Veera Rajagopal
@doctorveera
🇮🇳 MBBS, MD, 🇩🇰 PhD | 🧬 Scientist @ 🇺🇸 Regeneron | Translating genetic insights into life-saving medicines | Weekly thoughts @ gwasstories.com
Rare variant architecture of epilepsy
Great paper from the Epi25 collaborative on the rare variant associations of different types of epilepsy based on WES analysis of ~54k individuals. This paper is packed with insightful findings. I'll highlight a few 🧵
medrxiv.org/content/10.1101/2023.02.22.23286310v1
The authors studied three types of eplipesy.
One rare, severe form: developmental and epileptic encephalopathies (DEE N=~2k), which is often comorbid with developmental delay.
Major human genetic discoveries made with small sample size
While I appreciate the sentiment, I am not a fan of such blind rules. Let me start with a 🧵 of some major human genetic discoveries (many translated to therapeutics) made with very few samples.
twitter.com/ewanbirney/status/1628340273594961920?s=20
Human genetics led discovery of a receptor-ligand pair
Beautiful story of how human population genetic and proteomic studies have led to the discovery of SVEP1 as the natural ligand of the receptor PEAR1. It's been a while since I read such a fantastic paper. 🧵
nature.com/articles/s41467-023-36486-0
I am big fan of GWAS of molecular traits as they often reveal clear and interpretable cis and trans signals reiterating the known biology of the trait.
New GWAS of ADHD captures convergence of common and rare variants in SORCS3
New GWAS of ADHD based on 38,691 cases and >180k controls.
Congrats! @DemontisDitte, @AndersBorglum, @iPSYCHdk and collaborators. 🧵
nature.com/articles/s41588-022-01285-8
Despite a higher prevalence (~5%) than schizophrenia (~1%), ADHD GWAS lagged far behind Schizophrenia GWAS. The latest GWAS of schizophrenia included >76k cases.
twitter.com/doctorveera/status/1513349006750994441?s=20&t=DYhRtjXpXU92HOK-jDQcSw
Examples of human genetic variations causing tissue-specific gene knock-out/knock-in
Great question! In fact, I've been recently in search of examples of human genetic variations that cause tissue-specific knock-out and knock-in. Few examples that I know now 🧵
twitter.com/SherifMorris/status/1619730369334624258?s=20&t=RBQDeFapsMSAHFVnNoAcMA
1. A Greenland specific nonsense variant (p.Arg684Ter) knocks out the gene TBC1D4 only in the skeletal muscle (the variant causes late termination and so affects only the long isoform that is expressed only in skeletal muscle)
nature.com/articles/nature13425
DGAT1 inhibitors and diarrhea--an example of human genetics informing drug adverse effects
I am always on the lookout for cool examples of human genetics informing drug adverse effects. Here is an interesting one I recently came across in this great review article 🧵
nature.com/articles/s41576-022-00572-8
Genetic basis of cellular morphology
My first favourite GWAS of the year.
Here the authors derived >3k cellular morphological traits using microscopic images of iPSCs from 297 donors and studied their associations with common and rare variants. Amazing
biorxiv.org/content/10.1101/2023.01.09.522731v1
@soumya_boston @DrAnneCarpenter
Genetic links between language ability, psychiatric risk and creativity
Better late than never. Happy and relieved to share a final published version of one of my PhD projects in which we uncovered a fascinating genetic link between language ability, psychiatric risk and creativity. 🧵
nature.com/articles/s41598-022-26845-0
Endophenotypes are at the heart of human genetics research. They not only help discover disease genes, but they can also inform about the disease's pathophysiology, signs, symptoms etc.
SNP-heritability of gout--Europeans vs East Asians
Among the 14 disease endpoints meta-analyzed in GBMI, the largest difference in SNP heritability between ancestries was observed for gout. This is due to both differences in allele frequencies and effect size between ancestries.
twitter.com/yingWANGyw1/status/1612143974927720448?s=20&t=YwpRYM5JY-A6OTTy9U4hyA