Past eQTL studies have mostly focused on one gene at a time. But in the human genome, genes often occur in clusters and tend to be co-regulated by shared mechanisms. So why not consider neighboring genes together when mapping eQTLs? A new preprint tests this idea and introduces a new class of eQTLs: cis-principal component eQTLs (cis-pc eQTLs). These are identified by calculating principal components from the expression of nearby genes and associating those components with genetic variants. Using GTEx data, the authors uncover thousands of genetic signals missed by traditional single-gene approaches. Many of these pcQTLs colocalize with GWAS hits, offering new insights into complex traits. It’s a compelling reminder that genes often work in packs—and understanding disease may sometimes require zooming out to see the bigger regulatory landscape. Paper: Lawrence et al. Focus on single gene effects limits discovery and interpretation of complex trait-associated variants. bioRxiv, 2025

X chromosome dosage compensation through the lens of human genetics! Females have two X chromosomes, but males have one. To compensate for this, one X is randomly inactivated in female cells. Some genes escape from this inactivation. Because both males and females are functionally hemizygous for chromosome X, X-linked genes are thought to upregulate their expression to match autosomes (Ohno's hypothesis, 1967) With availability of large scale human genetic data, we can test the effect of these dosage compensations through genetic analysis! Using UK Biobank genetic data, here the authors tested 48 quantitative traits separately in males and females and found: - Chr X heritability (X-h2) is ~2x higher in males than females (supports random X inactivation in females that dilutes the average) - In height, X-h2 in females > males suggesting more frequent escape from X inactivation for height-associated genes - per allele effect is larger for X genes than autosomal genes (supporting Ohno's hypothesis) Fascinating work! Fu et al. AJHG cell.com/ajhg/fulltext/S0002…