EP 114: The Biggest Stories of 2023 with Dr. Veera Rajagopal (Part 1)
December 21, 2023
In this annual round-up episode, we welcome back Dr. Veera Rajagopal to cover some of the biggest stories in genetics and precision medicine from 2023! 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 Veera’s personal achievements to the approval of Casgevy and understanding the impacts of studying rare variants for drug development!
0:00 Introduction
1:30 Veera’s personal highlights of 2023
1:30 Veera’s personal highlights of 2023
- Publication in Nature Genetics: Rare coding variants in CHRNB2 reduce the likelihood of smoking, an exome-wide association study identifying rare coding variants in CHRNB2 that may reduce the likelihood of smoking.
- Designing cover art
- Genetic links to neural circuits and their role in addiction
10:50 The most exciting story of the year: the first successful translation of a GWAS discovery into medicine
- A milestone year in GWAS-driven drug development: FDA Approval of Casgevy, a cell based gene therapy for the BCL11A transcription factor, in the US and UK to treat sickle cell disease
- Strong genetic support for the ongoing development of APOL1 inhibitors to treat kidney disease
- Additional disease modifier variants, including the APOE4 variant in Alzhemer’s Disease
34:52 How rare Mendelian diseases can offer insights into drug developments
- Looping back to BCL11A: how neurodevelopmental disorder patients with BCL11A haploinsufficiency provided insights into sickle cell treatment
- BCL11A knockdown to induce fetal hemoglobin production and alleviate sickle cell disease
- Recessive mutations in HMGCR provide the missing link into why statins can induce myopathy. Learn more in this Atlantic article.
- The often underappreciated importance of studying rare Mendelian diseases
51:31 The value of common variants vs rare variants in informing drug targets
- Why are pharmaceutical companies studying rare variants?
- How the FTO locus associated with obesity highlights challenges in identifying causal gene variants
- Surprising twists in translating mice physiology to human physiology, and decades-long quest to understanding the mechanism behind this extremely early GWAS hit
1:00:32 Genetic drift, endogamy, and consanguinity
- The rise of large-scale studies looking beyond European populations
- The FinnGen study: a significant step forward in understanding the genetic basis of diseases in founder populations
- Interesting discoveries from integrating non-European populations in biobanks and Direct to Consumer databases
- A recent 23andMe paper that identifies a founder variant in Puerto Rican populations associated with a strong risk effect on cataract development
1:13:40 Concluding remarks and looking ahead to Part 2!
Check out Veera's substack, GWAS Stories, and follow him on Twitter, @doctorveera