MarigortaLab retweeted
A great resource from FinnGen offering access to single-cell eQTLs and caQTLs for peripheral blood mononuclear cells (PBMCs) from 1,108 individuals.
They identify cis-eQTLs in at least one cell type for 76% of the tested genes.
Strikingly, for some traits, these eQTLs and caQTLs, together with pLoF/missense coding variants, can now explain the majority of GWAS hits (figure below).
MarigortaLab retweeted
The Lp(a)HORIZON trial tested one of the most genetically validated targets in medicine, but failed to meet its primary endpoint of cardiovascular event reduction in secondary prevention.
While other therapeutic programs are also supported by genetic data, what was special about the Lp(a) hypothesis was that genetic estimates were used to predict the effect expected in trials, and these predictions partly informed the design of Lp(a)HORIZON.
The results therefore offer a unique opportunity to ask how well estimates from genetic studies translate into clinical risk reduction.
In this new piece (link in the comments), I go through the genetic evidence, the trial results, how they agree or disagree, and where this leaves the Lp(a) hypothesis.
2026? Nope, @sciam in 1868! 😅
“It is not too much to say that (...) more prolific discoveries have been made, grandeur achievements have been realized, in the course of the 50 years of our own lifetime than in all the previous lifetime of the race”
From rogermartin.medium.com/what-…
MarigortaLab retweeted
🚨 It's finally out! 🚨 This is the big one. 100 cultures, 12,000 people, 108 researchers. Why people (and our most-used surveys) get collectivism wrong and how to fix it. Join me for a fun thread! 🧵 @NatureHumBehav nature.com/articles/s41562-0…
MarigortaLab retweeted
Breaking the therapeutic ceiling of immune-mediated diseases (IMIDs) is a major medical challenge.
@CellRepMed we identify drug combinations that are more likely to complement each other and help prioritization to clinical stages
cell.com/cell-reports-medici…
"The Coronary Artery Inflammation Controversy" by @EricTopol
➡️Two "succesful yet failed" cardiovascular trials 😨
➡️A surrogate in blood is not the pathogenic process
➡️Also in IBD, we need to distinguish risk markers from targetable disease biology
erictopol.substack.com/p/the…
"A choice is a strategy choice only if the opposite is not stupid on its face. If the opposite is stupid, making your choice is merely non-stupid, not particularly meritorious. And it certainly wouldn’t lead you to competitive advantage"
rogerlmartin.substack.com/p/…
MarigortaLab retweeted
Most omics studies include cross-sectional quantifications at a single timepoint.
Serial assessment is important for understanding the dynamic changes, if we envision using omics signatures as clinical biomarkers.
Two studies in the last month offer such resources👇
Revisiting a lovely gem from....20 years ago! 😍
"Most Rare Missense Alleles Are Deleterious in Humans: Implications for Complex Disease and Association Studies"
sciencedirect.com/science/ar…
MarigortaLab retweeted
A new blog post on GWAS Stories this week on a beautiful piece of work from @soumya_boston's lab. The authors have taken a well characterized GWAS locus, CD40, associated with multiple autoimmune diseases, and dismantled it all the way down to the base pair and the cell state that drive the signal.
gwasstories.com/p/a-gwas-loc…
MarigortaLab retweeted
Alex is a very talented statistician who is doing groundbreaking research on methods to disentangle genetic from environmental influences on human traits.
I'm no expert in that field and have only an amateur interest in it, but he is also one of the few voices I trust on the topic because I have never caught him making a sloppy argument or lying for ideological reasons, which sadly is more than I can say about most people on both sides of the general debate about nature/nurture.
If you can afford it, please consider donating so he can continue his work and be killed by robots in a few decades from now, like the rest of us.
In March 2024, at the age of 35, I was diagnosed with stage IV rectal cancer with a metastasis in my liver. This was a shock: I had no family history, and none of the doctors suspected it. After two years of chemotherapy, radiation, and multiple surgeries, I'm still not cured. Now I'm asking for help to get a personalized cancer vaccine.
This is my story so far.
Following diagnosis, I was treated with total neoadjuvant therapy at UCLA. I had 6 weeks of radiation and chemotherapy (Xeloda). This was followed by 6 rounds of oxaliplatin infusions and Xeloda. I tolerated this unusually well. During this period, I managed to hike up to over 11,000ft multiple times in the Sierras, and I wrote the main text of a 72 author meta-analysis paper and submitted it to Nature where it is still in review.
I showed a good clinical response, and at the end of October I had surgery: I was under for 9 hours, and they cut out a bit of my rectum, 1/3rd of my liver, and gave me a temporary ileostomy. Waking up from this was probably the strangest experience of my life: I felt more machine than man, and I had wild hallucinations form such a large dose of anesthesia.
It took a while to feel OK after that surgery. However, I still had the ostomy. I had that reversed at the end of January in another surgery, which took a greater toll on me than I expected.
I only just started to feel OK again and I got bad news: I got a positive circulating tumor DNA test (ctDNA), the signatera test from natera. Unfortunately, the ctDNA carried on rising, and in July 2025 a new lesion appeared in a lymph node near my liver (periportal).
I was treated with irinotecan and panitumumab infusions, which showed a good response, followed by live MRI guided SBRT radiation treatment to the lesion. However, after finishing this treatment, the ctDNA remained positive and began rising again. I restarted irinotecan and panitumumab infusions, which brought ctDNA back to negative (signatera), although it remained positive on the more sensitive Personalis assay.
During this period I had begun to develop stomach pain and digestive symptoms. Then I collapsed vomiting blood while out in Santa Monica and was rushed to the ER. They found out I had a duodenal ulcer that had bled. I had some blood transfused, and I was sent home to complete an intensive course of antibiotics for H. Pylori infection.
However, after about a week, I started to get very weak. I collapsed again and went back to the ER in an ambulance. They found my hemoglobin was 5g/dL, a dangerously low level (normal is over 13.5). Multiple blood transfusions didn't bring it up and I collapsed again in the night after passing a large amount of blood. They took me to intensive care and performed an emergency endoscopy where they clipped and sprayed the ulcer. Thankfully this worked and I was discharged after another 3 nights in hospital.
Unsurprisingly, nearly bleeding to death wasn't good for me, and my ctDNA began to spike rapidly. I had a PET-CT and it revealed 3 new disease sites in abdominal lymph nodes. I restarted irinotecan and panitumumab infusions after barely recovering from the ulcer incident. This showed an excellent response, with the sites resolving on imaging, although ctDNA remained positive.
I've now started bot/bal immunotherapy, a not yet approved immunotherapy treatment that is the first of its kind to show strong results in my kind of cancer, micro-satellite stable colorectal cancer. This was possible thanks to a donation from an anonymous benefactor and supporter of free and open inquiry in science.
Hopefully this treatment will be effective, but it is unlikely to be enough on its own to prevent future disease recurrence.
I am asking for help to get a personalized neoantigen cancer vaccine, which could substantially increase my chances of surviving this deadly disease that is likely incurable under standard care.
While cancer vaccines have shown promising results, they are not yet approved, meaning one has to pay for the design, manufacture, and administration of the vaccine. The total cost of which is $104,133, beyond my means or those of my family.
Any help would be greatly appreciated! I've started a GoFundMe here: gofundme.com/f/cancer-vaccin…. Please donate and share with anyone who might be interested in helping.
I've carried on working throughout this period and I'm still running a research group in statistical genetics at UCLA. I'm hoping to continue making contributions to science for as long as I can, hopefully longer with your help.
MarigortaLab retweeted
In March 2024, at the age of 35, I was diagnosed with stage IV rectal cancer with a metastasis in my liver. This was a shock: I had no family history, and none of the doctors suspected it. After two years of chemotherapy, radiation, and multiple surgeries, I'm still not cured. Now I'm asking for help to get a personalized cancer vaccine.
This is my story so far.
Following diagnosis, I was treated with total neoadjuvant therapy at UCLA. I had 6 weeks of radiation and chemotherapy (Xeloda). This was followed by 6 rounds of oxaliplatin infusions and Xeloda. I tolerated this unusually well. During this period, I managed to hike up to over 11,000ft multiple times in the Sierras, and I wrote the main text of a 72 author meta-analysis paper and submitted it to Nature where it is still in review.
I showed a good clinical response, and at the end of October I had surgery: I was under for 9 hours, and they cut out a bit of my rectum, 1/3rd of my liver, and gave me a temporary ileostomy. Waking up from this was probably the strangest experience of my life: I felt more machine than man, and I had wild hallucinations form such a large dose of anesthesia.
It took a while to feel OK after that surgery. However, I still had the ostomy. I had that reversed at the end of January in another surgery, which took a greater toll on me than I expected.
I only just started to feel OK again and I got bad news: I got a positive circulating tumor DNA test (ctDNA), the signatera test from natera. Unfortunately, the ctDNA carried on rising, and in July 2025 a new lesion appeared in a lymph node near my liver (periportal).
I was treated with irinotecan and panitumumab infusions, which showed a good response, followed by live MRI guided SBRT radiation treatment to the lesion. However, after finishing this treatment, the ctDNA remained positive and began rising again. I restarted irinotecan and panitumumab infusions, which brought ctDNA back to negative (signatera), although it remained positive on the more sensitive Personalis assay.
During this period I had begun to develop stomach pain and digestive symptoms. Then I collapsed vomiting blood while out in Santa Monica and was rushed to the ER. They found out I had a duodenal ulcer that had bled. I had some blood transfused, and I was sent home to complete an intensive course of antibiotics for H. Pylori infection.
However, after about a week, I started to get very weak. I collapsed again and went back to the ER in an ambulance. They found my hemoglobin was 5g/dL, a dangerously low level (normal is over 13.5). Multiple blood transfusions didn't bring it up and I collapsed again in the night after passing a large amount of blood. They took me to intensive care and performed an emergency endoscopy where they clipped and sprayed the ulcer. Thankfully this worked and I was discharged after another 3 nights in hospital.
Unsurprisingly, nearly bleeding to death wasn't good for me, and my ctDNA began to spike rapidly. I had a PET-CT and it revealed 3 new disease sites in abdominal lymph nodes. I restarted irinotecan and panitumumab infusions after barely recovering from the ulcer incident. This showed an excellent response, with the sites resolving on imaging, although ctDNA remained positive.
I've now started bot/bal immunotherapy, a not yet approved immunotherapy treatment that is the first of its kind to show strong results in my kind of cancer, micro-satellite stable colorectal cancer. This was possible thanks to a donation from an anonymous benefactor and supporter of free and open inquiry in science.
Hopefully this treatment will be effective, but it is unlikely to be enough on its own to prevent future disease recurrence.
I am asking for help to get a personalized neoantigen cancer vaccine, which could substantially increase my chances of surviving this deadly disease that is likely incurable under standard care.
While cancer vaccines have shown promising results, they are not yet approved, meaning one has to pay for the design, manufacture, and administration of the vaccine. The total cost of which is $104,133, beyond my means or those of my family.
Any help would be greatly appreciated! I've started a GoFundMe here: gofundme.com/f/cancer-vaccin…. Please donate and share with anyone who might be interested in helping.
I've carried on working throughout this period and I'm still running a research group in statistical genetics at UCLA. I'm hoping to continue making contributions to science for as long as I can, hopefully longer with your help.
"The hidden geometry of breeding constraints"
rdcu.be/fu1J1
▶️Breeders dont allow the full genetic landscape to manifest. The "constrained" manifold then seems additive, and misses lots of potential for improvement
🤔Useful angles for human complex disease genomics...?
MarigortaLab retweeted
1/When we diagnose IBD, we don't know which therapy will work for that patient. Could the biopsies we already take give us clues?
Presenting a valuable intestinal cell atlas: doi.org/10.1172/JCI202488
@MikeKattahMD, @alexis_combes & team @UCSFMedicine applied spatial gene mapping to archived colitis biopsies, identifying immune cell neighborhoods that explain why some patients are resistant to vedolizumab and others respond well.
@MayoClinic
#Colitis #IBD
✅ Genetic effects easier to discover in young and low risk folk (same effects less affected by noisy environmental variance)
"Hiding in plain sight: uncovering the genetic basis of complex phenotypes through low-risk groups" 👇
academic.oup.com/genetics/ad…
PGS Browser: a public platform for personalized
polygenic score analysis and interpretation 😮
nature.com/articles/s41467-0…
➡️Massive evaluation of PGSs across traits in FinnGen
➡ Many AUC >0.6, few at 0.8 (IMIDs on top)
➡️Each PGS associated with 81 traits on averaeg (PheWAS atlas)
LLMs currently raise the floor more than the ceiling, and in the meantime, may lead to gradual difficult-to-notice stifling of creativity...
What a great piece!
theinfinitesimal.substack.co…
MarigortaLab retweeted
Predictive performance of polygenic scores seems to be highly context-dependent. This paper shows widespread interactions with environmental exposures, medical history, and biomarkers.
If they are ever to make it to the clinic, PRS research needs to move from population-based studies like UK Biobank to focused studies testing performance in concrete clinical scenarios.
I liked this 🧐
Beyond the baseline: mapping the context-specific regulatory landscape of disease dlvr.it/TRSJ8F





























