Medizinische Genetik最新文献

Polygenic scores are nowadays common tools in psychiatric genetic research and are also increasingly applied in clinical settings. In this article, we give an overview of polygenic scores in psychiatric research, focusing on recent trends and novel applications such as using polygenic scores in family studies. Furthermore, we discuss use cases of polygenic scores in clinical studies and clinical practice, for instance using polygenic scores to predict treatment response to medication. While some challenges of polygenic scores are not unique to psychiatry (e.g. limited reliability or transferability across ancestries), we also highlight the specialties of using polygenic scores in psychiatric research and clinical practice (e.g. clinical and biological heterogeneity across and within psychiatric conditions), as well as limitations of other applications beyond research, e.g. using polygenic scores for psychiatric conditions for embryo selection. We further make the case for careful communication of genetics to patients and the general public. We conclude by providing an outlook which includes future directions and applications of polygenic scores in psychiatric research and clinical practice.

Inter-individual variability in drug response remains a major challenge in clinical pharmacology. While clinical pharmacogenetics is largely based on actionable single-gene variants, increasing GWAS evidence indicates that many drug-response phenotypes are polygenic. Polygenic risk scores (PRS) offer a framework to capture cumulative effects across pharmacokinetic, pharmacodynamic, and disease-related pathways, enabeling probabilistic risk stratification beyond monogenic models. This review summarizes the current status of PRS in pharmacogenomics (PGx-PRS), highlighting key challenges including limited sample sizes of drug-exposed cohorts, heterogeneous phenotype definitions, ancestry-related portability issues, and incomplete representation of complex pharmacogenes such as CPY2D6. Current applications are discussed across cardiovascular, psychiatric, and oncological settings, where PRS show emerging potential for benefit-risk stratification but remain insufficiently validated for routine care. Clinical implementation will require standardized methodologies multi-ancestry validation, integration with rare-high impact ADME (Absorption, Distribution, Metabolism, and Excretion) variants, and clearer regulatory pathways. With these advances, PGx-PRS may become clinically relevant tools for precision prescribing and drug development.

Mendelian diseases are caused by rare pathogenic variants with large effects. However, phenotypes are often different between individuals carrying the same variant ("variable expressivity"), or even absent in some carriers ("incomplete penetrance"), suggesting that the genetic architecture of Mendelian diseases is more complex than previously thought. Common genetic variants are a potential modifier of observed phenotypes. Individual common variants usually have small effects, but in aggregate their effects can be substantial and be quantified as a polygenic score (PGS). The present review summarises available data on how PGS modify phenotypes in Mendelian diseases. We show that modifying effects of PGS on penetrance and expressivity have been observed in carriers of rare pathogenic variants across a broad range of conditions. This suggests that in Mendelian diseases, a modifying effect of the common variant background on penetrance and expressivity might be the rule rather than the exception. We anticipate that increasing data availability and methodological advances will improve our understanding of the genetic architecture of Mendelian diseases, including the joint consideration of both common and rare variants.

Polygenic risk scores (PRS) have emerged as a powerful tool to refine cancer risk prediction beyond age, family history, and modifiable environmental risk factors, enabling individualized prevention and early detection strategies. Evidence from breast, colorectal, and prostate cancer demonstrates that PRS significantly improve risk stratification in both sporadic and hereditary settings and can modify penetrance of pathogenic germline variants. Integrating PRS into multifactorial models such as CanRisk enhances predictive accuracy and supports risk-adapted preventive approaches. While implementation studies show feasibility, prospective validation and standardization as well as ancestry-specific calibration remain key challenges for clinical translation.

The sudden and often fatal onset of many cardiovascular disease (CVD) calls for improved risk prediction and personalized preventive strategies. Polygenic risk score (PRS) captures inherited susceptibility and may add precision to guideline-recommended clinical risk score. Given the spectrum of CVD, the utility of PRS varies from being a clinically meaningful diagnostic tool to a scientific instrument that brings light into the complex aetiologies. This review summarizes the current understanding of PRS in CVD. We discuss methodological strategies for its construction and outline clinical scenarios for PRS across major CVDs, including coronary artery disease, aortic aneurysms, cardiomyopathies, atrial fibrillation in the context of heart failure, and hypertension, highlighting their potential to enhance risk stratification beyond traditional factors. Finally, we outline current knowledge gaps that limit the clinical implementation of PRS.