Analysis of 173,303 exomes and genomes in the Pakistan Genome Resource

[Pakistan Space Agency]

Analysis of 173,303 exomes and genomes in the Pakistan Genome Resource​

17/06/2026

• Christopher Koch,
• Shareef Khalid,
• Regeneron Genetics Center,
• Danish Saleheen

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Nature (2026) Cite this article

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Abstract​

Naturally occurring loss-of-function variants in human genes enable drug target discovery because they mimic pharmacological inhibition of proteins. However, the study of these genetic variants is constrained by their rarity. Sequencing of diverse populations, particularly those enriched in familial relatedness, has been postulated to promote discovery of rare genetic variants<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Plenge, R. M., Scolnick, E. M. &amp; Altshuler, D. Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581–594 (2013)." href="https://www.nature.com/articles/s41586-026-10667-5#ref-CR1">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Alazami, A. M. et al. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10, 148–161 (2015)." href="https://www.nature.com/articles/s41586-026-10667-5#ref-CR2">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Minikel, E. V. et al. Evaluating drug targets through human loss-of-function genetic variation. Nature 581, 459–464 (2020)." href="https://www.nature.com/articles/s41586-026-10667-5#ref-CR3">3</a>. Here we present the Pakistan Genome Resource, a South Asian biobank with high familial relatedness comprising 173,303 participants, who collectively carry naturally occurring homozygous loss-of-function variants in 6,476 genes. We describe the genetic architecture of this population, associations between genes and biomarkers, the distribution of loss-of-function variants across molecular pathways, and recall-by-genotype studies of therapeutically relevant genes. The Pakistan Genome Resource expands the catalogue of human genetic variants, provides a comprehensive genetic reference resource for the Pakistani population, and demonstrates the value of studying diverse cohorts to advance human health.

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