275 Million New Genetic Variants Identified in NIH Precision Medicine Data | All of Us Research Program | NIH
Let's consider that from the point of view of someone who believes in intelligent [sic] design:
Why on Earth would an intelligent designer design so many variations on the same theme? An intelligent designer, especially one endowed with the foresight of omniscience and unlimited powers and who is omnibenevolent and perfect, would design the perfect solution to every problem, and stick with it, not design lots of different solutions to the same problem. And every iteration through the cycle of replication would produce an exact copy of that perfect design, so there is no logical way all those variations could be the result of random mutations which all happened to be equally good at whatever they did, so there was no element of selection involved.
Quite simply, lots of variations on the same theme are evidence not of intelligent design, but of utilitarian, mindless 'design' working without a plan and with no conception of the ideal or perfection. Variation is kept because it works; maybe not exactly as well as other alleles, but well enough for the carrier to survive and reproduce. Even if the differences are too small to play a significant part in evolution by natural selection, unless they are serious deleterious, genetic drift can account for them being a significant part of the species genome.
And we have the evidence in the form of this study that some 2 million of these variants are associated with areas of the genome that are implicated in diseases - not something that an omnibenevolent, intelligent designer would have designed, unless it is malevolent.
Homo sapiens in their present form, have been evolving in Africa for maybe half a million years or more and in Eurasia for about 40,000 years since the last interbreeding with Neandertals and Denisovans, from whom many of these variations will have been inherited, so 275 million small variations in the genomes of 250,000 randomly selected Americans is well within the capabilities of a natural process of random mutations, natural selection and genetic drift. Indeed, one of the major biological advantages of sexual reproduction is that it produces lots of variations and combinations of variations that enable the species to be responsive to environment change through the medium of natural selection. Species that had built in variance had built-in evolvability.
The study is described in an NIH news release:
Researchers have discovered more than 275 million previously unreported genetic variants, identified from data shared by nearly 250,000 participants of the National Institutes of Health’s All of Us Research Program. Half of the genomic data are from participants of non-European genetic ancestry. The unexplored cache of variants provides researchers new pathways to better understand the genetic influences on health and disease, especially in communities who have been left out of research in the past. The findings are detailed in Nature, alongside three other articles in Nature journals.More technical detail is given in the team's open access paper in Nature as well as background to the All of Us research program:
Nearly 4 million of the newly identified variants are in areas that may be tied to disease risk. The genomic data detailed in the study are available to registered researchers in the Researcher Workbench, the program’s platform for data analysis.
To date, more than 90% of participants in large genomics studies have been of European genetic ancestry. NIH Institute and Center directors noted in an accompanying commentary article in Nature Medicine that this has led to a narrow understanding of the biology of diseases, and impeded the development of new treatments and prevention strategies for all populations. They emphasize that many researchers are now utilizing the All of Us dataset to advance precision medicine for all.As a physician, I’ve seen the impact the lack of diversity in genomic research has had in deepening health disparities and limiting care for patients. The All of Us dataset has already led researchers to findings that expand what we know about health – many that may not have been possible without our participants' contributions of DNA and other health information. Their participation is setting a course for a future where scientific discovery is more inclusive, with broader benefits for all.
Dr. Josh Denny, M.D., M.S., co-author
Chief executive officer of the All of Us Research Program.
For example, in a companion study published in Communications Biology, a research team led by Baylor College of Medicine, Houston, reviewed the frequency of genes and variants recommended by the American College of Medical Genetics and Genomics across different genetic ancestry groups in the All of Us dataset. These genes and variants mirror those in the program’s Hereditary Disease Risk research results offered to participants. The authors found significant variability in the frequency of variants associated with disease risk between different genetic ancestry groups and compared with other large genomic datasets.
While more research is needed before these findings can be used to tailor genetic testing recommendations for specific populations, researchers believe the difference in the number of these variants may be influenced by past studies’ limited diversity and their disease-focused approach to participant enrollment, rather than a difference in the prevalence of the variants.
In a separate study, investigators with the eMERGE program tapped the All of Us dataset to calibrate and implement 10 polygenic risk scores for common diseases across diverse genetic ancestry groups. These scores calculate an individual’s risk of disease by taking into account genetic and family history factors. Without accounting for diversity, polygenic risk scores could cause false results that misrepresent a person’s risk for disease and create inequitable genetic tools. Without the diversity of the All of Us data, these polygenic risk scores would have only been applicable to some of the population.
More than 750,000 people have enrolled in All of Us to date. Ultimately, the program plans to engage at least one million people who reflect the diversity of the United States and contribute data from DNA, electronic health records, wearable devices, surveys, and more over time. The program regularly expands and refreshes the dataset as more participants share information.All of Us values intentional community engagement to ensure that populations historically underrepresented in biomedical research can also benefit from future scientific discoveries. This starts with building awareness and improving access to medical research so that everyone has the opportunity to participate.
Dr Karriem Watson, D.H.Sc., M.S., M.P.H., Co-author
Chief engagement officer of the All of Us Research Program.
To learn more about All of Us’ scientific resources, visit researchallofus.org.
AbstractI wonder how much more embarrassment for creationists will come from this research program? No wonder they regard scientific knowledge as so toxic.
Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics1,2,3,4. The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health5,6. Here we describe the programme’s genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1 billion genetic variants, including more than 275 million previously unreported genetic variants, more than 3.9 million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers through the All of Us Researcher Workbench using a unique data passport model with a median time from initial researcher registration to data access of 29 hours. We anticipate that this diverse dataset will advance the promise of genomic medicine for all.
Main
Comprehensively identifying genetic variation and cataloguing its contribution to health and disease, in conjunction with environmental and lifestyle factors, is a central goal of human health research1,2. A key limitation in efforts to build this catalogue has been the historic under-representation of large subsets of individuals in biomedical research including individuals from diverse ancestries, individuals with disabilities and individuals from disadvantaged backgrounds3,4. The All of Us Research Program (All of Us) aims to address this gap by enrolling and collecting comprehensive health data on at least one million individuals who reflect the diversity across the USA5,6. An essential component of All of Us is the generation of whole-genome sequence (WGS) and genotyping data on one million participants. All of Us is committed to making this dataset broadly useful—not only by democratizing access to this dataset across the scientific community but also to return value to the participants themselves by returning individual DNA results, such as genetic ancestry, hereditary disease risk and pharmacogenetics according to clinical standards, to those who wish to receive these research results.
Here we describe the release of WGS data from 245,388 All of Us participants and demonstrate the impact of this high-quality data in genetic and health studies. We carried out a series of data harmonization and quality control (QC) procedures and conducted analyses characterizing the properties of the dataset including genetic ancestry and relatedness. We validated the data by replicating well-established genotype–phenotype associations including low-density lipoprotein cholesterol (LDL-C) and 117 additional diseases. These data are available through the All of Us Researcher Workbench, a cloud platform that embodies and enables programme priorities, facilitating equitable data and compute access while ensuring responsible conduct of research and protecting participant privacy through a passport data access model.
The All of Us Research Program
To accelerate health research, All of Us is committed to curating and releasing research data early and often6. Less than five years after national enrolment began in 2018, this fifth data release includes data from more than 413,000 All of Us participants. Summary data are made available through a public Data Browser, and individual-level participant data are made available to researchers through the Researcher Workbench (Fig. 1a and Data availability).Participant data include a rich combination of phenotypic and genomic data (Fig. 1b). Participants are asked to complete consent for research use of data, sharing of electronic health records (EHRs), donation of biospecimens (blood or saliva, and urine), in-person provision of physical measurements (height, weight and blood pressure) and surveys initially covering demographics, lifestyle and overall health7. Participants are also consented for recontact. EHR data, harmonized using the Observational Medical Outcomes Partnership Common Data Model8 (Methods), are available for more than 287,000 participants (69.42%) from more than 50 health care provider organizations. The EHR dataset is longitudinal, with a quarter of participants having 10 years of EHR data (Extended Data Fig. 1). Data include 245,388 WGSs and genome-wide genotyping on 312,925 participants. Sequenced and genotyped individuals in this data release were not prioritized on the basis of any clinical or phenotypic feature. Notably, 99% of participants with WGS data also have survey data and physical measurements, and 84% also have EHR data. In this data release, 77% of individuals with genomic data identify with groups historically under-represented in biomedical research, including 46% who self-identify with a racial or ethnic minority group (Fig. 1c, Supplementary Table 1 and Supplementary Note).Fig. 1: Summary of All of Us data resources.
a, The All of Us Research Hub contains a publicly accessible Data Browser for exploration of summary phenotypic and genomic data. The Researcher Workbench is a secure cloud-based environment of participant-level data in a Controlled Tier that is widely accessible to researchers. b, All of Us participants have rich phenotype data from a combination of physical measurements, survey responses, EHRs, wearables and genomic data. Dots indicate the presence of the specific data type for the given number of participants. c, Overall summary of participants under-represented in biomedical research (UBR) with data available in the Controlled Tier. The All of Us logo in a is reproduced with permission of the National Institutes of Health’s All of Us Research Program.
Scaling the All of Us infrastructure
The genomic dataset generated from All of Us participants is a resource for research and discovery and serves as the basis for return of individual health-related DNA results to participants. Consequently, the US Food and Drug Administration determined that All of Us met the criteria for a significant risk device study. As such, the entire All of Us genomics effort from sample acquisition to sequencing meets clinical laboratory standards9.
All of Us participants were recruited through a national network of partners, starting in 2018, as previously described5. Participants may enrol through All of Us-funded health care provider organizations or direct volunteer pathways and all biospecimens, including blood and saliva, are sent to the central All of Us Biobank for processing and storage. Genomics data for this release were generated from blood-derived DNA. The programme began return of actionable genomic results in December 2022. As of April 2023, approximately 51,000 individuals were sent notifications asking whether they wanted to view their results, and approximately half have accepted. Return continues on an ongoing basis.
The All of Us Data and Research Center maintains all participant information and biospecimen ID linkage to ensure that participant confidentiality and coded identifiers (participant and aliquot level) are used to track each sample through the All of Us genomics workflow. This workflow facilitates weekly automated aliquot and plating requests to the Biobank, supplies relevant metadata for the sample shipments to the Genome Centers, and contains a feedback loop to inform action on samples that fail QC at any stage. Further, the consent status of each participant is checked before sample shipment to confirm that they are still active. Although all participants with genomic data are consented for the same general research use category, the programme accommodates different preferences for the return of genomic data to participants and only data for those individuals who have consented for return of individual health-related DNA results are distributed to the All of Us Clinical Validation Labs for further evaluation and health-related clinical reporting. All participants in All of Us that choose to get health-related DNA results have the option to schedule a genetic counselling appointment to discuss their results. Individuals with positive findings who choose to obtain results are required to schedule an appointment with a genetic counsellor to receive those findings.
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