Person:

Raychaudhuri, Soumya

On average, the Peruvian population is among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvians, and identify a novel, population-specific, missense variant in FBN1 (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency=4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). This is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin-1, a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals homozygous for G1297 compared to individuals homozygous for E1297. Moreover, we show that E1297G locus is under positive selection in non-African populations, and the E1297 variant shows subtle evidence of positive selection within the Peruvian population specifically. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, suggesting that short stature might be the result of adaptation to factors associated with the coastal environment in Peru.

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. For example, a T cell HLA-DQA1 eQTL (rs3104371) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

Non-coding genetic variants may cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by gene-regulation differences across fluid functional cell states within cell types. These states—for example, neurotransmitter-driven programs in astrocytes or perivascular fibroblast differentiation—are obscured in eQTL studies that aggregate cells1,2. Here, we modeled eQTLs at single-cell resolution in one complex cell type: memory T cells. Using >500,000 unstimulated memory T cells from 259 Peruvians, we show that around one-third of 6,511 cis-eQTLs had effects mediated by continuous multimodally defined cell states, such as cytotoxicity and regulatory capacity. In some loci, independent eQTL variants had opposing cell-state relationships. Autoimmune variants were enriched in cell-state-dependent eQTLs, including rheumatoid-arthritis risk variants near ORMDL3 and CTLA4, arguing that cell-state context is crucial to understanding potential eQTL pathogenicity. Moreover, continuous cell states explained more eQTL variation than conventional discrete categories, such as CD4+/CD8+, suggesting that modeling eQTLs and cell states at single-cell resolution can expand insight into gene regulation in functionally heterogeneous cell types.