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Genomic studies of type 1 diabetes have largely concentrated on Western European and North American cohorts, leaving Eastern and Central European populations under-represented and limiting the portabi...

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 p

Ultra-rare recessive disorders — homozygous copy number losses on exome · Eur J Hum Genet 2026

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 g...

From 173,000 exomes and genomes, scientists uncover new clues about disease and drug targets from an often overlooked population.

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming muta...

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.

From 173,000 exomes and genomes, scientists uncover new clues about disease and drug targets from an often overlooked population.

A groundbreaking analysis of 173,303 exomes and genomes from the Pakistan Genome Resource (PGR) has unveiled compelling insights into the genetic architecture of human diseases and the therapeutic

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 g...

We conducted burden tests to correlate pLoF variants and damaging missense variants to 46 biomarkers (Supplementary Table 3). We filtered high-confidence pLoF variants on the basis of position relative to the end of the transcript, predictions of splicing22, and multi-nucleotide or in-frame ‘rescue’ events, among other filters (Methods). For many genes (including LPA, PLA2G7, APOC3, GPT, ADIPOQ and SELP), pLoF variants (mask1) or pLoF variants combined with damaging missense variants (mask2) associated with reduced circulating levels or activity of the gene products at Bonferroni-adjusted P value thresholds (P < 9.9 × 10−8). Published biomarker associations were confirmed, including associations between triglycerides and pLoF in APOC3 (refs. 4,23) (β = −0.9, P = 8.2 × 10−258); and low-density lipoprotein cholesterol (LDL-C) and PCSK924 (β = −0.9, P = 1.9 × 10−35). These findings validate the pLoF variants, protein measurements and biomarker measurements in the PGR. For comparison, we include associations from the AstraZeneca PheWAS Portal25,26 (Supplementary Table 3). PGR biomarker data revealed directional causalities that were ambiguous in previous genome-wide association studies. Examples include the genes TIMD4 and HBB. Uncharacterized variants of TIMD4 were previously linked to triglyceride levels27,28. In PGR, TIMD4 pLoF variants were associated with increased triglycerides (β =...

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.