Primary familial brain calcification (PFBC), also known as Fahr’s disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.

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.

Mitochondrial dysfunction is involved in the pathogenesis of atherosclerosis, the primary risk factor for ischemic stroke. This study aims to explore the role of mitochondrial genomic variations in ischemic stroke, and to uncover the nuclear genes involved in this relationship. Eight hundred and thirty Taiwanese patients with a history of ischemic stroke and 966 normal controls were genotyped for their mitochondrial haplogroup (Mthapg). Cytoplasmic hybrid cells (cybrids) harboring different Mthapgs were used to observe functional differences under hypoxia-ischemia. RNA sequencing (RNASeq) was conducted to identify the particularly elevated mRNA. The patient study identified an association between Mthapg F1 and risk of ischemic stroke (OR 1.72:1.27–2.34, p = 0.001). The cellular study further demonstrated an impeded induction of hypoxic inducible factor 1α in the Mthapg F1 cybrid after hypoxia-ischemia. Additionally, the study demonstrated that Mthapg F cybrids were associated with an altered mitochondrial function, including decreased oxygen consumption, higher mitochondrial ROS production, and lower mitochondrial membrane potential. Mthapg F cybrids were also noted to be prone to inflammation, with increased expression of several inflammatory cytokines and elevated matrix metalloproteinase 9. The RNASeq identified significantly elevated expressions of angiopoietin-like 4 in Mthapg F1 cybrids after hypoxia-ischemia. Our study demonstrates an association between Mthapg F and susceptibility to ischemic stroke.