Arjun Bhattacharya

Out today in Nature Genetics: “Quantification method affects replicability of eQTL analysis, colocalization and TWAS,” led by outstanding postdoc @taylorhead.bsky.social at @mdanderson.bsky.social. This was a full lab effort, and I'm proud of them all for their hard work! rdcu.be/a2jiWvAMFaVa

biorxiv.orgImproving isoform-level eQTL and integrative genetic analyses of breast cancer risk with long-read RNA transcript assembliesMost eQTL and TWAS analyses quantify expression using aggregate, tissue-agnostic transcript annotations and ignore isoform-level regulation, potentially obscuring or misattributing regulatory mechanisms. Here, we developed a framework leveraging publicly available long-read RNA-seq data to perform tissue-informed inference of genetic regulation and prioritize candidate causal isoforms for breast cancer risk. We quantified gene- and isoform-level expression in breast tumor (TCGA), non-cancerous mammary tissue, and cultured fibroblasts (GTEx) using three transcriptome annotations: standard GENCODE, tissue-specific long-read-derived assemblies, and combined annotations incorporating transcript-isoforms from both. While GENCODE cataloged over 250,000 pan-tissue isoforms, the tissue-specific long-read assemblies captured reduced sets of 74,717 isoforms in tumor, 48,057 in fibroblasts, and 22,941 in healthy breast. We performed eQTL mapping and fine-mapping, followed by colocalization with overall and subtype-specific breast cancer GWAS and isoform-level TWAS. While most eGenes were concordant across annotations, approximately 1/3 of lead cis-eQTLs for shared eGenes differed between long-read assemblies and GENCODE. Further, eIsoform discovery was highly annotation-specific. In healthy breast tissue, the gold standard tissue for building gene expression prediction models for TWAS of breast cancer, 46% of eIsoforms identified by the long-read annotation were unique to that annotation even though 93.7% of them are present in GENCODE. Despite combined annotations expanding the GENCODE catalog by only 0.6-7.6% depending on tissue source, 69% of unique significant isoform-trait associations were specific to a single annotation. Long-read-informed annotations uncovered regulatory associations entirely missed by GENCODE, including a candidate regulatory isoform at the MARK1 locus captured only in fibroblasts and a previously unannotated splice variant prioritized as the likely effector transcript at NUP107 . These findings demonstrate that transcript annotation is not merely a technical consideration but critically defines the biological hypothesis space for regulatory mechanisms and shapes discovery. Incorporating tissue-resolved isoform annotations from long-read RNA-seq improves the specificity of regulatory inference and enhances identification of candidate causal isoforms at GWAS loci. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, R21CA293419, R01CA237541, R01CA264987

Huge credit to Taylor for the massive compute and bookkeeping, and to @seantbres.bsky.social, @hamiltonnolan.bsky.social, and William Wu for the initial analyses. Taylor is now pushing this into isoform-level QTLs, where the annotation problem is sharper: www.biorxiv.org/content/10.6...

Our lab keeps working on methods and software for annotation-aware eQTL/TWAS and isoform-level inference. Follow along if these problems are yours too. Preprint of the NG paper: www.biorxiv.org/content/10.1...

biorxiv.orgbiorxiv.org

The takeaway is simple but needs community buy-in: choices we treat as standard in a methods section are shaping which genes we nominate.

Our recommendations are basic for now: report annotation version/quantification tool. Update static QTL summary stats and TWAS models more regularly. As long-read datasets grow, use tissue-matched references. Short reads are still useful, but quantification uncertainty needs new data to address.

We pulled the revision and left that paper as a preprint. Then we asked: is this a quirk of ncRNAs, or something bigger? Taylor took it transcriptome-wide: 48 GTEx tissues, multiple annotations/pipelines, eQTL mapping, colocalization, TWAS, and simulations with a realistic data-generating process.

The effects were large. 39–43% discordance in eGene calls across methods, 32–39% across annotations. Expression prediction models were even more sensitive, and different pipelines often prioritized different genes at the same GWAS locus.

medrxiv.orgDistal gene regulation mediated by non-coding RNAs contributes to germline risk for breast and prostate cancerGenome-wide association studies (GWAS) have identified numerous genetic loci associated with breast and prostate cancer risk, suggesting that germline genetic dysregulation influences tumorigenesis. H...

This paper started as a headache. While revising our ncRNA-mediated distal eQTL study, we re-quantified expression with a newer GENCODE annotation. The results changed: the mediating ncRNAs and target genes shifted enough that we couldn’t tell the same story. www.medrxiv.org/content/10.1...

Sean’s been doing great work the last couple years and has really great ideas for an independent program. Come find him at ASHG!

Sean Bresnahan@seantbres.bsky.social

Last announcement: I'm on the faculty job market! My research integrates statistical, functional & evolutionary genomics to study how gestational exposures, maternal-fetal genetics & intragenomic conflict shape development and disease. Please DM me with leads! 🧬🐝🤰🌏

pubs.acs.orgNatural Variation in Transplacental Transfer Efficiency Reveals Distinct Transcriptional Network Architectures of PFAS Effects on Birth Weight and Gestational AgeAbstract. Distinguishing effects of environmental exposures mediated through maternal pathophysiology from those operating through direct fetal mechanisms

Excited to see this out in EHP. Led by talented postdoc/data scientist @seantbres.bsky.social in my group @mdanderson.bsky.social . Great collaboration with co-senior author @jonhuang.bsky.social and researchers at SDSU, A*STAR, and NUS Medicine: pubs.acs.org/evhpaz/artic...

Sean Bresnahan@seantbres.bsky.social

🧬Another new preprint with @jonhuang.bsky.social @uhmanoa.bsky.social & @arjunbhattac.bsky.social @mdanderson.bsky.social ! We used variation in how PFAS cross the placenta to dissect the transcriptional architecture of effects on birthweight & gestational age🧵 www.biorxiv.org/content/10.6...

medrxiv.orgICONIC: An R Package for Integrating Instrumental Variable- and Negative-Control-Informed Causal Discovery and Diagnostics in Multiomic StudiesUnmeasured confounding threatens causal inference and replicability in observational multi-omic studies across variable environments. Genetic instrumental variables (Mendelian randomization) and negat...

1 Sept

Great work by @seantbres.bsky.social and undergrad intern Charis Xiong in tackling a critical problem in molecular epi and genomics! Great collaboration as always with @jonhuang.bsky.social! Try out ICONIC, any and all feedback is welcome.

Sean Bresnahan@seantbres.bsky.social

Our new preprint introduces ✨ICONIC✨: an R package making causal inference accessible for observational omics. It unifies genetic instruments (Mendelian randomization) and negative controls (proximal inference) for mediation analysis under unmeasured confounding. www.medrxiv.org/content/10.6...

26 Mar

Another preprint from our group @mdanderson.bsky.social led by talented postdoc @seantbres.bsky.social! Joint with @jonhuang.bsky.social, exploring the intersection of environmental toxins, maternal/fetal health, and placental txomics. Tweet thread below!

Sean Bresnahan@seantbres.bsky.social

24 Mar

New work by talented postdoc @taylorhead.bsky.social in our group @mdanderson.bsky.social! Tweet thread below:

Taylor Head, PhD@taylorhead.bsky.social

New preprint on the genetic regulation of isoform expression and breast cancer risk! TL;DR: tissue-specific, long-read transcript annotations shape eQTL mapping, TWAS, and isoforms we prioritize at GWAS loci. @arjunbhattac.bsky.social www.biorxiv.org/content/10.6...

14 Oct 2025

Excited to see everyone in Boston at #ashg25! 🧵on my group’s presentations.

Arjun Bhattacharya@arjunbhattac.bsky.social

A few programming notes for #ashg25 from trainees in my group @mdanderson.bsky.social + a thread of me being a proud PI. Please drop by these sessions and talk to @taylorhead.bsky.social, @seantbres.bsky.social , @ytchang11.bsky.social, and me in Boston @geneticssociety.bsky.social next week!

medrxiv.orgFormal Statistical Replication Analysis in Lung Cancer Genome-Wide Association StudiesDozens of genome-wide association studies (GWAS) have identified thousands of single nucleotide polymor-phisms (SNPs) associated with lung cancer risk. However, it remains challenging to translate the...

Star PhD student @ytchang11.bsky.social will present an empirical Bayes method to formally test the replication composite null hypothesis in GWAS, effectively controlling FDR and maintaining strong power. Big downstream implications to check out in her pre-print: www.medrxiv.org/content/10.1....

Sean and Yung-Han both were awarded travel awards for their presentations, underscoring the importance of their work and the hard work they've put in for these projects. Looking forward to #ashg25.

Taylor also was recently nominated internally and submitted an early K99/R00 award to NCI. She did a tremendous amount of work for a really exciting proposal!

biorxiv.orgLong-read transcriptome assembly reveals vast isoform diversity in the placenta associated with metabolic and endocrine functionThe placenta plays a critical role in fetal development and mediates maternal metabolic effects on offspring health outcomes. Despite its importance, the placenta remains understudied in large-scale g...

@seantbres.bsky.social will talk about a placental long-read RNA-seq isoform reference + how using it with short reads improves transcript quantification and DTE/U analyses. Cool results in the preprint below. More maternal-fetal health work soon in GxE/POE analyses. www.biorxiv.org/content/10.1...

biorxiv.orgQuantification method affects replicability of eQTL analysis, colocalization, and TWASeQTL mapping and TWAS are widely used to contextualize GWAS, yet the impact of RNA-seq processing choices remains unexplored. We find that RNA-seq quantification method and transcriptomic reference su...

@taylorhead.bsky.social will talk about integrating long-read based transcript assemblies can improve QTL mapping and GWAS integration for breast cancer risk, building off her recent work showing eQTL colocalization and TWAS are HIGHLY sensitive to annotation choice. www.biorxiv.org/content/10.1...

Arjun Bhattacharya reposted

Harold Pimentel

@hjp.bsky.social

29 Sept 2025

Super excited to get this out. This collab started a few years ago and is the first paper from it. Here, with experimental and computational approaches we: 1. establish that cell villages can be just as accurate (one might argue more accurate!) than arrayed-based designs bsky.app/profile/bior...

bioRxiv Genetics@biorxiv-genetic.bsky.social

Cell villages and Dirichlet modeling map human cell fitness genetics https://www.biorxiv.org/content/10.1101/2025.09.26.678880v1

Arjun Bhattacharya reposted

Wolfgang Huber

@wkhuber.bsky.social

30 Aug 2025

When testing a computational data analysis method: simulated data are good for checking whether the method is doing what you think it should be doing, real data for checking whether what you think it should be doing is any good.

nature.comIsoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level - British Journal of CancerBritish Journal of Cancer - Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level

20 Aug 2025

Very proud of @ytchang11.bsky.social for her first publication from her doctoral research! She conducted very meticulous genomic analyses that uncovered novel isoform-specific mechanistic hypotheses underlying genetic loci associated with multiple cancers. www.nature.com/articles/s41...

nature.comEmerging Leaders | Emerging Leaders - British Journal of CancerBJC’s Emerging Leaders collection recognises stand-out early-to-mid career researchers, clinicians, and educators within the field of oncology.

20 Aug 2025

On a personal note, I'm honored to be named an Emerging Leader by BJC! We're excited to continue our work in genomic mechanisms for cancer risk and progression to discover novel biomarkers for risk stratification and prognosis. www.nature.com/collections/...

Arjun Bhattacharya reposted

Michael Love

@mikelove.bsky.social

18 Aug 2025

Excited to share this preprint from first author Jon Rosen, a postdoctoral fellow in the @klmohlke.bsky.social lab and my lab. We examine eQTL study sample size and how this affects signal discovery and rates of colocalization with GWAS. www.biorxiv.org/content/10.1...

biorxiv.orgHigher eQTL power reveals signals that boost GWAS colocalizationExpression quantitative trait locus (eQTL) studies in human cohorts typically detect at least one regulatory signal per gene, and have been proposed as a way to explain mechanisms of genetic liability...

Arjun Bhattacharya reposted

hanseulkim.bsky.social

@hanseulkim.bsky.social

3 July 2025

⚡🦠I'm very excited to share our latest work on the gut microbiome and metabolic dysfunction-associated steatotic liver disease (MASLD) is published in @natmetabolism.nature.com, with @hutlab.bsky.social & @longnguyen.bsky.social! 🔗Check out the paper here: www.nature.com/articles/s42...

Arjun Bhattacharya reposted

David A Knowles

@davidaknowles.bsky.social

2 July 2025

New work from the lab trying to wrap our heads around the massive complexity of the human transcriptome revealed by long-read RNA-seq! Fun collab with Gloria Sheynkman. www.biorxiv.org/content/10.1...

biorxiv.orgPerplexity as a Metric for Isoform Diversity in the Human TranscriptomeLong-read sequencing (LRS) has revealed a far greater diversity of RNA isoforms than earlier technologies, increasing the critical need to determine which, and how many, isoforms per gene are biologic...

doi.orgLong-read transcriptome assembly reveals vast isoform diversity in the placenta associated with metabolic and endocrine functionThe placenta plays a critical role in fetal development and mediates maternal metabolic effects on offspring health outcomes. Despite its importance, the placenta remains understudied in large-scale g...

2 July 2025

Excited to share new work investigating transcriptional diversity in the placenta from our group led by talented postdoc @seantbres.bsky.social! Thread below describing the salient results. Welcoming any feedback and comments.

Sean Bresnahan@seantbres.bsky.social

🧬🚨PREPRINT🚨- The first placental isoform reference from long-read seq & supporting data! We demonstrate how tissue-specific assembly improves transcript quantification with short-read data from multi-ancestry birth studies & reveals placenta-mediated effects of gestational diabetes on birth weight🫄

Arjun Bhattacharya reposted

Sean Bresnahan

@seantbres.bsky.social

18 June 2025

Much more important things going on in the world, but wanted to share this new work on parent-of-origin effects & “non-canonical” genomic imprinting in developmental plasticity of honey bees, out now in Genome Biology 🧪🧬🔄 link.springer.com/article/10.1...

link.springer.comIntragenomic conflict associated with extreme phenotypic plasticity in queen-worker caste determination in honey bees (Apis mellifera) - Genome BiologyBackground Caste determination of honey bees (Apis mellifera) exemplifies developmental plasticity, where differences in larval diet result in identical genotypes yielding either long-lived, reproduct...

substack.comFrom Code to ComplexityHow Our Cells Read Between the Lines (and Why Federally-Funded Research Matters)

7 May 2025

Drop by and say hi to @mdanderson.bsky.social Postdoctoral Data Scientist @seantbres.bsky.social if you’re at Biology of Genomes. He’ll be presenting some new work from our group that he’s championed. You’ll have an interesting science and/or science policy discussion!

Sean Bresnahan@seantbres.bsky.social

In NY for Biology of Genomes @cshlnews.bsky.social this week. During a layover on the way here, I tried to write a bit to communicate some of the work our group is doing, and why federal research funding for basic science matters substack.com/home/post/p-...

Arjun Bhattacharya reposted

Mark Peifer (He, him)

@peiferlabunc.bsky.social

10 Jan 2025

Neglected to share this good news this morning :)

Arjun Bhattacharya reposted

Yoav Gilad

@ygilad.bsky.social

10 Jan 2025

Friends and colleagues, I’ve written a book on effective functional genomics study design, which will be available on Amazon in a couple of weeks. Sharing the TOC to spark interest. I hope students and those planning genomics experiments will find it useful! I’ll share updates soon

Arjun Bhattacharya reposted

Jess Ewald

@ewaldlab.org

13 Dec 2024

🎉 I'm starting my own lab at EMBL-EBI (Cambridge, UK; June 2025) 🎉 We will focus on identifying and characterizing chemical hazards to humans and ecosystems using computational biology methods. I am beginning the search for two postdocs now - stay tuned for more details! ewaldlab.org

ewaldlab.orgEwald Lab@ EMBL-EBI. We identify and characterize chemical hazards to both humans and ecosystems with cell profiling data, machine learning, and integrative data analysis.

bit.lyCPRTP Summer Research Experience

17 Jan 2024

DEADLINE EXTENDED to Jan. 21! Open to grads & undergrads, join the world of cancer prevention this summer Jun 3 to Aug 9 at MD Anderson with an NCI funded internship working with too cancer researchers & clinicians! Apply at bit.ly/CPRTP-Summer

nature.comIsoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric d...A multivariate framework for isoform-resolution transcriptome-wide association studies enables modeling of a greater number of genes, with the benefit of identifying isoform-specific associations with...

30 Nov 2023

Our isoTWAS work with the Pasaniuc and Gandal labs is out at Nature Genetics! Great team effort, especially from Daniel Vo and Connor Jops. Appreciate the helpful and thoughtful comments from reviewers that improved our work! www.nature.com/articles/s41...

@michelnivard.bsky.social

30 Oct 2023

If you’re a trainee or know one looking for a postdoctoral position, let’s chat during ASHG this week!

Arjun Bhattacharya@arjunbhattac.bsky.social

Come join me at MD Anderson Cancer Center in Houston and the Texas Medical Center! I'm hiring a Postdoctoral Scholar to lead genetic and molecular epidemiology projects to study breast cancer or pregnancy/childhood outcomes. More details here: bit.ly/pd_blgc2023

Arjun Bhattacharya reposted

Michel Nivard

6 Oct 2023

This is a Bluesky feed that tracks #WCPG2023 posts for the world congres of psychiatric genetics 2023, SUBSCRIBE!: bsky.app/profile/did:...