EP 114: The Biggest Stories of 2023 with Dr. Veera Rajagopal (Part 1)

0:00 Introduction

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