EP 115: The Biggest Stories of 2023 with Dr. Veera Rajagopal (Part 2)

In the second instalment of our annual round-up episode, we welcome back Dr. Veera Rajagopal to cover the biggest stories in genetics and precision medicine of the last 12 months.

Don’t forget to give the first instalment of our 2023 round-up a listen.

Veera is a scientist at Regeneron with an interest in human genetics and drug target discovery in neuroscience and psychiatry. He is a prolific writer as well, both on his substack, GWAS Stories, and on Twitter, @doctorveera. Join us as Patrick and Veera cover the highlights of 2023, from milestone discoveries in South Asian genetics to cracking a 25-year-old genetic puzzle.

Summary:

00:00 Introduction and Part 1 recap

01:04 Understanding South Asian genetics

21:31 Low-hanging fruit

The ‘low-hanging fruit’ discovered earlier in the GWAS timeline, requiring just a few hundred participants.
An early-breaking story in Nature explores the underlying link between GDF15 (a hormone that is elevated during pregnancy) and a pregnancy-associated medical condition characterised by severe nausea.
Genome-Wide Association Studies (GWAS) of Reynaud’s phenomenon have been reported by two independent teams, who uncovered a strong signal near ADRA2A.

45:16 Rare variant discoveries

Momentum continues for rare variant discoveries based on UK biobank exome sequencing.
Gene BSN (Bassoon) continues to fascinate in 2023, as it’s discovered that it likely plays a key role in neurodegeneration.
In the world of non-coding variants, FOXA2 non-coding deletions are found to cause congenital hyperinsulinism and the loss of ZNF808 results in aberrant activation of silent transposons.

1:03:38 Tandem repeats

Paper from Decode quantifies the impressive mutation rate of STRs, which will put the de novo mutation rate of other variants to shame.
Paper from Po Ru Loh’s group shows that for two of the GWAS loci discovered early in the timeline, the causal variant is likely VNTRs.
A story from ASHG on Huntington highlights a major advancement in the understanding of HTT repeat-mediated neurodegeneration.

1:23:18 Looking to the future

The new and old genetic discoveries being translated into medicines.
A 25-year-old genetic puzzle that’s been solved using long-read sequencing.
Innovations in phenotyping and quantifying cellular phenotypes using microscopy.
Using discarded embryos to run genetic associations.

1:32:27 Concluding remarks