June 8, 2022 | The pioneering OneK1K study in Australia has identified an immune fingerprint of seven autoimmune disorders using single-cell RNA sequencing (scRNA-seq). The general framework, which combines the scRNA-seq data with genotype data to classify individual cells, can be applied to many different diseases, including other autoimmune disorders, cardiovascular diseases, neuroinflammatory conditions, and cancer where the immune system is thought to play a role, according to Joseph Powell, director of cellular science at the Garvan Institute of Medical Research.
Selection of the original seven diseasesmultiple sclerosis, rheumatoid arthritis, lupus, type 1 diabetes, spondylitis, inflammatory bowel disease, and Crohns diseasewere based on their prevalence in the world of autoimmune diseases and high genetic component, he says. The study relied on scRNA-seq data from 1.27 million peripheral blood mononuclear cells collected from 982 healthy donors, many of whom carry the genetic loci found in people who have these diseases.
Take Crohns disease, which has molecular markers found on roughly 190 positions in the genome, Powell cites as an example. On average, patients collectively have roughly 90 risk alleles at those loci, but individually about 60. It is the difference between having 60 and 90 that takes you over the threshold and leads to occurrences of disease.
This phenomenon holds true for most every disease afflicting humans, which is why a big population group is ideal for gaining mechanistic insights on disease-associated genes, he continues. At the cellular level, genome regulation changes brought on by those genes are the same even if there is no clinical manifestation of disease.
Using a Mendelian randomization approach, Powell and his colleagues uncovered the causal route by which 305 loci contribute to autoimmune disease through changes in gene expression in specific cell types and subsetsand that these genetic mechanisms are the same for healthy individuals as in autoimmune disease cohorts. Results published recently in Science (DOI: 10.1126/science.abf30).
Single-cell RNA sequencing was used to look at genetic variants affecting gene expression in 14 different immune cell types, says Powell. It is the largest study to date linking disease-causing genes to specific types of immune cells.
Researchers developed a classification method based on the transcriptomic signature found in individual cells and aligned it back to what is currently understood about more common immune cell types at the top of the hierarchy (e.g., T cells, CD4, CD8, nave to memory B cells). Although 68 immune cells have been classified, they focused on those they were sure to find enough copies of across the OneK1K cohort to confidently link the genetic differences between people to the signatures in the cells.
Tissue-To-Tissue Variability
Powell says he has been interested in genetic control of gene expression, and its contribution to disease, for more than a decade now. For many years, this involved bulk RNA analysis that produces an average signal.
An important clue emerged when researchers began seeing how vastly different the genetics worked in one tissue versus another, he says. Only a few years ago, the Genotype-Tissue Expression Program (GTEx) of the National Institutes of Health examined RNA sequencing samples from 49 tissues of postmortem donors to characterize genetic associations for gene expression and found regulatory associations for almost all genes. Cell type composition was identified as a key factor in understanding gene regulatory mechanisms.
That study showed instances where genetic effects were seen in one tissue and not another, or generated completely different effects, Powell notes. It was published in 2020 when scRNA-sequencing was just emerging as a staple technologyand Powell had just started his computational genomics laboratory at the Garvan Institute.
We were stuck with this interesting question: If we see these differences between tissues, and know the tissues are comprised of really distinct cell types with really specific functional roles, and the transcriptomic cell signatures are different, can we try to create a system to undo the genetics we saw in tissue inside a cell? That led Powell and his colleagues to scale up their scRNA-sequencing efforts.
At the time, the vast amount of generated transcript data generated from 1,000 individuals would have made scRNA-sequence data entirely cost-prohibitive to generate. But Powell helped pioneer a biometric technique to pool cells from multiple samples, as well as a method to analyze the transcripts of individual cells that solved the challenge of determining what portion of them would provide the most useful information in defining a cell type.
Up until then, a few other groups had published studies using samples from perhaps 50 or 100 individuals suggesting signatures of disease, but they were all under-powered, says Powell. They could show genetic differences between cells, but they were all too under-powered to link them to disease, or to resolve why there were differences between cells.
Statistically speaking, disease fingerprints that capture the genetic heterogeneity of patients will never be fully defined, says Powell. But the OneK1K study has probably moved the needle from the 10th percentile to the 50th percentile on the saturation curve.
Powell is now aiming for the 95th percentile with a TenK10K study that will be seeking to enroll 10,000 individuals and generate single cell data on about 50 million cells. The multi-year initiative will involve partnerships with multiple hospitals across Australia, and both a healthy population group and patients newly diagnosed with autoimmune disorders, cardiovascular disease, and cancer.
Autoimmune diseases affect about one in 12 Australians, he notes. They are incurable and require lifelong treatments to minimize the damage. Patients often try many different treatments before finding one that works for them.
The genetic mechanisms are actually really generic, he says. You can learn a lot by linking what we see in [OneK1K study] data to what already know just about genetic positions in disease. Now, were taking those genetic positions from genome-wide association studies and will show mechanisms of action and specifically the cell types they are acting in.
Pure fundamental science is a major driver for the work, says Powell, knowledge creation for human disease... and making all the data publicly available. Since the Science paper published in April, he has been fielding multiple data requests daily.
The more translational outcome is the possibility that the catalogue of genetic mechanisms will be useful in predicting which treatments will work best for individual patients, Powell says. To test that hypothesis, Powells lab is in the process of conducting a series of retrospective and prospective signal-seeking studies using currently marketed drugsstarting with immunotherapy treatment of cancer.
If successful, patients will one day be able to get a very cheap test costing literally tens of dollars [in Australia anyway] to guide the clinical decision-making of their treating physician, Powell says. We think that across a population we will be able to move the efficacy of a drug from, say, 30%which is pretty common for immunotherapy and a lot of inhibitory drugs in autoimmune diseaseto 50% or 60%. Even a 10-percentile gain for a single drug would be remarkable in terms of patient impact, he adds.
Along the way, the molecular mechanisms of disease are being unearthed at the cellular RNA level and that data could be shared with pharmaceutical companies to inform their early-stage drug development work, including which targets to take forward to phase 1 clinical trials, says Powell. Already, four pharma companies and one biotech have approached him about just such partnering opportunity, which would additionally aid them in the selection of patient groups for treatment trials.
Scientific strides have been a team effort by many committed individuals, he says, crediting the 16 co-authors on the latest study hailing from Sydney, Hobart, Melbourne, Brisbane, and San Francisco. They consider themselves part of the larger, decade-long movement toward open science, marked by transparency, open communication, and access to the data and computer code used to reach conclusions.
See the original post:
Genetic Control Of Autoimmune Disease Mapped To Cellular Level - Bio-IT World
- Is ALS Hereditary? Genetics, Inheritance Patterns, and More - Healthline - May 5th, 2024
- Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits ... - Nature.com - May 5th, 2024
- Genetic association of inflammatory marker GlycA with lung function and respiratory diseases - Nature.com - May 5th, 2024
- Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy - Nature.com - May 5th, 2024
- Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute ... - Nature.com - May 5th, 2024
- Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects | npj Genomic Medicine - Nature.com - May 5th, 2024
- Reply to: Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects | npj Genomic Medicine - Nature.com - May 5th, 2024
- Lifespan is influenced more by lifestyle than genetics - Earth.com - May 5th, 2024
- Scientists discover over 100 new genomic regions linked to blood pressure - National Institutes of Health (NIH) (.gov) - May 5th, 2024
- Genetics studies have a diversity problem that researchers struggle to fix - The Lund Report - May 5th, 2024
- Researchers discover the genetic cause of the most common brain malformation - EL PAS USA - May 5th, 2024
- Genetic link between adolescent drinking and adult anxiety may offer therapy target | UIC today - UIC Today - May 5th, 2024
- Phylogenomics and genetic analysis of solvent-producing Clostridium species | Scientific Data - Nature.com - May 5th, 2024
- New genes are involved in the adaptation of acorn barnacles to sessile life - Nature.com - May 5th, 2024
- Rachel Khong explores genetics, race and the idea of being American in new novel - Wyoming Public Media - May 5th, 2024
- Genetic testing led to early cancer detection for father, daughter - Roswell Park Comprehensive Cancer Center - May 5th, 2024
- EYE ON HEALTH: High risk and genetic testing being offered at local hospital - Local 3 News - May 5th, 2024
- Fatty Liver: Is It Hereditary? - Healthline - May 5th, 2024
- Southern Seven Health Department to expand genetic cancer testing - KFVS - May 5th, 2024
- Genetic associations of key genes in breast cancer pathogenesis - News-Medical.Net - May 5th, 2024
- Mating Study Unlocks the Genetic Code of Attraction - Neuroscience News - March 18th, 2024
- Mindfulness in your DNA? Capacity to be present is partly a function of genetics, study finds - PsyPost - March 18th, 2024
- Genetic testing scam targets Medicare recipients, including those in Spokane - KXLY Spokane - March 18th, 2024
- Some people are genetically predisposed to gain weight. These 5 tips can help - CNN - March 18th, 2024
- SOPHiA GENETICS and The French Kidney Cancer Research Network (UroCCR) Publish Results from Multiyear ... - PR Newswire - March 18th, 2024
- Tissue samples show the deep genetic and cellular impacts of smoking - Medical Xpress - March 18th, 2024
- The regulatory landscape of chromatin accessibility - Nature.com - March 18th, 2024
- Genome assemblies of 11 bamboo species highlight diversification induced by dynamic subgenome dominance - Nature.com - March 18th, 2024
- Research reveals the genetic code behind non-identical twins - Medical Xpress - March 18th, 2024
- How genetic therapies transformed the lives of sickle cell patients - KPVI News 6 - March 18th, 2024
- The Next Wave of Privacy Litigation: The Illinois Genetic Information Privacy Act - Perkins Coie - March 18th, 2024
- State initiates study on genetic cancers, Lynch Syndrome - The Times of India - March 18th, 2024
- How genetic therapies transformed the lives of sickle cell patients - Citizentribune - March 18th, 2024
- Dr Plichta on Areas of Interest for Genetic Testing Research in Breast Cancer - OncLive - March 18th, 2024
- The Genetic History of the Jews Mosaic - Mosaic - March 18th, 2024
- New insights into genetic mechanisms could improve treatment of liver fibrosis - Medical Xpress - March 18th, 2024
- 5 Questions To Ask About The Ethics Of Genetic Data - Forbes - March 18th, 2024
- Couple raising money to fix sons club feet caused by rare genetic condition - 21 Alive News - February 18th, 2024
- What can bulls tell us about men? Genetic discovery could translate to human fertility research - Medical Xpress - February 18th, 2024
- Legislation seeks to bar life insurance companies from purchasing recreational genetic testing data - Delaware First Media - February 18th, 2024
- Family-based study identifies potential new genetic factors linked to Alzheimer's risk in people with African ancestry - National Institute on Aging - February 18th, 2024
- Genetic determinants of micronucleus formation in vivo - Nature.com - February 18th, 2024
- Near-gapless and haplotype-resolved apple genomes provide insights into the genetic basis of rootstock-induced ... - Nature.com - February 18th, 2024
- Accurate and sensitive mutational signature analysis with MuSiCal - Nature.com - February 18th, 2024
- CRISPR, the Genetic Revolution of the 21st Century | OpenMind - BBVA OpenMind - February 18th, 2024
- Genetic control of thermomorphogenesis in tomato inflorescences - Nature.com - February 18th, 2024
- Natural selection and genetic diversity maintenance in a parasitic wasp during continuous biological control application - Nature.com - February 18th, 2024
- Understanding how natural genetic variation contributes to adaptive responses to low oxygen - News-Medical.Net - February 18th, 2024
- Division of Epidemiology and Genetics - Epidemiology and Genetics - University of Southern California - February 18th, 2024
- Genetic study clarifies the link between birth weight and adult morbidity - Medical Xpress - February 18th, 2024
- AI and genetics underpin project to speed up CVD diagnosis and personalise treatment - Hospital Healthcare - February 18th, 2024
- Study Reveals Complex Interaction Between Genetics and Environment in Brain Functioning - Medriva - February 18th, 2024
- Unraveling the Impact of Genetics and Socioeconomic Status on Behavioral and Psychiatric Traits - Medriva - February 18th, 2024
- Genetic Investigation Reveals CETP Gene Variants Linked to Cardiovascular Resilience in Genome-Wide Association ... - Physician's Weekly - December 30th, 2023
- Raha Kapoor's blue eyes remind fans of her great-grandfather, Raj Kapoor; here's what genetics says - IndiaTimes - December 30th, 2023
- Genetic clue to pericarditis inflammation points to promising new treatments - News-Medical.Net - December 30th, 2023
- Certain genetic predispositions may increase risk of atrial fibrillation among those with high alcohol consumption - 2 Minute Medicine - December 30th, 2023
- Understanding the genetic basis of hereditary diffuse gastric cancer - News-Medical.Net - December 30th, 2023
- Genetic engineering was meant to save chestnut trees. Then there was a mistake. - The Washington Post - December 30th, 2023
- Unraveling the mystery of hereditary diffuse gastric cancer - EurekAlert - December 30th, 2023
- What is Genetics? | AMNH - American Museum of Natural History - December 22nd, 2023
- Who killed Shelley Connolly? Genetic genealogy leads authorities to a suspect and a conviction - Alaska's News Source - December 22nd, 2023
- C.S. Lewis, Atheism, and the Genetic Fallacy - Word on Fire - December 22nd, 2023
- FDA approves first genetic test to assess opioid addiction risk using DNA sample - Fox News - December 22nd, 2023
- Genetic blueprint of wild grapes could help breed better grapes - University of California, Davis - December 22nd, 2023
- Unlocking the genetic secrets of grape seedlessness - Phys.org - December 22nd, 2023
- Unlocking the genetic secrets of drought resilience in Persian walnuts - Phys.org - December 22nd, 2023
- FDA approves genetic test to assess patients risk of developing an opioid addiction - KXAN.com - December 22nd, 2023
- How researchers are CReATiNG synthetic chromosomes faster and cheaper - EurekAlert - December 22nd, 2023
- The promise of genetic therapies in sickle cell disease - The Lancet - December 22nd, 2023
- Assessment of genetic diversity, population structure and wolf-dog hybridisation in the Eastern Romanian Carpathian ... - Nature.com - December 22nd, 2023
- Genetics and Heart Disease: What you need to know - IndiaTimes - December 22nd, 2023
- How to become a geneticist - University of Sydney - December 22nd, 2023
- Study sheds light on the ancestry and genetics of Coast Salish woolly dogs | News | Vancouver Island University ... - Vancouver Island University News - December 22nd, 2023
- Human genetics | Description, Chromosomes, & Inheritance - December 13th, 2023
- BASIC GENETICS INFORMATION - Understanding Genetics - NCBI Bookshelf - December 13th, 2023
- Introduction to Genetics - Open Textbook Library - December 13th, 2023
- Clues to preventing Alzheimer's come from patient who, despite genetics, evaded disease Washington University ... - Washington University School of... - December 13th, 2023
- Environmental stress rather than genetics influenced height differences in early Neolithic people: Study - Phys.org - December 13th, 2023
- What is trisomy 18? Why the fatal genetic disorder is in the news and what it's like to get the diagnosis. - Yahoo Life - December 13th, 2023