Human Genetic Research Articles

Genetic Risk Factors for Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of liver disease, and its burden on health systems worldwide continues to rise at an alarming rate. MASLD is a complex disease in which the interactions between susceptible genes and the environment influence the disease phenotype and severity. Advances in human genetics over the past few decades have provided new opportunities to improve our understanding of the multiple pathways involved in the pathogenesis of MASLD. Notably, the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 single nucleotide polymorphisms have been demonstrated to be robustly associated with MASLD development and disease progression. These genetic variants play crucial roles in lipid droplet remodeling, secretion of hepatic very low-density lipoprotein and lipogenesis, and understanding the biology has brought new insights to this field. This review discusses the current body of knowledge regarding these genetic drivers and how they can lead to development of MASLD, the complex interplay with metabolic factors such as obesity, and how this information has translated clinically into the development of risk prediction models and possible treatment targets.

Introduction to androgenetics: terminology, approaches, and impactful studies across 60 years.

Across six decades, androgenetics has consistently concentrated on discovering genetic causes and enhancing the molecular diagnostics of male infertility, disorders of sex development, and their broader implications on health, such as cancer and other comorbidities. Despite vast clinical knowledge, the training of andrologists often lacks fundamental basics in medical genetics. This work, as part of the Special Issue of Andrology "Genetics in Andrology", provides the core terminology in medical genetics and technological advancements in genomics, required to understand the ever-progressing research in the field. It also gives an overview of study designs and approaches that have frequently led to discoveries in androgenetics. The rapid progress in the methodological toolbox in human genetics is illustrated by numerous examples of impactful androgenetic studies over 60 years, and their clinical implications.

Improving polygenic prediction from summary data by learning patterns of effect sharing across multiple phenotypes.

Polygenic prediction of complex trait phenotypes has become important in human genetics, especially in the context of precision medicine. Recently, mr.mash, a flexible and computationally efficient method that models multiple phenotypes jointly and leverages sharing of effects across such phenotypes to improve prediction accuracy, was introduced. However, a drawback of mr.mash is that it requires individual-level data, which are often not publicly available. In this work, we introduce mr.mash-rss, an extension of the mr.mash model that requires only summary statistics from Genome-Wide Association Studies (GWAS) and linkage disequilibrium (LD) estimates from a reference panel. By using summary data, we achieve the twin goal of increasing the applicability of the mr.mash model to data sets that are not publicly available and making it scalable to biobank-size data. Through simulations, we show that mr.mash-rss is competitive with, and often outperforms, current state-of-the-art methods for single- and multi-phenotype polygenic prediction in a variety of scenarios that differ in the pattern of effect sharing across phenotypes, the number of phenotypes, the number of causal variants, and the genomic heritability. We also present a real data analysis of 16 blood cell phenotypes in the UK Biobank, showing that mr.mash-rss achieves higher prediction accuracy than competing methods for the majority of traits, especially when the data set has smaller sample size.

Exploring the Role of Glycine Metabolism in Coronary Artery Disease: Insights from Human Genetics and Mouse Models.

Background: Circulating glycine levels have been associated with reduced risk of coronary artery disease (CAD) in humans but these associations have not been observed in all studies. We evaluated whether the relationship between glycine levels and atherosclerosis was causal using genetic analyses in humans and feeding studies in mice. Methods: Serum glycine levels were evaluated for association with risk of CAD in the UK Biobank. Genetic determinants of glycine levels were identified through a genome-wide association study (GWAS) and used to evaluate the causal relationship between glycine and risk of CAD by Mendelian randomization (MR). A dietary supplementation study was carried out with atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice to determine the effects of increased circulating glycine levels on cardiometabolic traits and aortic lesion formation. Results: Among 105,718 UK Biobank subjects, elevated serum glycine levels were associated with significantly reduced risk of prevalent CAD (Quintile 5 vs. Quintile 1 OR = 0.76, 95% CI 0.67-0.87; p < 0.0001) and incident CAD (Quintile 5 vs. Quintile 1 HR = 0.70, 95% CI 0.65-0.77; p < 0.0001) after adjustment for age, sex, ethnicity, anti-hypertensive and lipid-lowering medications, blood pressure, kidney function, and diabetes. A GWAS meta-analysis with 230,947 subjects identified 61 loci for glycine levels, of which 26 were novel. MR analyses provided modest evidence that genetically elevated glycine levels were causally associated with reduced systolic blood pressure and risk of type 2 diabetes, but did not provide significant evidence for an association with decreased risk of CAD. Glycine supplementation in mice had no effects on cardiometabolic traits or atherosclerotic lesion development. Conclusions: While expanding the genetic architecture of glycine metabolism, MR analyses and in vivo feeding studies did not provide evidence that the clinical association of this amino acid with atherosclerosis represents a causal relationship.

Recent advances in MASLD genetics: Insights into disease mechanisms and the next frontiers in clinical application.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.

Boundary-work of genomic medicine: safeguarding the future of diagnostic next-generation sequencing in the clinic

Next-generation sequencing (NGS) technologies – which allows to look at large parts or even the whole genome at once - are making their way into diagnostic clinical care. With trends towards ‘mainstreaming’ genetic services into general medicine, significant ethical challenges, and a disputed clinical utility and cost-benefit ratio, genomic medicine’s autonomy and dominance in defining and offering NGS care may come under increased pressure from the outside (e.g., regulators, other healthcare providers and facilities, ethicists, and patients). In this paper, we show how the field of genomic medicine engages in substantial boundary work in reaction to these circumstances. Building on multi-sited fieldwork in two centres for human genetics in Belgium and the Netherlands, we show how acts of demarcation serve to uphold an image of expertise and authority which helps to maintain the field’s autonomy and dominance. Through examining the delineations put forward in interviews, practice (based on observations in multidisciplinary meetings and consultations), and grey and academic literature, we show the politics involved in moving NGS forward fairly seamlessly in a way that suits the field. First, we show how genetic healthcare professionals have redefined what makes a genetic test ‘valuable’ so that it underlines its current value. Secondly, we examine how a genetic imaginary is put forward that both emphasizes the extraordinary character of genomic medicine and the normalcy of NGS testing. By underlining the need for their expertise whilst simultaneously normalizing the ethical challenges and positioning themselves as most capable of reflecting on these, the field minimized external regulation and kept a close grip on defining ethical issues and policy. Despite their current dominance in shaping the future of genomic care, we argue that the closedness of the field hinders it in benefiting from external expertise, reflection and monitoring to ensure enduring and broad support for this future.

The Soviet delegation at the IV International Congress on Human Genetics in Paris in 1971

The article is devoted to the participation of Soviet scientists in the IV International Congress on Human Genetics, which was held in Paris in 1971. This event is analyzed in the context of the development of Soviet-French scientific relations. Excerpts from reports of well-known domestic geneticists are given, reflecting both the level of scientific activity and the state of foreign science. The unrealized initiative of N.P. Dubinin to hold a congress in Moscow and a forum in Mexico City in 1976 are mentioned. Despite the small number of the delegation, representatives of the USSR were elected to the organizing committee of both congresses. It is safe to say that the trip to France played an important role in the development of human genetics in the USSR, and also stimulated research on cytogenetics, which became more extensive and systematic.

Acknowledgement to Reviewers of Human Population Genetics and Genomics in 2024

Acknowledgement to Reviewers of Human Population Genetics and Genomics in 2024

Engaging adolescents and young adults in decisions about return of genomic research results: study protocol for a mixed-methods longitudinal clinical trial protocol

BackgroundTo protect minors’ future autonomy, professional organizations have historically discouraged returning predictive adult-onset genetic test results and carrier status to children. Recent clinical guidance diverges from this norm, suggesting that when minors have genomic sequencing performed for clinical purposes, parents and children should have the opportunity to learn secondary findings, including for some adult-onset conditions. While parents can currently opt in or out of receiving their child’s secondary findings, the American Society of Human Genetics Workgroup on Pediatric Genetic and Genomic Testing suggests including adolescents in the decision-making process. However, it is not clear what factors young people consider when given the opportunity to learn genetic findings for themselves. In this manuscript, we report on the methods for a clinical trial that examines adolescents’, young adults’, and their parents’ decisions about learning genomic information for the adolescent or young adult.MethodsWe are enrolling assenting (ages 13–17) adolescents and consenting (ages 18–21) young adults in a prospective genomic screening study to assess the choices they make about receiving individual genomic results. Participants use an online tool to indicate whether they want to learn their personal genetic risk for specific preventable, treatable, and adult-onset conditions, as well as carrier status for autosomal recessive conditions. We are examining (1) how choices differ between adolescent and young adult cohorts (as well as between adolescents/young adults and parents) and (2) decisional conflict and stability across study timepoints. Results are returned based on participants’ choices. Qualitative interviews with a subset of participants explore decisional stability, adolescent/young adult engagement with parents in decision-making, and the impact of learning pathogenic/likely pathogenic and autosomal recessive carrier results.DiscussionThis study explores decision making and decision stability between adolescents and parents (where applicable), as well as the ethical implications and impact of return of clinical-grade genetic research results to adolescents and young adults. The results of this study will contribute empirical evidence to support best practices and guidance on engaging young people in genomic research studies and clinical care that offer return of results.Trial registrationClinicalTrials.gov Identifier: NCT04481061. Registered 22 July 2020.

The multi-scale complexity of human genetic variation beyond continental groups.

Traditional clustering and visualization approaches in human genetics often operate under frameworks that assume inherent, discrete groupings1,2. These methods can inadvertently simplify multifaceted relationships, functioning to entrench the idea of typological groups3. We introduce a network-based pipeline and visualization tool grounded in relational thinking4, which constructs networks from a variety of genetic similarity metrics. We identify communities at multiple resolutions, departing from typological models of analysis and interpretation that categorize individuals into a (predefined) number of sets. We applied our pipeline to a dataset merged from the 1000 Genomes and Human Genome Diversity Project5, revealing the limitations of traditional groupings and capturing the complexities introduced by demographic events and evolutionary processes. This method embraces the context-specificity of genetic similarities that are salient depending on the question, markers of interest, and study individuals. Different numbers of communities are revealed depending on the resolution chosen and metric used, underscoring a fluid spectrum of genetic relationships and challenging the notion of universal categorization. We provide a web application (https://sohail-lab.shinyapps.io/GG-NC/) for interactive visualization and engagement with these intricate genetic landscapes.

Human genetics implicate thromboembolism in the pathogenesis of long COVID in individuals of European ancestry.

SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organs. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and thromboembolism; however, compelling evidence from humans is limited and causal associations remain unclear. Here, we tested the association of thromboembolism-related genetic variants with long COVID in the Long COVID Host Genetics Initiative ( n cases =3,018; n controls =994,582). Primary analyses revealed that each unit increase in the log-odds of genetically predicted venous thromboembolism risk was associated with 1.21-fold odds of long COVID (95%CI: 1.08-1.35; P =1.2 × 10 -3 ). This association was independent of acute COVID-19 severity, robust across genetic instruments and methods, and replicated in external datasets for both venous thromboembolism and long COVID. Downstream analyses using gene-specific instruments, along with protein and gene expression data, suggested the protease-activated receptor 1 (PAR-1) as a potential molecular contributor to long COVID. These findings provide human genetic evidence implicating thromboembolism in long COVID pathogenesis. .

From early methods for DNA diagnostics to genomes and epigenomes at high resolution during four decades - a personal perspective.

In the 1980s, my research career begun with microbial DNA diagnostics at Orion Pharmaceutica in Helsinki, Finland, where I was part of an innovative team that developed novel methods based on the polymerase chain reaction (PCR) and the biotin-avidin interaction. One of our key achievements during this time was the invention of the solid-phase minisequencing method for genotyping single nucleotide polymorphisms (SNPs). In the 1990s, I shifted focus to human genetics, investigating mutations of the 'Finnish disease heritage'. During this period, I also developed quantitative methods using PCR and minisequencing of mitochondrial mutations and for forensic analyses. In the late 1990s and early 2000s, microarray-based SNP genotyping became a major topic for my research, first in Helsinki and later with my research group at Uppsala University in Sweden. By the mid-2000s, I began collaborating with leading clinicians on genetics of autoimmune disease, specifically systemic lupus erythematosus and later worked on the classification and clinical outcome of pediatric acute lymphoblastic leukemia, when large-scale genomics and epigenomics emerged. These collaborations, which focused on integrating genomics into clinical practice, lasted almost two decades until I retired from research in 2022. In parallel with my research activities, I led the SNP/DNA Technology Platform in the Wallenberg Consortium North program from 2001 to 2006. I continued as Director of the SNP&SEQ Technology Platform, which expanded rapidly during the 2010s, and became part of Science for Life Laboratory in 2013. Today (in 2024), the SNP&SEQ Technology Platform is one of the largest units of the Swedish National Genomics Infrastructure hosted by SciLifeLab. The present article provides a personal perspective on nearly four decades of research, highlighting projects and methods I found particularly exciting or important.

NIAGADS: A Comprehensive National Data Repository for Alzheimer's Disease and Related Dementia Genetics and Genomics Research.

NIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimers Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimers Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a FISMA moderate compliant cloud-based platform that fully supports the NIH Genome Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of Alzheimers disease.

Understanding genetic variants in context.

Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes - most notably functional regulatory elements - in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants - at all scales, from other genetic variants and gene regulation to cell biology to organismal environment - are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.

Population-based genetic carrier screening. A consensus statement from the Spanish societies: AEGH, AEDP, ASEBIR, SEAGEN, SEF and SEGCD.

Autosomal recessive or X-linked disorders are passed from parents to offspring through Mendelian inheritance patterns and may lead to severe clinical manifestations in early childhood development. Together, the Spanish Association of Human Genetics (AEGH), Association for the Study of Reproductive Biology (ASEBIR), Spanish Association of Genetic Counselling (SEAGEN), Spanish Fertility Society (SEF), Spanish Society of Clinical Genetics and Dysmorphology (SEGCD), and the Spanish Association of Prenatal Diagnostics (AEDP) developed a consensus statement for population-based genetic carrier screening (GCS). The presented opinion statement recommends that preconception GCS services be included in the public healthcare system to support couples' reproductive autonomy and timely medical decision-making. Program design and implementation strategies, as well as key technical, ethical, and legal considerations are discussed.

Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for the diagnosis of inborn errors of immunity (IEI)

BackgroundInborn errors of immunity (IEIs) are more than 500 different rare congenital disorders of the immune system characterized by susceptibility to infections and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High throughput sequencing techniques may allow a timely genetic definition. Guidelines for the use and the interpretation of genetic testing produced by the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) do not cover specificities for the application to IEIs. ObjectiveThe aim of this consensus study is to define the best approach to genetic testing for IEIs. MethodsA panel of experts in the context of the Italian Primary Immunodeficiency Network (IPINet) composed a list of statements that were evaluated using Delphi method. ResultsThe experts recommend that genetic testing for IEIs should be offered to selected patients with warning signs for IEIs and highlight the crucial role of thorough phenotyping and functional tests for the conclusive diagnosis of IEI. Comprehensive educational programs targeted to health care professionals and the public should be developed to increase IEIs awareness and reduce the diagnostic delay. Ethical issues should be pondered over the diagnostic advantages of genetic tests requested for diagnostic purposes. ConclusionAdherence to the guidelines on the use and interpretation of genetic testing for the diagnosis of IEIs should help limiting the inappropriate use of these techniques and reduce the risk of misdiagnosis and apprehension for inconclusive genetic results.

Advances and Perspectives of Genetic Pathologies in the 21st century.

Introduction: The discovery of deoxyribonucleic acid in 1953 marks the difference between classical genetics that was based on clinical observation to make diagnoses and perform genomic modifications empirically, which triggered a series of genetic aberrations that compromise the dignity of the human being and the new genetics, an era that allowed understanding the starting point in the mechanisms of regulation and gene expression and its role when coding DNA which has allowed the study of diseases of genetic or hereditary origin and give a targeted treatment. The new genetics brings with it novel tools to objectify the alterations that occur either at the level of genes, chromosomes or multifactorial disorders and to be able to identify and classify them in a pertinent manner, simplifying the understanding of these pathologies. Objective: This article aims to keep the scientific community updated on the different genetic pathologies and their classification taking into account the nomenclature and key points of each one. Methodology: A review of scientific articles was performed in databases such as Pubmed, Web of Science, Dynamed and Uptodate, with search terms for artificial intelligence in medicine, clinical research, legal framework, bioethical principles, automated analysis, among others. No language restrictions were applied. Medical subject headings (MeSH) were used. Additionally, reference lists, review articles and grey literature were manually searched for relevant articles not captured in the electronic scan. Conclusion: Human genetics and its pathologies are of constant interest, since through its knowledge different DNA variants of the coding and replication process are explained, knowing the latest definitions covering the subject is of great importance for its understanding.

Mapping enhancer-gene regulatory interactions from single-cell data.

Mapping enhancers and their target genes in specific cell types is crucial for understanding gene regulation and human disease genetics. However, accurately predicting enhancer-gene regulatory interactions from single-cell datasets has been challenging. Here, we introduce a new family of classification models, scE2G, to predict enhancer-gene regulation. These models use features from single-cell ATAC-seq or multiomic RNA and ATAC-seq data and are trained on a CRISPR perturbation dataset including >10,000 evaluated element-gene pairs. We benchmark scE2G models against CRISPR perturbations, fine-mapped eQTLs, and GWAS variant-gene associations and demonstrate state-of-the-art performance at prediction tasks across multiple cell types and categories of perturbations. We apply scE2G to build maps of enhancer-gene regulatory interactions in heterogeneous tissues and interpret noncoding variants associated with complex traits, nominating regulatory interactions linking INPP4B and IL15 to lymphocyte counts. The scE2G models will enable accurate mapping of enhancer-gene regulatory interactions across thousands of diverse human cell types.

Genetic Variants Linked to Opioid Addiction: A Genome-Wide Association Study.

Opioid use disorder (OUD) affects millions of people worldwide. While it is known that OUD originates from many factors, including social and environmental factors, the role of genetic variants in developing the disease has also been reported. This study aims to investigate the genetic variants associated with the risk of developing OUD upon exposure. Twenty-three subjects who had previously been given opioid-based painkillers to undergo minor surgical treatment were recruited at Prisma Health Upstate clinic and elsewhere. Eleven were considered nonpersistent opioid users (controls), and 12 were persistent opioid users (cases) at the time of sample collection after an initial surgery. The subjects were asked to provide saliva samples, which were subjected to DNA sequencing at Clemson University Center for Human Genetics, and variant calling was performed. The genome-wide association studies (GWASs) for genes known to be associated with OUD resulted in 13 variants (intronic or SNV) with genome-wide significance (raw p-value < 0.01) and two missense variants, rs6265 (p.Val66Met in BNDF isoform a) and rs1799971 (p.Asn40Asp) in OPRM1, previously reported in the literature. Furthermore, extending the GWASs to find all genomic variants and filtering the variants to include only variants found in cases (persistent opioid users) but not in controls (nonpersistent opioid users) resulted in 11 new variants (p-value < 0.005). Considering that OUD is a complex disease and the effect might come from different variants in the same genes, we performed a co-occurrence analysis of variants on the genes. We identified eight additional genes that harbor multiple variants, including four genes: LRFN3, ZMIZ1, RYR3, and OR1L6, with three or more variants in the case subjects but not in the control individuals. The performed PPI network construction, along with functional enrichment, indicated that the variants occur in calcium signaling, circadian entrainment, morphine addiction, alcoholism, and opioid signaling pathways, which are closely related to OUD or addiction in general.

The Impact of Animal Flesh Consumption on Human Genetics

Abstract The animal flesh has been consumed for millions of years by humans. Although the attention has been increased in recent years on its effect on human genetics, exploring the complex interplay between animal flesh consumption and human genetics sheds light on both potential benefits and risks associated with dietary choices.