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<p>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<sup><CitationRef AdditionalCitationIDS="CR2" CitationID="CR1">1</CitationRef>–<CitationRef CitationID="CR3">3</CitationRef></sup>. 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Christopher Koch,
  • Shareef Khalid,
  • Maleeha Zaman Khan,
  • Shruthi Bandyadka,
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  • Daniel P. Denning,
  • Muhammad Jahanzaib,
  • Muhammad Rehan Mian,
  • Wafa Gul,
  • Muhammad Bilal Liaqat,
  • Aneeqa Bano,
  • Marium Dahar,
  • Namra Saqib,
  • Lubna Kamani,
  • Nazish Butt,
  • Anjum Jalal,
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  • Musfireh Siddiqeh,
  • Muhammad Haroon,
  • Asadullah Khan,
  • Khalid Parvez Babar,
  • Aflak Rasheed,
  • Javed Iqbal,
  • Faizan Aslam,
  • Umar Usman,
  • Muhammad Akram Bajwa,
  • Ali Hyder,
  • Muhammad Sadik Memon,
  • Nauman Hashmani,
  • Mohsin Iqbal Haroon,
  • Ambreen Muddassir,
  • Syed Asif Raza Zaidi,
  • Mateen Akram,
  • Muhammad Hussain,
  • Saima Naz Mohsin,
  • Samreen Bugti,
  • Tariq Mehmood,
  • Abdul Lateef Rodeni,
  • Shahid Mukhtar,
  • Tahir Rasool,
  • Adil Mahmood,
  • Muhammad Noor Wazir,
  • Sheraz Jamal Khan,
  • Muhammad Asghar Khan,
  • Rahmat Ghaffar,
  • Sanaullah Jan,
  • Noor Ul Hadi,
  • Roshina Anjum,
  • Rehan Abdullah,
  • Muhammad Usman Musharraf,
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  • Muhammad Ali,
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  • Makoto Asaumi,
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  • Katherine R. Smith,
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  • Mira Tang,
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  • Rita Guerreiro,
  • Amit Joshi,
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  • Mary Haas,
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  • Jonas Bovijn,
  • Tanima De,
  • Luanluan Sun,
  • Olukayode Sosina,
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  • Peter Dornbos,
  • Juan Rodriguez-Flores,
  • Gannie Tzoneva,
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  • Anna Alkelai,
  • Ariane Ayer,
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  • Jacqueline Otto,
  • Jose Bras,
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摘要

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 variants1–3. 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.