Excellent question! We briefly looked into singleton burden causing deviation from PGS for schizophrenia and bipolar disorder. The signal wasn't quite as robust, but perhaps an opportunity for future work!

Thanks for sharing our preprint! :)

For those curious, here's our graphical abstract

Thank you to senior authors @astheeggeggs.bsky.social and @ceclindgren.bsky.social , and my co-authors Frederik Lassen, @barneyhill.bsky.social , @samvidav.bsky.social, @hannahcurrant.bsky.social !

We also performed an exome-wide scan for novel genes associated with misalignment...

♀️Age at Menopause: We identified KANK1 as a gene associated with later-than-expected age at menopause, suggesting a potential protective role against primary ovarian insufficiency.

We found "misaligned" individuals are enriched for rare variants:

🦴 Bone Density: Low misaligned enriched for pLoF in COPB2 & GORAB.

🩸 T2D: Cases with rare HNF1A/HNF4A variants had significantly lower polygenic risk.

🫀 CAD: Controls with protective ANGPTL3 variants had higher polygenic risk.

Why do some individuals defy their polygenic score?

In the largest study of its kind (402k UKB individuals; 7 continuous traits + 3 diseases), we asked: If your phenotype deviates from common-variant polygenic score prediction, what's driving that difference?

www.medrxiv.org/content/10.6...

This research was made possible through funding from @wellcometrust.bsky.social, the Clarendon Scholarship, and the Oxford-Bendich scholarship from @pembrokeoxford.bsky.social

Thanks to co-authors İlknur Sur Erdem (co-first), @samvidav.bsky.social, Saskia Reibe, Philip Charles, Elena Navarro Guerrero, @barneyhill.bsky.social, Frederik Heymann Lassen, Melina Claussnitzer, and senior authors @astheeggeggs.bsky.social and @ceclindgren.bsky.social for their contributions!

Read about our recent paper here: www.bdi.ox.ac.uk/news/first-d...

✨ NEW PUBLICATION ✨

We combined large-scale human genetics with CRISPR-Cas9 editing in fat cells to identify genes linked to fat accumulation.

Check out the full study, now published in AJHG! www.cell.com/ajhg/fulltex...

Check out this PhD opportunity to work with a great supervisor at Oxford! 🌟

And thank you to @wellcometrust.bsky.social, Clarendon Scholars' Association, and @pembrokeoxford.bsky.social for funding my DPhil!

Grateful as always to my co-authors @samvidav.bsky.social, Frederik Heymann Lassen, @hannahcurrant.bsky.social and mentors @astheeggeggs.bsky.social, @ceclindgren.bsky.social for their support!

So excited to give a talk at #ESHG2025! ✨

I presented our work demonstrating that individuals whose phenotype deviates from genetic expectation are enriched for rare damaging variants.

This has implications for:
- Screening of rare disorders 🔎
- Target discovery 💊
- Improving trait prediction 📈