ESCC was 50 to 59 years, whereas the risk of esophageal adenocarcinoma increased progressively with age. The risk of ESCC was significantly unfavorable for the most disadvantaged group, either in occupation or income, while in EAC, risk was unrelated to either factor. The stage of cancer at diagnosis was lower in the highest income groups than in the other two groups. Conclusion: Significant SES disparities in esophageal cancer incidence, based on occupation and income, are present in Taiwan. Low SES populations have a higher percentage of late-stage diagnosis. Resolution of the increasing socioeconomic disparities and narrowing the gaps in health inequities in Taiwan are needed.

Incorporating pharmacogenetics into clinical practice promises to improve therapeutic outcomes by optimizing drug selection and dosage based on genetic factors affecting drug response. A key advantage of PGx-guided therapy is to decrease the likelihood of adverse events. To evaluate the clinical impact of PGx risk variants, we performed a retrospective study using genetic and clinical data from the largest Han Chinese cohort, comprising 486,956 individuals, assembled by the Taiwan Precision Medicine Initiative. We found that nearly all participants carried at least one genetic variant that could affect drug response, with many carrying multiple risk variants. Here we show the detailed analyses of four gene-drug pairs, azathioprine ( NUDT15 / TPMT ), clopidogrel ( CYP2C19 ), statins ( ABCG2 / CYP2C9 / SLCO1B1 ), and NSAIDs ( CYP2C9 ), for which sufficient data exists for statistical power. While the results validate previous findings that PGx risk variants are significantly associated with drug-related adverse events or ineffectiveness, the excess risk of adverse events or lack of efficacy is small compared to that found in those without the PGx risk variants, and most patients with PGx variants do not suffer from adverse events. Our results point to the complexity of implementing PGx in clinical practice and the need for integrative approaches to optimize precision medicine.