Biology subjects

Stefansdottir, L.

Publications and source records attributed to Stefansdottir, L..

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↗

bioRxiv2018

Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions

Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P<5x10-8), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p<1.28x103) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.

genomics↗