Annals of Human Genetics最新文献

Background

Alzheimer's disease (AD) predominantly affects older women, with research suggesting elevated follicle-stimulating hormone (FSH) levels in postmenopausal women correlate with AD risk and cognitive decline. Understanding the causal relationship between FSH and AD is essential.

Materials and Methods

We selected single-nucleotide polymorphisms (SNPs) linked to FSH as instrumental variables (IVs) for Mendelian randomization (MR). Statistical methods, including inverse variance weighted (IVW), MR Egger, Weighted Median, Weighted Mode, and Simple Mode, were employed to assess causality and potential pleiotropy. Shared genetic loci between FSH and AD were explored.

Results

We carefully identified and utilized a total of 20 valid SNPs as IVs to assess the potential causal relationship between FSH and AD. Our analysis revealed a significant causal association between genetically determined FSH levels and AD [beta = −0.004; OR = 0.996, 95% confident interval (CI): 0.994–0.999; p = 0.002]. We successfully identified 20 SNPs that correspond to 8 differentially expressed genes (DEGs) between AD and non-demented (ND). These genes have not been previously reported to be linked to either FSH or AD. We conducted an in-depth analysis to explore the potential roles of these genes in the context of FSH and AD.

Conclusion

Our MR study revealed that FSH potentially has a causal association with AD. Additionally, FSH might possess distinctive biological mechanisms that influence the development of AD.

Background

The culmination of the Human Genome Project in the early 2000s came wreathed in promises of a revolution in medicine and healthcare. The ensuing quarter century has seen remarkable growth in genomic medicine, as well as notable shifts in the promissory rhetoric that accompanies it.

Methods

This essay draws on a contextualist close reading of scientific and policy literature published from the 1990s to the present, using thematic and narrative analysis informed by perspectives from the sociology of expectations, to examine the role of different kinds of promissory claims in shaping the development of genomic medicine in the UK, and particularly England, over that period.

Results

Early promises about the medical benefits that will follow from the development of genomic medicine have been scaled back and refocused as the possibilities and limitations of genomic technologies have become apparent; while investment has shifted from basic discovery resources aimed at elucidating the genetics of common disorders to clinical facilities focused on the genomics of rare diseases and cancer. Research in these areas has delivered a range of highly-publicised diagnostic and therapeutic innovations, but so far the benefits to patients have generally been modest or confined to relatively small populations, and come at a high cost, both financial and human. Meanwhile, a rather different set of promises, focused on economic growth through biomedical innovation, has been instrumental in shaping how the field of genomic medicine has developed, especially within the National Health Service. One consequence has been a blurring of the distinction between medical care and biomedical research, with genomic medicine patients and their data increasingly being reframed as an economic resource for purposes of commercially-driven innovation.

Conclusion

In this context, efforts to persuade patients of the personal or public value of research participation, and especially proposals to abandon the principle of clinical non-directiveness in genomic healthcare, raise uncomfortable questions about just whose interests genomic medicine, as currently constituted, is best designed to serve.

Background

The recent emergence of technologies that capture and analyse genetic variation patterns obtained from a person's DNA sample has led to numerous academic and commercial endeavours to infer individuals' ancestries. In theory, a person's genome contains a wealth of readily accessible information regarding their ancestors, despite only some of our ancestors contributing to the DNA we carry. This makes genetic tests an attractive alternative to the painstaking reconstruction of family trees or directly contacting long-lost relations, particularly when, unless there are notable individuals in the tree, historical and genealogical records tend to diminish in frequency with each generation. However, while powerful, there are limits to what genetic data can unearth, as well as important assumptions underlying these analyses.

Methods

This review describes some of the early history and latest advances in techniques and data used to infer ancestry using genetics, highlighting both the power and limitations of current studies.

Conclusion

While genetics is a powerful means of exploring aspects of people's ancestry, a stronger focus on conveying uncertainty will allow both academics and non-academics to avoid the ever-present risks of over-interpretation.

Background

The classification of sequence variants is at the core of human genetic diagnostics and is the basis for clinical guidance - incorrectly classified variants may cause great harm to patients and their families.

Methods

We provide an overview of the evolution of ideas and algorithms that have led to the formulation of elaborate classification systems over the last decades, culminating in the ACMG/AMP classification system. Furthermore, we address a still unsolved problem in the clinical translation of DNA analyses: variants of unclear significance (VUS).

Results

Rigorous data sharing and the sub-categorisation of VUS could facilitate a clearer interpretation of VUS.

Conclusion

This review underscores the efforts of the HUGO Education Committee to empower professional—sespecially in resource-limited settings—with the expertise needed for high-quality variant interpretation, fostering equitable access to the transformative potential of genomic medicine.

The recent study by Makay et al. significantly advances our understanding of artificial intelligence (AI)-based tools for evaluating facial dysmorphism, particularly within underrepresented populations such as Central African children. This commentary underscores the importance of integrating AI phenotyping technologies with traditional clinical assessments, emphasizing their complementary roles rather than replacement. The commentary further explores methodological enhancements, including the integration of three-dimensional facial analysis, and highlights the necessity for ongoing validation studies in diverse ethnic cohorts to optimize algorithmic precision and clinical applicability. These refinements are essential for improving dysmorphology evaluations globally, particularly in regions with limited genetic healthcare resources.

Background

Idiopathic pulmonary fibrosis (IPF), the predominant idiopathic interstitial pneumonia, is marked by progressive, irreversible lung damage with a 3-year median survival rate in the elderly. Cardiovascular disease (CVD) is the most common disease in the elderly population and its incidence is increasing all the time, especially in the Asia-Pacific region, coinciding with the rise in global mortality. Despite clinical indications of a link between IPF and CVD, the mechanisms are not well understood. This study applies a bidirectional two-sample Mendelian randomization (MR) approach to explore potential causalities between IPF and CVD.

Methods

Summary data from public genome-wide association study (GWAS) databases for IPF (27,449 participants) and CVD were utilized. Single nucleotide polymorphisms (SNPs) served as instrumental variables in MR analysis, employing inverse variance-weighted (IVW), weighted median (WM), and MR-Egger methods. Heterogeneity was assessed with Cochran's Q test, and sensitivity analyses were conducted using MR-PRESSO.

Results

The IVW analysis revealed no significant associations between genetically predicted IPF and CVD, except for a significant negative association with large artery atherosclerosis stroke and IPF. The WM method supported this inverse relationship. MR-Egger intercept indicated pleiotropy in the link between IPF and heart failure, with no outliers detected by MR-PRESSO. Cochran's Q test showed no significant heterogeneity for the relationships.

Conclusion

The bidirectional MR study suggests a potential negative influence of large artery atherosclerosis stroke on IPF, hinting at a protective role of IPF in stroke incidence. The absence of significant associations with other CVDs and IPF implies a more complex relationship than previously considered. Further research is needed to clarify the intricate connections between IPF and CVD.

Introduction

Southeast Asia (SEA) is a region with enriched human diversity and complex population history. Despite numerous small-scale population genetics studies being carried out, the map of human migration in this landmass remains fragmentary. Notably, the genetic affinities of the Orang Asli from Peninsular Malaysia and other SEA natives have not been comprehensively assessed.

Methods

In this study, publicly available genotypic datasets were gathered and imputed. The genetic relationships and ancestry make-up of 19 SEA native populations, covering Peninsular Malaysia, Indonesia, Papua New Guinea, the Philippines, Vietnam, and Andaman, were comprehended and benchmarked with 14 global populations.

Results

With ∼20 million SNPs coverage, we provided supporting evidence to (i) a possible ancient genetic link between the Andamanese, Papuan and the Philippines and Peninsular Negrito; (ii) gene flow from the ancestors of Andamanese to Papuan, and the Negrito from Peninsular Malaysia and the Philippines; (iii) different genetic structures between the island SEA (iSEA) and mainland (mSEA) populations; (iv) close genetic affinity between the Proto-Malay Seletar with the iSEA populations and (v) close genetic affinity between the Senoi Mah Meri with the Proto-Malays.

Conclusion

To our knowledge, this study reported the highest genomic sequence coverage and the most comprehensive SEA native populations covered thus far. Our results not only have provided strong supporting evidence to the earlier hypothesis, but also novel insights into the genetic diversity of the SEA native populations.