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Veera M. Rajagopal Profile picture
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Dec 31, 2022 • 16 tweets • 7 min read
Here it is. The final GWAS story for the year! I look back at all the exciting stories I tweeted in the last 12 months. It has been truly an amazing year. I'll highlight a selected few in this thread. 🧵
gwasstories.substack.com/p/2022-roundup…
1. Ancient DNA research stole the show this year with the Nobel Prize announcement and this mind-blowing paper on the positive selection driven by the Black Death.
2. No matter how big the sample sizes grow every year, still, the discoveries that absolutely blow my mind are the ones made in a handful of patients like this stunning work that was published just a few days ago.
3. And this one, preprinted in 2021 and published in 2022, still blows my mind every time I think about the beautiful biology underneath this discovery. It goes into both my 2021 and 2022 top lists.
nature.com/articles/s4158…
4. Being a GWAS scientist, this is what I'd consider the biggest biggest story of 2022. A GWAS of height in 5.4 million individuals has revealed what would be the end of a GWAS journey or perhaps the beginning of the end.
5. As usual UK Biobank continues to advance human genetics research to the limits beyond our imagination. Last year we had 450k exomes. And this year, 150k whole genomes. Seriously, what we'd even do without UK Biobank?
6. For a long time, the GWAS field was fixated only on the first half of the central dogma of biology (DNA->RNA). Thanks again to UK Biobank, now we have a large-scale proteomics dataset to look at the full picture (DNA->RNA-> proteins)
7. The behavioral genetics field has reached a major milestone this year by publishing the first GWAS with a within-family design that is robust to population stratification and family environmental effects
8. Non-European genetic databases have finally started rising and this will get better in the upcoming years. This year, the MCPS cohort joins the big data league. It's the first largest non-European cohort to be exome-sequenced at scale.
The PCSK9 discovery (I write about the backstory in the post) gave birth to the field of protective genetics. Thanks again to UK Biobank without which the many exciting drug target discoveries that happened this year wouldn't have happened.
9. Discovery of the CIDEB as a drug target for liver disease
10. Discovery of CHRNB2 as a drug target for smoking addiction.
11. Discovery of MAP3K15 as a drug target for type 2 diabetes. (And few more in the substack post)
And coming to psychiatric genetics, a field that is close to my heart.
12. Two big papers were published this year paint a full picture of the genetic architecture of schizophrenia.
13. And finally, autism genetics was really on a roll this year with at least 6 major publications
1. nature.com/articles/s4158…
2. nature.com/articles/s4158…
3. nature.com/articles/s4158…
4. nature.com/articles/s4158…
5. pnas.org/doi/10.1073/pn…
6. cell.com/cell-genomics/…
I cover a lot more papers in the substack post along with some interesting backstories. I have put a lot of thought into this post and I hope you'll appreciate it. Wish you all a very happy new year 2023!
gwasstories.substack.com/p/2022-roundup…

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More from @doctorveera

Veera M. Rajagopal Profile picture
Dec 22, 2022
Agouti gene (Asip) is the first obesity gene to be discovered in 1992 in agouti mice--a fat yellow mice with a mutation that reprograms a skin specific protein to express throughout the body. However, no mutations in this gene has been reported in humans since 1992. 🧵
Thirty years later, now scientists have encountered the first human patient who is a near phenocopy of the agouti mice--a girl with red hair, hyperphagia, extreme obesity, tall stature, severe hyperinsulinemia and hepatic steatosis.
Routing screening for mutations in known obesity genes came negative. Then, the scientists started looking for clues in the adipose tissue biopsied from the girl during the gastric bypass surgery (that helped the girl to lose 40kg weight !!)
Read 12 tweets
Veera M. Rajagopal Profile picture
Nov 1, 2022
Excited to share our new preprint in which we report an exome-wide association study of smoking behavior in up-to ~750,000 individuals which discovered a beautiful drug target. Please take a seat. It's storytelling time. 🧵
medrxiv.org/content/10.110…
Smoking is the poster child of behavioral traits; it's a compelling example of a behavioral trait where GWAS has led to biologically meaningful signals. e.g. CHRNA5/A3/B4 genes in medial habenula that control aversion to nicotine overdosing.
sciencedirect.com/science/articl…
Smoking has a high heritability (twin h2 ~45%), with contributions from both common and rare variants. But most of the genetic studies of smoking published to date have focussed only on common variants, with a few exceptions, like the one below.
nature.com/articles/s4156…
Read 27 tweets
Veera M. Rajagopal Profile picture
Oct 30, 2022
One thing that stood out for me at the #ASHG22 is that now there is more emphasis being given to genetic diversity in the context of ancestry and its impact on human health. 🧵
It is often considered taboo to talk about phenotypic differences across genetic ancestries. While it is true that many of these differences are environmental in origin, there is sometimes a genetic component as well.
Irrespective of their origins, the fact that there are phenotypic differences (especially in terms of disease risks) between genetically defined groups requires attention. This knowledge can help doctors and scientists improve the quality of health care.
Read 21 tweets
Veera M. Rajagopal Profile picture
Oct 29, 2022
Fantastic talk by @kapoormanav on the genetic architecture of South Asian Indian population based on analysis of more than 15,000 exomes from Rajasthan and Maharashtra states of India. #ASHG22
India is one of the most diverse country in the world with 22 official spoken languages, ~3000 castes, 25,000 sub castes and a population size of 1.4 billion. And yet India is one of the most underrepresented countries in the genetic studies.
The extreme diversity in terms language, caste and culture makes Indian population so unique as these factors have sculpted the genetic architecture of Indians over hundreds to thousands of years.
Read 24 tweets
Veera M. Rajagopal Profile picture
Oct 25, 2022
Danish Saleheen stunned the audience with his story of building the world's largest cohort of human knockouts in Pakistan, which is the world's 5th most populous country with highest level of consanguinity ever known. #ASHG22 #DRIFT22 Image
Starting with around 10k individuals sequenced in 2017, now the cohort comprise of around 200k individuals recruited, of which 80,000 were exome sequenced. Goal is to sequence 1 Million.
nature.com/articles/natur…
Based on these data, they have identified so far >14000 human knockouts for >5000 genes. To achieve the same in European populations, you'll have to sequence >11 million individuals. Image
Read 14 tweets
Veera M. Rajagopal Profile picture
Oct 25, 2022
Fantastic talk by @cdbustamante about an ambitious initiative to set up one of the world's largest diverse biobank with a focus on Latin American populations with a target sample size of 10 Million(!!). Welcome to the biobank of the Americas! #ASHG22
bbofa.org
The motivation behind this massive undertaking is something that is obvious to the field: massive underrepresentation of Non-European populations in the genetic databases.
The participants recruitment is targeted mainly in the Latin America and Caribbean diaspora that holds ~8% of the world population and comprise 700+ ethnic groups and yet represent <1% of the global genetic databases.
Read 7 tweets

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