Christopher Koch, Shareef Khalid, Maleeha Khan, Shruthi Bandyadka, Brian Doyon, 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, Riffat Sultana, Shahid Abbas, 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, M. Shahid Mukhtar, Tahir Rasool, Adil Mahmood, Muhammad Noor Wazir, S Khan, M Asif Khan, Rahmat Ghaffar, Sanaullah Jan, Noor Ul Hadi, Roshina Anjum, Rehan Abdullah, Muhammad Usman Musharraf, Muhammad Tahir Bashir, Muhammad Ali, Irfan Majeed, Muhammad Bilal, Shahzad Ali Khan, Chihiro Hata, Ikuyo Kou, Makoto Asaumi, Wataru Morii, Katherine R. Smith, Kousik Kundu, Kieren Lythgow, Stewart MacArthur, Sebastian Wasilewski, Slavé Petrovski, RGC Management and Leadership Team, Aris Baras, Gonçalo Abecasis, Adolfo Ferrando, Giovanni Coppola, Andrew Deubler, Luca Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Katherine Siminovitch, Jason Portnoy, Marcus B. Jones, Lyndon Mitnaul, Alison Fenney, Jonathan Marchini, Manuel Allen Revez Ferreira, Maya Ghoussaini, Mona Nafde, William Salerno, C Willer, Lourdes Crane, Sequencing and Lab Operations, Christina Beechert, Erin Fuller, Laura M. Cremona, Eugene Kalyuskin, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Alexander Lopez, Kia Manoochehri
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. The Pakistan Genome Resource compiles biobank data from 173,303 individuals with high familial relatedness, broadening the catalogue of human genetic variation and establishing a population-specific genomic reference for Pakistan.