The Sequence 2/19-2/25

Unleashing the Power of Us: Some Insights from the All of Us Data Collection

Unleashing the Power of Us: Some Insights from the All of Us Data Collection

All of Us is a research program dedicated to building one of the most diverse health databases in history to learn how our biology, lifestyle, and environment affect health. With 750,000 people already enrolled to date, All of Us intends to engage at least one million people who reflect the diversity of the United States. Participants contribute data from DNA, electronic health records, wearable devices, surveys, and more over time, and in return the program shares results with participants who have consented to receive them.

This week, a package of papers was published distilling the results from analyses of up to 245,000 genomes gathered by the All of Us program. Almost half of the genomes analyzed were from participants who self-identified as non-European. Here I’ll discuss how these breakthroughs enhance our understanding of health and disease, especially for underrepresented groups.

What did they find?

1. New genetic variants associated with diabetes: An effort known as the Type 2 Diabetes (T2D) Global Genomics Initiative analyzed genetic information from more than 2.5 million people from several databases, including All of Us. The data included 428,452 individuals with T2D, and nearly 40% of the data came from individuals of non-European ancestry. The team found 611 genetic markers that might drive the development and progression of the disease, 145 of which have never been reported before. The variants were further broken down into clusters based on their associations with cells that play a role in cardiometabolic traits, for example genes that play a role in the development of adipocytes, endothelial cells, and neuroendocrine cells. The diverse dataset helped to further assess genetic associations specific to T2D clusters linked to certain traits.

2. Increased known pathogenic variation in people with European ancestry: Researchers at Baylor College of Medicine, the University of Washington, and elsewhere used All of Us cohort data to explore ancestry-related differences in pathogenic or likely pathogenic variant frequencies. They examined the number of pathogenic variants, or harmful genetic variants that increase a person’s risk of developing a particular disease, in different ancestries. The group found pathogenic variants among 2.3% of people with European ancestry and among only 1.6% of people with African ancestry. Since there should be no difference in the frequencies of pathogenic variation among different ancestries, the result points to disparities in genomic research. To date, more than 90% of participants in large genomics studies have been of European genetic ancestry. Because of this, we know more about genetic variations in the European population, leading to more certainty in our understanding of disease-causing genetic variation. Study co-author Eric Venner, a computational geneticist at Baylor College of Medicine in Houston, emphasized the urgent need to study non-European genomes in more detail based on this data.

3. Improved polygenic risk scores (PRS): A polygenic risk score is a number, or a ‘score’ that estimates an individual’s risk for a certain condition. They are used in conditions that are caused by changes in many genes, often coupled with environmental factors. To calculate a score for a particular disease, researchers develop an algorithm that is trained on thousands of genomes from people who either do or don’t have the disease. A person’s own score can then be calculated by feeding their genetic data into the algorithm. However, PRS tend to be less accurate for minority populations for whom we have less accurate data. In one of the current papers, researchers used All of Us data to improve scores for 23 conditions including coronary heart disease and diabetes, even recommending 10 to be prioritized for use in the clinic.

How else might this data be used?

The whole-genome sequencing data that All of Us has made available on samples from nearly a quarter of a million individuals from diverse backgrounds will accelerate genomic medicine discoveries benefiting all of us. Summary-level data are publicly available, and researchers can access individual-level data through the easily accessible All of Us Researcher Workbench. The program plans to release new data every year, representing new enrollees and genomes.

What’s the takeaway?

Until now, there has been an incomplete understanding of the burden of genomic variation on diverse populations. Gathering and using more genomic and health data from diverse populations will be especially important for generating a more accurate picture of a person’s risk of developing a disease as a result of their genetics. In a corresponding commentary to the new publications in Nature Medicine, All of Us Research Program investigator Joshua Denny invited all to include

“all disease domains, diverse populations, common and rare genomic variants, social and commercial determinants of health, or other modalities to ensure the advancement of precision health, medicine, and equity for everyone."

Newsletter Sources:

1. Image: https://www.canva.com/photos/MAEENhzbk4c/

2. https://allofus.nih.gov/

3. https://www.nih.gov/news-events/news-releases/275-million-new-genetic-variants-identified-nih-precision-medicine-data

4. https://www.genomeweb.com/sequencing/nih-all-us-program-returns-first-health-related-genetic-results-participants#.Y5ndoezMK3I

5. https://theweeklysequence.substack.com/p/the-sequence-19-115

6. https://www.nature.com/articles/d41586-024-00502-0

7. https://www.nature.com/articles/s41586-024-07019-6

8. https://www.nature.com/articles/s42003-023-05708-y

9. https://www.nature.com/articles/s41591-024-02796-z

10. https://www.genome.gov/Health/Genomics-and-Medicine/Polygenic-risk-scores

11. https://www.genomeweb.com/sequencing/all-us-data-leads-new-genetic-variants-disease-risk-contributors?utm_source=Sailthru&utm_medium=email&utm_campaign=GWDN%20Tues%20AM%202024-02-20&utm_term=GW%20Daily%20News%20Bulletin

12. https://www.nature.com/articles/s41591-023-02744-3

13. https://theweeklysequence.substack.com/p/the-sequence-1031-116

14. https://theweeklysequence.substack.com/p/the-sequence-125-1211

15. https://theweeklysequence.substack.com/p/the-sequence-1219-1225

16. https://theweeklysequence.substack.com/p/the-sequence-1212-1218