Biology subjects

Lopez de Lapuente Portilla, A.

Publications and source records attributed to Lopez de Lapuente Portilla, A..

3 recordsLinked to original sources

bioRxiv2026

BloodVariome: a high-resolution atlas of inherited genetic effects in human immune cells

Genome-wide association studies have linked thousands of sequence variants to immune-mediated diseases, yet their cellular mechanisms remain largely unresolved. Here we present BloodVariome, a high-resolution atlas of genetic effects across the human immune cell hierarchy. Combining deep immunophenotyping with automated pattern-recognition, we quantified 1,533 traits across 127 immune cell populations in 11,983 individuals. We identified 259 significant associations, the vast majority of which are not captured by conventional bulk blood trait studies. Most associations were restricted to single immune lineages or cell populations, revealing a fine-grained genetic compartmentalization of the immune system. By linking known disease risk alleles to specific immune cell phenotypes, BloodVariome illuminates cellular mechanisms underlying autoimmunity, immunodeficiency, and hematologic malignancy. Moreover, we implicate novel regulators of human immune cell development and function. By bridging the gap between cohort size and phenotypic depth, BloodVariome establishes a high-resolution framework for interpreting how genetic variation shapes cellular immunity at population-scale.

genomics↗

bioRxiv2026

Population-scale immunoglobulin genetics resolves the human B-cell system

Immunoglobulins (Ig) mediate adaptive humoral immunity, yet the regulation of B-cell responses in vivo in humans remains inaccessible to direct experimentation. Here we use population-scale Ig genetics to resolve molecular regulation of the human B-cell system. Analysis of circulating IgA, IgG, IgM, and six composite Ig traits in 114,697 individuals identifies 504 genetic associations. Integration with regulatory genomics, plasma proteomics, and immunophenotyping maps these effects across the B-cell hierarchy, recovering known regulators and revealing previously unrecognized genes in humoral immunity. At key control nodes - including Fc{gamma} receptors, the immunoglobulin heavy-chain locus and the TACI-APRIL signaling axis - variants form allelic series generating graded perturbations of antibody output. Ig-associated loci show extensive overlap with autoimmunity, immunodeficiency and B-cell malignancy. These findings demonstrate that Ig traits, analyzed at population scale, encode fine-grained information about the regulation of the human B-cell system and link natural variation in humoral immunity to immune-mediated disease.

genomics↗

bioRxiv2021

Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood

Understanding how hematopoietic stem and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and stem cell transplantation. To date, HSPC regulation has been extensively studied in vitro and in animal models, but less is known about the mechanisms in vivo in humans. Here, in a genome-wide association study on 13,167 individuals, we identify 9 significant and 2 suggestive DNA sequence variants that influence HSPC (CD34+) levels in human blood. The identified loci associate with blood disorders, harbor known and novel HSPC genes, and affect gene expression in HSPCs. Interestingly, our strongest association maps to the PPM1H gene, encoding an evolutionarily conserved serine/threonine phosphatase never previously implicated in stem cell biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. By functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, rs772557-A selectively increases HSPC subpopulations in which the MYB site is active, and PPM1H shRNA- knockdown increased CD34+ and CD34+90+ cell proportions in umbilical cord blood cultures. Our findings represent the first large-scale association study on a stem cell trait, illuminating HSPC regulation in vivo in humans, and identifying PPM1H as a novel inhibition target that can potentially be utilized clinically to facilitate stem cell harvesting for transplantation.

genomics↗