Genetics

African plasma proteome–genome map highlights T2D-relevant proteins and novel pQTLs

Plasma levels of 2,873 proteins were measured in 163 Ugandan individuals with type 2 diabetes or prediabetes and 362 normoglycemic controls. Eighty-eight proteins were differentially expressed between dysglycemic and normoglycemic participants, suggesting ancestry-relevant biomarkers and pathways. A pQTL map revealed 399 independent associations, including 37 novel pQTLs not reported in any population. Sixteen point seven percent of cis-pQTLs and all trans-pQTLs were previously unreported in African ancestry, narrowing diversity gaps. Colocalization with T2D risk loci implicated specific proteins as causal mediators, informing ancestry-tailored target and biomarker development. 1

Long-read genome sequencing adds actionable detail in pediatric neurologic diagnostics

In 100 children with neurological disorders, short-read and long-read genome sequencing each achieved a 29% diagnostic yield. Long-read sequencing provided additional diagnostic value in 13 cases by clarifying 17 variants, including phasing biallelic variants and SMN1 copy status. It improved detection and sizing of short tandem repeats, structural variant architecture, and resolution of an unbalanced der(14)t(8;14) translocation breakpoint. Long-read data also revealed disease-associated methylation abnormalities at the Prader–Willi region and across an FMR1 expansion. As a first-line singleton test, long-read genome sequencing reduced follow-up studies and enabled more precise, integrated variant interpretation. 2

Biobank-scale analysis maps germline modifiers of tandem repeat instability

Sequencing data from more than 900,000 UK Biobank and All of Us participants were analyzed to quantify germline and blood somatic repeat instability. Loci showed wide variability in tissue-specific mutation and age-related expansion behavior of tandem repeats across the population. Genome-wide association identified 29 loci where inherited variants modified somatic expansion of unstable repeats in blood. Polygenic scores for repeat-instability modifiers produced approximately fourfold differences in expansion rates at specific repeats between individuals. Expanded GLS 5′UTR repeats associated with stage 5 chronic kidney disease and liver diseases with high odds ratios, suggesting clinical relevance. 3

Protein–protein interactions structure trans-pQTL effects and connect GWAS loci to function

Re-analysis of large pQTL datasets showed that genes with trans-pQTLs but no cis-pQTLs are highly constrained and particularly informative for GWAS loci. Trans-pQTLs and their target proteins frequently participated in protein–protein interactions and were enriched for missense variants at interaction interfaces. Using protein–protein interaction annotations, investigators mapped 17,662 trans-pQTLs affecting 961 protein–protein interaction clusters after adjusting for blood cell composition. These trans-pQTLs colocalized with about 36% of loci per trait across 27 complex traits, strengthening functional attribution of GWAS signals. At autoimmune risk loci, convergent trans effects implicated shared protein complexes and signaling pathways, nominating mechanistically grounded therapeutic targets. 4