Lorenzo Bomba

Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity Genes and Health (G&H) is a biomedical study of adult British-Pakistani and -Bangladeshi research volunteers enriched for autozygosity. We performed whole exome sequencing in 44,028 G&H participants, ...

Preprint alert! 🚨
doi.org/10.1101/2025...

Our manuscript on Exome sequencing and analysis of 44,028 British South Asians, using @genesandhealth.bsky.social is now available at @medrxivpreprint.bsky.social!

We present several great results, and I’m thrilled to highlight the pieces I worked on:

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Special thanks to @Ketian Yu for her invaluable dedication to this project during her summer internship, to all the members of the @Estonia team, and finally @Karol Estrada and @Arthur Wuster for their mentorship and support. 13/13

Huge thanks to a fantastic team that contributed to this work @Ketian Yu, @Karol Estrada, @Tõnu Esko, @Mart Kals, @Tiit Nikopensius, @jaanikakronberg.bsky.social, @urmovosa.bsky.social, @Arthur Wuster
Read the full paper here: doi.org/10.3390/meta.... 12/13

Concluding, our findings contribute to the growing body of knowledge on the biochemical consequences of genetic variation, integrating metabolomics with genetic data. This work aids in drug discovery and the development of targeted therapies. 11/13

Limitation of the study include reduced statistical power due to sample size and absence of validation in an independent cohort. Future research should aim to validate these associations through functional experiments. 10/13

Our findings expand upon previous research, such as the work by Saleheen et al., highlighting the enrichment of the Estonian population with human knockout due to its population history and structure, characterized by high homozygosity resulting from recent and regional bottlenecks. 9/13

Figure 2: Pyrimidine degradation pathway and metabolism of β-aminoisobutyric acid (BAIBA): pyrimidines degradation pathway showing the genes associated with metabolites and the position of pLoF carriers compared to control distribution.

We also found an interesting link between Pyrimidine degradation pathway and metabolism of β-aminoisobutyric acid (BAIBA). Read the paper for a more detailed discussion on this. 8/13

Top associations involved genes and metabolites in the pyrimidine degradation pathway.
DPYD and UPB1 gene KOs showed significant changes in metabolite levels, providing opportunities to investigate biochemistry, gene function, and phenotypic consequences. 7/13

54% of reported associations are gene targets of approved drugs or bioactive compounds. Most identified associations had clear biochemical functions described in the literature, allowing us to better elucidate gene functions and their implications in disease (Table 1). 6/13

We identified 48 associations linking rare pLoF variants in 22 genes to 43 metabolites. 27 associations were found in genes causing inborn errors of metabolism.
DPYD gene KOs were associated with elevated levels of uracil, confirming DPD-deficiency as a cause of severe 5-Fluorouracil toxicity. 5/13

Figure 1

In 150,000 EstBB participants, we identified 723 KOs with 152 different predicted loss of function (pLoF) variants in 115 genes. 1387 metabolites were profiled using ultra-high-performance liquid chromatography–tandem mass spectrometry. 4/13

We assessed the impact of human gene knockouts (KOs) on metabolite levels of Estonian Biobank (EstBB) participants, integrating results with electronic health record data. 3/13

@metabolon.bsky.social , @estbiobank.bsky.social, @mdpiopenaccess.bsky.social, #EstonianBiobank, #Genetics, #Metabolomics, #Sequencing, #RareGeneticVariants, #DrugTargets #LossOfFunction, #HumanKnockOut. 🧬🧬🧬 2/13

Our paper on plasma metabolic outliers identified in Estonian human knockouts is now out in Metabolites!!. doi.org/10.3390/meta.... 🧵🧵 1/13

Introducing a major upgrade to OmicsPred platform (www.omicspred.org) — a resource to enhance the accessibility and usability of genetic scores for multi-omic traits and their phenotypic associations. (1/N)