Human Genetic Resources Research Articles

Indigenous Peoples' human genomic sovereignty: Lessons for Africa.

Human genomics research with indigenous peoples has often been characterised by tension between the 'western' science ideologies and indigenous peoples' cultural beliefs in relation to their human genetic resources and data. This article explores this tension from the lens of the concept of indigenous peoples' human genomic sovereignty and tests the applicability of the concept in Africa. The article achieves this by first highlighting the tension between 'western' science and indigenous peoples through three case studies from Canada, the USA, and South Africa. It then analyses indigenous peoples' human genomic sovereignty in the USA and Canada and compares it with the notion of indigenous peoples' sovereignty in Africa. The article concludes by highlighting lessons that indigenous groups in Africa can draw from the USA and Canada in their quest for human genomic sovereignty.

Benefit-Sharing by Design: A Call to Action for Human Genomics Research.

The ethical standards for the responsible conduct of human research have come a long way; however, concerns surrounding equity remain in human genetics and genomics research. Addressing these concerns will help society realize the full potential of human genomics research. One outstanding concern is the fair and equitable sharing of benefits from research on human participants. Several international bodies have recognized that benefit-sharing can be an effective tool for ethical research conduct, but international laws, including the Convention on Biological Diversity and its Nagoya Protocol on Access and Benefit-Sharing, explicitly exclude human genetic and genomic resources. These agreements face significant challenges that must be considered and anticipated if similar principles are applied in human genomics research. We propose that benefit-sharing from human genomics research can be a bottom-up effort and embedded into the existing research process. We propose the development of a "benefit-sharing by design" framework to address concerns of fairness and equity in the use of human genomic resources and samples and to learn from the aspirations and decade of implementation of the Nagoya Protocol.

The Legal Status and Improvement Path of Human Genetic Data in Gene Therapy in China.

In the legal context of Chinese law, genetic data are an object of complex rights. At the level of private law, genetic data contain personal information, thus being protected by the Civil Code and the Personal Information Protection Law. At the level of public law, genetic data are important genetic resource that embody both public and national interests, which should also be regulated by public laws such as the Biosecurity Law and the Data Security Law. The recently issued Regulation on the Administration of Human Genetic Resources have refined the approval and record procedure, in order to promote the utilization of genetic data in China. At present, China still lacks sufficient protection for genetic data privacy, and the "informed consent" and "anonymization" system cannot work effectively. On the path of improvement, we should break constraints of individualism and start from the following three levels to strengthen genetic data privacy protection: formulating specialized legislation and leveraging the functions of group organizations and public interest litigation systems.

The Identification Standard of “Serious Circumstances” in the Crime of Infringing Human Genetic Resources

The Identification Standard of “Serious Circumstances” in the Crime of Infringing Human Genetic Resources

Comprehensive information management system for a medical research cohort biobank based on quality by design

BackgroundWith the development of big health and big data, cohort research has become a medical research hotspot. As an important repository of human genetic resources, biobanks must adapt to the requirements of large-scale and efficient operation. Thus, biobanks urgently need to design and build a legal, convenient, and efficient information management system.MethodsThis study applies the concept of “quality by design” to build a comprehensive biobank information management system based on the analysis of user requirements, legal and regulatory risks, and industry-standard requirements. The system integrates the management of scientific research projects, biological specimens, clinical information, quality control, and multi-dimensional information query and development. After 10 months of its operation, the comprehensive management system was evaluated through statistical analysis of the efficiency of the construction of the pregnancy–birth cohort and the quality of genetic resources.ResultsSince the system’s launch, the statistics on cohort construction efficiency show that the enrollment rate of eligible pregnant women has increased, and the rate of missing volunteers has dropped. The time needed to establish a 1000-person cohort (with complete biological samples and clinical information in early, middle, and late pregnancy) was reduced, and the effective tracking rate of the samples was 77.42%. The error rate of the deep cryogenic refrigerator decreased, with a clinical information integrity rate of 96.47%.ConclusionsThe comprehensive biobank information management system constructed with the “quality by design” concept is well suited to meet the requirements of medical research. This study provides a solution for designing a comprehensive information system for medical institutions’ biobanks.

Gravidity modifies the associations of age and spousal age difference with couple's fecundability: a large cohort study from China.

Do couple's age ranges for optimal fecundability, and the associations with fecundability of couple's age combinations and age differences differ with gravidity? The couple's age range of optimal fecundability and age combinations differed with gravidity, and gravidity might modify the associations of age and spousal age difference with couple's fecundability. Age is one of the strongest determinants of fecundability, but the existing studies have certain limitations in study population, couple's extreme age combinations and age differences, and have not explored whether the association between age and fecundability differs with gravidity. Retrospective cohort study. 5 407 499 general reproductive-aged couples (not diagnosed with infertility) participated in the National Free Pre-conception Check-up Projects during 2015-2017. They were followed up for pregnancy outcomes through telephone interviews every 3 months until they became pregnant or were followed up for 1 year. The main outcome was time to pregnancy, and the fecundability odds ratios and 95% CIs were estimated using the Cox models for discrete survival time. The associations of age and spousal age difference with fecundability were evaluated by restricted cubic splines. In this large cohort of general reproductive-aged population, the age of optimal fecundability of multigravida couples was older than that of nulligravida couples, but their subsequent fecundability declined more sharply with age. The decline in female fecundability was more pronounced with age, with fecundability dropping by ∼30% in both nulligravida and multigravida couples whose female partners aged ≥35 years. In the nulligravida group, the fecundability of couples who were both ≤24 years with the same age was the highest, which decreased steadily with the increase of spousal age difference, and younger male partners did not seem to contribute to improving couple's fecundability. In the multigravida group, couples with female partners aged 25-34 years and a spousal age difference of -5 to 5 years showed higher fecundability, and the effect of spousal age difference on couple's fecundability became suddenly apparent when female partners aged around 40 years. Young male partners were unable to change the decisive effect of female partner's age over 40 years on couple's reduced fecundability, regardless of gravidity. Lacking the time for couples to attempt pregnancy before enrollment, and some couples might suspend pregnancy plans during follow-up because of certain emergencies, which would misestimate the fecundability. Due to the lack of information on sperm quality and sexual frequency of couples, we could not adjust for these factors. Moreover, due to population characteristics, the extrapolation of our results required caution. The couple's age range of optimal fecundability, age combinations, and spousal age difference on fecundability varied with gravidity. Female age-related decline in fecundability was more dominant in couple's fecundability. Targeted fertility guidance should be provided to couples with different age combinations and gravidities. This research received funding from the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the National Human Genetic Resources Sharing Service Platform (Grant No. 2005DKA21300), People's Republic of China. The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript. The authors report no conflict of interest. N/A.

PECSS: Pulmonary Embolism Comprehensive Screening Score to safely rule out pulmonary embolism among suspected patients presenting to emergency department

BackgroundPulmonary embolism is a severe cardiovascular disease and can be life-threatening if left untreated. However, the detection rate of pulmonary embolism using existing pretest probability scores remained relatively low and clinical rule out often relied on excessive use of computed tomographic pulmonary angiography.MethodsWe retrospectively collected data from pulmonary embolism suspected patients in Zhongshan Hospital from July 2018 to October 2022. Pulmonary embolism diagnosis and severity grades were confirmed by computed tomographic pulmonary angiography. Patients were randomly divided into derivation and validation set. To construct the Pulmonary Embolism Comprehensive Screening Score (PECSS), we first screened for candidate clinical predictors using univariate logistic regression models. These predictors were then included in a searching algorithm with indicators of Wells score, where a series of points were assigned to each predictor. Optimal D-Dimer cutoff values were investigated and incorporated with PECSS to rule out pulmonary embolism.ResultsIn addition to Wells score, PECSS identified seven clinical predictors (anhelation, abnormal blood pressure, in critical condition when admitted, age > 65 years and high levels of pro-BNP, CRP and UA,) strongly associated with pulmonary embolism. Patients can be safely ruled out of pulmonary embolism if PECSS ≤ 4, or if 4 < PECSS ≤ 6 and D-Dimer ≤ 2.5 mg/L. Comparing with Wells approach, PECSS achieved lower failure rates across all pulmonary embolism severity grades. These findings were validated in the held-out validation set.ConclusionsCompared to Wells score, PECSS approaches achieved lower failure rates and better compromise between sensitivity and specificity. Calculation of PECSS is easy and all predictors are readily available upon emergency department admission, making it widely applicable in clinical settings.Trail registrationThe study was retrospectively registered (No. CJ0647) and approved by Human Genetic Resources in China in April 2022. Ethical approval was received from the Medical Ethics Committee of Zhongshan Hospital (NO.B2021-839R).

Updates in psoriasis diagnosis and treatment status in China: results from the National Psoriasis Center Registry.

Updates in psoriasis diagnosis and treatment status in China: results from the National Psoriasis Center Registry.

Using human genetics to improve safety assessment of therapeutics.

Human genetics research has discovered thousands of proteins associated with complex and rare diseases. Genome-wide association studies (GWAS) and studies of Mendelian disease have resulted in an increased understanding of the role of gene function and regulation in human conditions. Although the application of human genetics has been explored primarily as a method to identify potential drug targets and support their relevance to disease in humans, there is increasing interest in using genetic data to identify potential safety liabilities of modulating a given target. Human genetic variants can be used as a model to anticipate the effect of lifelong modulation of therapeutic targets and identify the potential risk for on-target adverse events. This approach is particularly useful for non-clinical safety evaluation of novel therapeutics that lack pharmacologically relevant animal models and can contribute to the intrinsic safety profile of a drug target. This Review illustrates applications of human genetics to safety studies during drug discovery and development, including assessing the potential for on- and off-target associated adverse events, carcinogenicity risk assessment, and guiding translational safety study designs and monitoring strategies. A summary of available human genetic resources and recommended best practices is provided. The challenges and future perspectives of translating human genetic information to identify risks for potential drug effects in preclinical and clinical development are discussed.

EHypertension: A prospective longitudinal multi‐omics essential hypertension cohort

eHypertension: A prospective longitudinal multi‐omics essential hypertension cohort

GSA-Human: Genome Sequence Archive for Human.

The Genome Sequence Archive for Human (GSA-Human) is a data repository specialized for human genetic related data derived from biomedical researches, and also supports the data collection and management of National Key Research and Development Projects. GSA-Human has a data security management strategy according to the national regulations of human genetic resources. It provides two different models of data access: Open-access and Controlled-access. Open-access data are universally and freely accessible for global researchers, while Controlled-access ensures that data are accessed only by authorized users with the permission of the Data Access Committee (DAC). Till July 2021, GSA-Human has housed more than 5.27 PB of data from 750 datasets.

Construction and utilization of human genetic resources in large population cohorts.

In the era of big data and precision medicine, large population cohort studies are one of the preferred designs for studying the etiology of chronic diseases, and cohort genetic resources have become important strategic resources of China. Promoting the standardized construction and utilization of cohort genetic resources can effectively promote the original innovation of research and technological development in the field of biomedicine, and make full use of the rich genetic resources of China. To provide a reference for the construction and utilization of genetic resources in the cohort research in China, we took the Taizhou Longitudinal Study (TZL) as an example and introduced the principles, methods, standard system, and practical experience of the collection, preservation, and shared utilization of genetic resources in the process of the cohort construction.

Construction and application of human genetic resources in the China Kadoorie Biobank.

China is facing a heavy burden of chronic diseases, so it is urgent to promote the relevant researches for early prevention of chronic diseases. Large population cohorts are one of the primary study designs for etiology evidence of chronic diseases, which are helpful to explore feasible intervention measures. Moreover, clarifying the genetic associations between risk factors and diseases from the genetic level of large population cohort can also open up a new way to the exploration of causality. This article aimed to introduce the study "China Kadoorie Biobank (CKB)" jointly carried out by the Chinese Academy of Medical Sciences, Peking University and University of Oxford, with emphasis on the construction progress of genetic resources and the recent published genetic studies, in order to provide reference for the in-depth mining and utilization of genetic resources in large population cohort in China.

Accurate diagnosis and prognosis prediction of gastric cancer using deep learning on digital pathological images: A retrospective multicentre study.

BackgroundTo reduce the high incidence and mortality of gastric cancer (GC), we aimed to develop deep learning-based models to assist in predicting the diagnosis and overall survival (OS) of GC patients using pathological images.Methods2333 hematoxylin and eosin-stained pathological pictures of 1037 GC patients were collected from two cohorts to develop our algorithms, Renmin Hospital of Wuhan University (RHWU) and the Cancer Genome Atlas (TCGA). Additionally, we gained 175 digital pictures of 91 GC patients from National Human Genetic Resources Sharing Service Platform (NHGRP), served as the independent external validation set. Two models were developed using artificial intelligence (AI), one named GastroMIL for diagnosing GC, and the other named MIL-GC for predicting outcome of GC.FindingsThe discriminatory power of GastroMIL achieved accuracy 0.920 in the external validation set, superior to that of the junior pathologist and comparable to that of expert pathologists. In the prognostic model, C-indices for survival prediction of internal and external validation sets were 0.671 and 0.657, respectively. Moreover, the risk score output by MIL-GC in the external validation set was proved to be a strong predictor of OS both in the univariate (HR = 2.414, P < 0.0001) and multivariable (HR = 1.803, P = 0.043) analyses. The predicting process is available at an online website (https://baigao.github.io/Pathologic-Prognostic-Analysis/).InterpretationOur study developed AI models and contributed to predicting precise diagnosis and prognosis of GC patients, which will offer assistance to choose appropriate treatment to improve the survival status of GC patients.FundingNot applicable.

Following the Trace of HVS II Mitochondrial Region Within the Nine Iranian Ethnic Groups Based on Genetic Population Analysis.

The Iranian gene pool is seen as an important human genetic resource for investigating the region connecting Mesopotamia and the Iranian plateau. The main objective of this study was to explore gene flow in nine Iranian ethnic/subpopulation groups (402 samples) by examining mtDNA HVS2 sequence variations. This then allowed us to detect mtDNA HVS2 sequence mutations in two independent thalassemia and cystic fibrosis patient sample groups. The patient groups did not explicitly belong to any of the aforementioned nine subpopulations. Across all subpopulations, the haplogroups B4a1c3a, H2a2a1, N10b, H2a2a2, and J1 were seen to be predominant. High haplogroup diversities along with admixture of the exotic groups were observed in this study. The Arab subpopulation was shown to be independent from the others. It was revealed that there is a far distant relationship between Arab and Azeri groups. The thalassemia patient group, represented an almost random sample of most Iranian ethnic groups, and revealed few significant differences (P < 0.05) in their HVS2 sequence. It turned out that the IVS II-I (G → A) mutation in the thalassemia β-globin gene was highly significant. Since the thalassemia patients in the present study represent many unique haplotypes, we can begin to comprehend the importance of mtDNA with this disease and the necessity for more studies in this context.

Institutional Framework for the Management of Human Genetic Resources in China.

China has made efforts toward the preservation and utilization of human genetic resources (HGRs). In recent years, in the face of various issues that have become increasingly prominent in HGR research, China has continuously strengthened legislation and ethics, and has initially established a relatively complete legal system and ethical guidelines. In the design of regulatory responsibilities, a multisectoral linkage of the Ministry of Science and Technology (MOST), the National Health Commission (NHC), the National Medical Products Administration (NMPA), and the National Intellectual Property Administration (CNIPA) has been formed. In the supervision system, it includes a three-tier structure of Laws/Acts-Regulations-Guidance. In terms of management content, it mainly draws on the basic principles of international conventions such as the Convention on Biological Diversity (CBD), and implements examination and approval filing management and ethical supervision of HGR research in China.

Ancestry-Specific Genome-Wide Association Analyses Identify Shared and Unique Genetic Architecture for Venous Thrombosis in the Han Chinese Population

Background: Venous thromboembolism (VTE) is a complex disease caused by both genetic and environmental risk factors. Although genetic determinants are known to be associated with VTE for individuals with European (EUR) ancestry, a large proportion of the VTE heritability remains unexplained, particularly the genetic architecture of VTE in the East Asian (EAS) population. Findings: We identified three independent genetic loci (FGG, ABO, AKAP12) associated with VTE from GWAS analysis, where AKAP12 is novel. TWAS further identified six (LRAT , KLKB1, GGT7, GSS, EDEM2 and PROCR) independent regulatory signals, of which three are associated with coagulation functions, and three are novel genes with metabolic functions (LRAT, GGT7, GSS). There are shared genetic effects of common variants between Han Chinese and EUR populations (genetic correlation = 0.93 ± 0.27). The individuals with the top 10% polygenic risk score had over three-fold increased risk for VTE relative to the general Han Chinese population. Interpretation: Our results suggest both shared and unique genetic characteristics of VTE between EAS and EUR populations. We identified novel loci suggesting the involvement of metabolic pathways in VTE occurrence in the Han Chinese population. Funding Information: The National Key Research and Development Program of China (No. 2016YFC0905600) National Natural Science Foundation of China (No. 81570049; 81970058); Beijing Natural Science Foundation (No.7152062). Declaration of Interests: Authors report no relevant conflicts of interest. Ethics Approval Statement: This study was conducted under the human and ethical research principles of The Ministry of Science and Technology, People's Republic of China (Regulation of the Administration of Human Genetic Resources, July 1, 2019). All the participants provided informed consent and agreed to participate in this research under a protocol approved by the Ethical Committee of China-Japan Friendship Hospital (Cases) and WeGene (Controls). The study's ethical approval was obtained from the Ethics Committee in China-Japan Friendship Hospital (2016-SSW-7).

Bioethics in China's Biosecurity Law: forms, effects, and unsettled issues.

The Biosecurity Law has laid down a regulatory framework on bioethics in China, from raising awareness through education, requiring researchers to conform to ethical principles and conduct ethical reviews on biomedical research, to giving special attention to human genetic resources. The law constructively leaves a wide range of discretion to medical institutions and professionals in ethical decision-making, adaptive to the biotechnology-ethics-regulation dynamics. This regulatory strategy poses crucial institutional challenges in its implementation, particularly on how to safeguard institutional review boards (IRB), a core mechanism in the governance, to effectively protect human subjects but not unnecessarily hinder the progress of biomedical research. Further measures need to clarify important issues on the IRB-based governance, including legal status of the IRB review decision, potential liabilities, and protections of the IRB members.

A Cysteinyl-tRNA Synthetase Mutation Causes Novel Autosomal-Dominant Inheritance of a Parkinsonism/Spinocerebellar-Ataxia Complex

Background: We observed a 90-member family with a rare combination of multiple neurodegenerative-disease phenotypes and performed a genetic study to identify the causative gene. Methods: We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia, parkinsonism, and cognitive function, as well as brain magnetic resonance imaging (MRI) scans with seven sequences. We performed whole-genome sequencing on four affected and three unaffected members to identify the genetic cause of the phenotypes in the affected members. We searched for co-segregations of abnormal repeat-expansion loci, pathogenic mutations in known SCA-related genes, and novel rare mutations. Subsequently, a novel co-segregating missense mutation in CARS gene was validated by Sanger sequencing in an additional five affected and four unaffected members. Additionally, we generated Cars+/- knockout mice using CRISPR/Cas9 technology to investigate the functional role of the CARS gene. Findings: We found a novel late-onset parkinsonism/spinocerebellar-ataxia complex in this pedigree, which presented core characteristics (i.e., cerebellar ataxia, parkinsonism, and pyramidal signs) in all nine affected members and non-core neurodegenerative characteristics that differed across different posterity's families. Brain MRI showed cerebellar/pons atrophy, pontine-midline linear hyperintensity, decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus, and hypointensities of the cerebellar dentate nuclei, basal ganglia, mesencephalic red nuclei, and substantia nigra, all of which suggested neurodegeneration with iron accumulation. We identified a heterozygous mutation in CARS (E795V) that significantly co-segregated in the pedigree. Remarkably, balance-related deficits and gait disturbances were observed in Cars+/− mice. In addition, pathological findings further revealed that CARS knockout induced dopaminergic neuronal loss in the substantia nigra and reduced parkin levels in the cerebellum. Interpretation: All family members carrying the CARS mutation had the same clinical manifestations of parkinsonism and spinocerebellar-ataxia, which corresponded to neuropathologic changes revealed via brain MRI that were replicated in transgenic animals with similar behavioral changes and pathological manifestations. Funding: This study was funded by the following: NIH-NIA Research Project; The National Key RD The Natural Science Foundation of China; CAMS Innovation Fund for Medical Sciences; Shenzhen Municipal of Government of China; The Strategic Priority Research Program of the Chinese Academy of Science. Declaration of Interest: The authors declare no competing interests. Ethical Approval: The animal experiments were approved by the Ethical Committee of the University of Science and Technology of China (USTC). The genetic data sharing was approved (2020BAT0031) by the Human Genetic Resources Administration of China (HGRAC).

Environmental Exposure to Perfluoroalkyl Substances in Early Pregnancy, Maternal Glucose Homeostasis and the Risk of Gestational Diabetes: A Prospective Cohort Study

Background: Humans are widely exposed to environmental perfluoroalkyl substances ( PFAS ), which may alter glucose homeostasis . However, research linking PFAS exposure to glucose tolerance during pregnancy is limited and the results were inconsistent. We aimed to investigate the association between PFAS exposure and glucose homeostasis in pregnancy in a large prospective cohort. Methods: A total of 2747 pregnant women who participated in the Shanghai Birth Cohort, had blood samples in early pregnancy and completed a 75 g oral glucose tolerance test (OGTT) at 24-28 gestational weeks were included. 10 PFAS were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples in early pregnancy. Logistic regression was used to explore the associations between PFAS concentrations and gestational diabetes mellitus (GDM), while multiple linear regression was used to model the associations between PFAS and OGTT fasting, 1-h and 2-h glucose levels. Potential confounders were adjusted. Bayesian kernel machine regression (BKMR) and a quantile-based g-computation approach were employed to explore the joint and independent effects of PFAS on glucose homeostasis. Findings: The incidence of GDM was 11·8%. One log-unit increment in plasma concentrations in early pregnancy was associated with an increased risk of GDM for perfluorobutane sulfonate (PFBS) [adjusted odd ratio (aOR)=1·23, 95% confidence interval (95% CI): 1·05,1·44] and perfluoroheptanoic acid (PFHpA) (aOR=1·25, 95% CI: 1·07,1·46). Perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonate (PFHxS) and PFHpA were positively correlated with 1-h and 2-h glucose levels. Results of the mixed exposure model showed that the joint effects of PFAS were significantly associated with abnormal glucose homeostasis; PFOS, PFNA and PFHpA may be the main contributors. The above associations were more prominent among women with a normal prepregnant BMI. Interpretation: Environmental exposure to PFAS may affect glucose homeostasis in pregnancy and increase the risk of GDM, especially in normal weight women. Funding Statement: This study was funded by the National Nature Science Foundation of China (41991314 and 81530086) and the Collaborative Innovation Program of the Shanghai Municipal Health Commission (2020CXJQ01), the Ministry of Science and Technology of China (2019YFA0802501), and supported in part by the National Human Genetic Resources Sharing Service Platform (2005DKA21300). Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics Approval Statement: This project was approved by the Research Ethics Committees of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine.