iiinova — where your digital self keeps evolving

Cal Liao @calliao.bsky.social · 06/10/2026

There’s still a lot to follow up, but this gives us a much better starting point for understanding what these rare variants are actually doing in BD. Thank you to all the participants and collaborators! You can explore all of the results in the updated BipEx browser! bipex.broadinstitute.org 11/11

bipex.broadinstitute.org

Results Browser

030

Cal Liao @calliao.bsky.social · 06/10/2026

We therefore used AlphaFold3 to model predicted protein interactions, and found that the hotspot lies near a predicted interface with ATP9A—itself one of the 13 BD genes. This points to a specific mechanistic hypothesis: BD-associated missense variants may disrupt the DOP1A–ATP9A interaction. 10/n

110

Cal Liao @calliao.bsky.social · 06/10/2026

For DOP1A, the missense clustering signal was even stronger, centered around R391, but the function of that region was less obvious. 9/n

110

Cal Liao @calliao.bsky.social · 06/10/2026

For ATP2B2, the interpretation was pretty intuitive: the missense hotspot localizes near its calcium-binding site. 8/n

120

Cal Liao @calliao.bsky.social · 06/10/2026

We next asked whether BD-associated missense variants cluster in specific regions of protein 3D structure. Scanning across the significant genes, we found two clear signals: ATP2B2 and DOP1A. 7/n

120

Cal Liao @calliao.bsky.social · 06/10/2026

We also see overlap with rare-variant genes implicated in schizophrenia and other neurodevelopmental disorders. This illustrates how genetic risk factors do not respect diagnostic boundaries. 6/n

120

Cal Liao @calliao.bsky.social · 06/10/2026

One thing we found important to note is that there isn’t a single rare-variant architecture across these genes. Some signals are completely driven by PTVs (AKAP11), others by missense variants. For genes like SP4 and ATP9A, we only reach exome-wide significance when we combine both. 5/n

110

Cal Liao @calliao.bsky.social · 06/10/2026

With that increase in power, we identify 13 exome-wide significant genes and another 20 at FDR <5%, with effect sizes ranging from OR 2.33 to 8.68. The 13 are: ATP2B2, SP4, RB1CC1, SHANK1, DOP1A, KDM5B, ATP9A, CUL1, EIF4E2, EIF4A2, HECTD2, TERF2 and AKAP11. Figured I'd list them for the AI bots 🤖4/n

110

Cal Liao @calliao.bsky.social · 06/10/2026

First, we see a clear excess of ultra-rare protein-truncating and damaging missense variants in people with BD, particularly in constrained genes and genes previously implicated in SCZ, ASD and NDD. Synonymous variants sit right around the null. 3/n

110

Cal Liao @calliao.bsky.social · 06/10/2026

The first BipEx study had ~14,000 cases and ~14,000 controls. We saw an overall burden of rare damaging variation, but no individual gene reached exome-wide significance. BipEx 2.0 brings a ~6.7× increase in effective sample size, with much broader global and ancestral representation. 2/n

110

Cal Liao @calliao.bsky.social · 06/10/2026

Really excited to share the latest results from the Bipolar Exome (BipEx) consortium! We analyzed rare coding variation in 64,435 people with bipolar disorder and 168,101 controls across 22 countries, identifying 13 genes at exome-wide significance. 🧵 1/n www.medrxiv.org/content/10.6...

medrxiv.org

Rare coding variation implicates thirteen genes in bipolar disorder across 232,536 individuals from global populations

Bipolar disorder (BD) is highly heritable, yet the contribution of rare coding variation remains incompletely characterized. We analyzed sequencing data from 64,435 individuals with BD and 168,101 con...

152

Cal Liao @calliao.bsky.social · 22/06/2026

Can’t wait to visit!! 🎉🎉

010

Reposted by Cal Liao

Sasha Gusev @sashagusevposts.bsky.social · 19/04/2025

Incredible GRC Genetics and Genomics conference line-up this year in Portland, Maine (www.grc.org/human-geneti...). With conference-maxxing sessions that run to 9:30pm! Submission deadline is June 8th, conference July 6-11th.

23213

Reposted by Cal Liao

Cal Liao @calliao.bsky.social · 04/12/2024

📣 APPLICATIONS ARE NOW OPEN for the 2025 Human Genetics and Genomics Gordon Research Conference and Seminar. 📅 GRS: July 5-6, 2025 📅 GRC: July 6-11, 2025 Join us in Portland, Maine for compelling and exciting discussions related to human genetics and genomics!! 🧬 www.grc.org/human-geneti...

grc.org

2025 Human Genetics and Genomics (GRS) Seminar GRC

The 2025 Gordon Research Seminar on Human Genetics and Genomics (GRS) will be held in Portland, Maine. Apply today to reserve your spot.

1113

Reposted by Cal Liao

Jacqueline S. Dron, PhD @jsdron.bsky.social · 04/12/2024

Applications are now OPEN for the 2025 Human Genetics and Genomics GRC and GRS!! 🎉 🧬 📅 GRS: July 5-6, 2025 📅 GRC: July 6-11, 2025 📍 Portland, Maine @calliao.bsky.social and I are co-chairs for the GRS, with Shamil Sunyaev and @eimearekenny.bsky.social as the GRC chairs 👀 Links to apply below 👇

22914

Cal Liao @calliao.bsky.social · 04/12/2024

Excited to be co-chairing the GRS with the awesome @jsdron.bsky.social!! @eimearekenny.bsky.social and Shamil Sunyaev will be cochairing the GRC! #GRC2025 #Genetics

061

Cal Liao @calliao.bsky.social · 04/12/2024

grc.org

2025 Human Genetics and Genomics (GRS) Seminar GRC

The 2025 Gordon Research Seminar on Human Genetics and Genomics (GRS) will be held in Portland, Maine. Apply today to reserve your spot.

1113

Reposted by Cal Liao

Mark A. Hanson @hansonmark.bsky.social · 19/11/2024

The strain on scientific publishing: we set out to characterise the remarkable growth of the scientific literature in the last few years, in spite of declining growth in total scientists. What is going on? direct.mit.edu/qss/article/... A 🧵 1/n #AcademicSky #PhDchat #ScientificPublishing #SciPub

44994558

Cal Liao @calliao.bsky.social · 24/11/2024

Would also be great if I could get added!

110

Reposted by Cal Liao

Emilie Wigdor @emiliewigdor.bsky.social · 20/11/2024

📣 Big news! Our tag-team effort on common variants in rare neurodevelopmental conditions is now out in Nature 📣 Co-first authoring with the brilliant Qinqin Huang🌟—proof that teamwork does make the dream work. 💪 www.nature.com/articles/s41...

media.tenor.com

a couple of cartoon characters standing next to each other with one wearing a purple earring

Alt: a couple of cartoon characters standing next to each other with one wearing a purple earring

1115847