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Stefansson, K.

Publications and source records attributed to Stefansson, K..

At least 19 recordsLinked to original sources
bioRxiv2026

Sex differences in the genetic basis of human recombination within 190,000 parent-child pairs

Structured AbstractO_ST_ABSIntroductionC_ST_ABSSexual reproduction uses a specialized cell division called meiosis, in which a single round of DNA replication is followed by two cell divisions to create hap-loid gametes. Genetic recombination in meiosis assures faithful segregation of chromosomes and establishes patterns of genetic linkage and inheritance. Meiotic recombination is thus a fundamental genomic process that shapes major features of the genomic landscape, influences mutation, and creates genetic diversity. RationaleThe genetic basis of between-individual variation in the occurrence and genomic location of meiotic recombination events remains poorly understood in humans. In particular, we lack an understanding of whether the same DNA regions shape vari-ation in recombination rates across studies. We address this by curating 112,144 maternal and 78,653 paternal meiosis events (parent-child pairs) across cohorts from four countries, creating the largest dataset of its kind. ResultsWe identify 58 independent genomic regions associated with the occurrence and genomic location of recombination events, 24 of which are unique across phe-notypes. Of the 24 unique regions, 6 are novel and specific to female meiotic recombination harboring genes linked to ovarian function, a 7th novel region is linked to male recombination. Many regions have significant sex-dependent ef-fects across studies. We estimate the between-sex genetic correlation for meiotic recombination rate to be 0.374 (0.072 SD), which captures the extent to which the genetic factors influencing a trait in one sex also impact the same trait in the other. 30-40% of the individual-level variation in recombination rate is at-tributable to DNA markers, of which only 37.7% (2.7% SD) and 47.1% (3.8% SD) is attributable to previously known global modulators of meiotic recombi-nation, in females and males respectively. We create a polygenic predictor that significantly predicts recombination rates of both women and men after adjusting for age and year of birth. We find significant correlations between female meiotic recombination, reproductive outcomes and reproductive aging, after adjusting for study ascertainment. ConclusionsIn the largest meta-analysis to date of human meiotic recombination, we identify novel loci with sex-specific effects that influence male and female recombination rate across multiple cohorts.

genomics↗
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↗
bioRxiv2026

Endometriosis lesions are oligoclonal structures derived from the normal endometrium

Endometriosis is characterized by the presence of endometrium-like tissue outside the uterus. The origin of this ectopic tissue is debated, with leading theories including retrograde menstruation and embryonic remnants. Using somatic mutations as markers, we show that endometriosis lesions consist of unrelated clones of epithelial cells, with stromal cells being distinct, and that lesions at different body sites have different sets of clones. We observed that mutation burdens, signatures and driver landscapes are similar in cells from lesions and normal endometrium and the distribution of somatic mutations along the length of chromosomes is consistent with uterine origin. Furthermore a large-scale screen of the normal endometrium of endometriosis patients identified clones that are ancestral to endometriosis, indicating that the ectopic tissue in endometriosis originates from the normal endometrium.

genetics↗
bioRxiv2025

Predicting Drug Response with Multi-Task Gradient-Boosted Trees in Epilepsy

MotivationDespite the availability of numerous anti-seizure medications (ASMs), drug resistance remains a major issue for people with epilepsy. The probability of achieving seizure freedom diminishes with each unsuccessful drug trial, and the impact of genetic and clinical markers on ASM response remains unclear. To address this issue, we used state-of-the-art machine learning (ML) methods to predict the response of people with epilepsy to individual ASMs based on their clinical and genomic information. ResultsTo overcome data sparsity for less common drugs, we implement a multi-task (MT) learning approach for gradient-boosted trees (GBTs), assuming that predicting responses to different ASMs involves similar tasks. This strategy allows models for less prevalent drugs to leverage the more abundant data available for other drugs during training. The proposed model outperforms individual and combined drug-response predictions for most drugs. Our findings identify key genomic and clinical features influencing drug response, enhancing understanding of individual drug responses in people with epilepsy, and aiding clinicians in making informed treatment decisions. Availability and ImplementationDue to privacy reasons data is not publically available. The code will be made available upon acceptance under https://github.com/pfeiferAI/MT-GBT

bioinformatics↗
bioRxiv2025

Robust inference and widespread genetic correlates from a large-scale genetic association study of human personality

Personality traits describe stable differences in how individuals think, feel, and behave and how they interact with and experience their social and physical environments. We assemble data from 46 cohorts including 611K-1.14M participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience), and data from 51K participants for within-family GWAS. We identify 1,257 lead genetic variants associated with personality, including 823 novel variants. Common genetic variants explain 4.8%-9.3% of the variance in each trait, and 10.5%-16.2% accounting for measurement unreliability. Genetic effects on personality are highly consistent across geography, reporter (self vs. close other), age group, and measurement instrument, and we find minimal spousal assortment for personality in recent history. In stark contrast to many other social and behavioral traits, within-family GWAS and polygenic index analyses indicate little to no shared environmental confounding in genetic associations with personality. Polygenic prediction, genetic correlation, and Mendelian randomization analyses indicate that personality genetics have widespread, potentially causal associations with a wide range of consequential behaviors and life outcomes. The genetic architecture of personality is robust and fundamental to being a human.

genomics↗
bioRxiv2025

Population-scale analysis of inheritance patterns across 858,635 individuals reveals recent historical migration patterns across the North Sea from the Middle Ages to the Industrial Revolution

The North Seas historical migrations have impacted the genetic structure of its neighbouring populations. We analysed haplotype sharing among 858,635 modern individuals from Denmark and Britain to infer migration history from the Middle Ages to the modern day. We estimated the genetic relationship among 370,259 Danes using Danish healthcare registries and validated those with retrievable pedigree relationships from a national family registry. We also compared their haplotype sharing with 488,376 British individuals from the UK Biobank. Our analysis revealed the fine-grained population genetic history of Denmark and identified distinct coastal and island communities with a history of genetic isolation and bottlenecks. We observed a significant population decline in Jutland compared to Zealand from the late medieval period to the start of early modern period, accompanied by migration from Jutland to Zealand, corresponding to historical evidence. We identified two major haplotype sharing patterns between Denmark and Great Britain: (1) early coast-to-coast connections between South Jutland and eastern England, likely driven by migration, settlement, continuous trade and the movement of people across the North Sea from the Middle Ages through early modern times, and (2) later city-to-city connections such as those between London and Kobenhavn, likely shaped by the reorientation of economic and trading centres in Britain and Denmark, and the increased shipping from early modern times towards the Industrial Revolution. Further comparisons using other North Sea countries showed both shared and unique histories of genetic exchange with Denmark and Britain. Our study provides novel genetic evidence of migration across the North Sea from the Middle Ages to the Industrial Revolution. It highlights the power of nationwide biobanks in reconstructing fine-scale historical population movements among closely related populations.

genetics↗
bioRxiv2024

CNValidatron, automated validation of CNV calls using computer vision

BackgroundLarge rare copy number variants (CNVs) are a main source of genetic variation in the genome and are important in both evolution and disease risk. CNVs can be detected using different data sources, including genome sequencing, genotyping arrays and quantitative PCR experiments, but in most large cohorts, genotyping arrays remain the most prevalent source. Current methods to call CNVs from genotyping array data suffer from high false positive rates and while multiple approaches, including QC filtering, visual inspection of intensity tracks, and wet-lab validation are commonly applied to counter this problem, such methods are often non-specific (QC filtering) or inefficient (visual and wet-lab validations) at a genome-wide scale. ResultsWe have assembled the largest collection of human-verified CNV calls using visual validation, totaling almost 60,000 calls from 22,500 samples from three cohorts genotyped on several different arrays. Across all cohorts our visual validation found the majority of CNV calls to be false positive (53.7%) or unclear (9.7%). The false positive fraction varied substantially across datasets and genomic regions, and we show that existing filtering methods based on QC metrics are inefficient in removing false calls. Given the supremacy of visual validation over existing filtering methods in controlling the false positive fraction, we used a subset of our visual validation dataset to train a convolutional neural network to automate the validation of CNVs through machine vision. We tested the efficacy of the model using the remainder of the dataset and found the performance exceeded 90% in most measures, approximating that of a human analyst. Cross-validation with genome sequencing data found our visual validation to be highly accurate, with only 1.7% of calls supported by the sequencing dataset deemed as false by the human analyst, and a further 7.5% deemed as unclear. ConclusionsVisual inspection is the only effective validation approach for CNV calls. Our model is capable of automating this task at scale with very high accuracy, as shown by testing both within-sample and out-of-sample. The software is available as an R package at https://github.com/SinomeM/CNValidatron_fl.

bioinformatics↗
bioRxiv2022

The Norwegian Mother, Father, and Child cohort study (MoBa) genotyping data resource: MoBaPsychGen pipeline v.1

BackgroundThe Norwegian Mother, Father, and Child Cohort Study (MoBa) is a population-based pregnancy cohort, which includes approximately 114,500 children, 95,200 mothers, and 75,200 fathers. Genotyping of MoBa has been conducted through multiple research projects, spanning several years; using varying selection criteria, genotyping arrays, and genotyping centres. MoBa contains numerous interrelated families, which necessitated the implementation of a family-based quality control (QC) pipeline that verifies and accounts for diverse types of relatedness. MethodsThe MoBaPsychGen pipeline, comprising pre-imputation QC, phasing, imputation, and post-imputation QC, was developed based on current best-practice protocols and implemented to account for the complex structure of the MoBa genotype data. The pipeline includes QC on both single nucleotide polymorphism (SNP) and individual level. Phasing and imputation were performed using the publicly available Haplotype Reference Consortium release 1.1 panel as a reference. Information from the Medical Birth Registry of Norway and MoBa questionnaires were used to identify biological sex, year of birth, reported parent-offspring (PO) relationships, and multiple births (only available in the offspring generation). ResultsIn total, 207,569 unique individuals (90% of the unique individuals included in the study) and 6,981,748 autosomal SNPs passed the MoBaPsychGen pipeline. A further 174,462 chromosome X and 3,200 PAR SNPs are available in a subset of these individuals (N = 204,913 and 135,593, respectively). The relatedness checks performed throughout the pipeline allowed identification of within-generation and across-generation first-degree, second-degree, and third-degree relatives. The individuals passing post-imputation QC comprised 64,471 families ranging in size from singletons to 84 unique individuals (singletons are included as families as other family members may not have been genotyped, imputed, or passed post-imputation QC). The relationships identified include 287 monozygotic twin pairs, 22,884 full siblings, 117,004 PO pairs, 23,299 second-degree relative pairs, and 10,828 third-degree relative pairs. DiscussionMoBa contains a highly complex relatedness structure, with a variety of family structures including singletons, PO duos, full (mother, father, child) PO trios, nuclear families, blended families, and extended families. The availability of robustly quality-controlled genetic data for such a large cohort with a unique extended family structure will allow many novel research questions to be addressed. Furthermore, the MoBaPsychGen pipeline has potential utility in similar cohorts.

genetics↗
bioRxiv2022

Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample

Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain and Cognition Developmental study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.

neuroscience↗
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↗
bioRxiv2020

Analysis of diffusion tensor imaging data from UK Biobank confirms dosage effect of 15q11.2 copy-number variation on white matter and shows association with cognition

BackgroundCopy-number variations at the 15q11.2 BP1-BP2 locus are present in 0.5 to 1.0% of the population, and the deletion is associated with a range of neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy-number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to replicate and expand these findings, using a larger sample of participants (n=30,930), higher resolution imaging, and examining the implications for cognitive performance. MethodsDiffusion tensor imaging measures from participants with no neurological/psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n=103) and duplication (n=119) carriers to a large cohort of control individuals with no neuropsychiatric copy-number variants (n=29,870). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance. ResultsDeletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum, and decreases in the posterior thalamic radiation, compared to both duplication carriers and controls (who had intermediate values). Deletion carriers had lower scores across cognitive tasks compared to controls, which were mildly influenced by white matter alterations. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers. ConclusionsThis study, together with our previous findings, provides convergent evidence for a dosage-dependent effect of 15q11.2 BP1-BP2 on white matter microstructure. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function.

neuroscience↗
bioRxiv2020

Variable Number Tandem Repeats mediate the expression of proximal genes

Variable Number Tandem Repeats (VNTRs) account for a significant amount of human genetic variation. VNTRs have been implicated in both Mendelian and Complex disorders, but are largely ignored by whole genome analysis pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks for fast read recruitment. On 55X whole genome data, adVNTR-NN genotyped each VNTR in less than 18 cpu-seconds, while maintaining 100% accuracy on 76% of VNTRs. We used adVNTR-NN to genotype 10,264 VNTRs in 652 individuals from the GTEx project and associated VNTR length with gene expression in 46 tissues. We identified 163 eVNTR loci that were significantly associated with gene expression. Of the 22 eVNTRs in blood where independent data was available, 21 (95%) were replicated in terms of significance and direction of association. 49% of the eVNTR loci showed a strong and likely causal impact on the expression of genes and 80% had maximum effect size at least 0.3. The impacted genes have important role in complex phenotypes including Alzheimers, obesity and familial cancers. Our results point to the importance of studying VNTRs for understanding the genetic basis of complex diseases.

genomics↗
bioRxiv2020

The genetic structure of Norway

The aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norways long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been the most isolated region in Norway, highlighting the open sea as a barrier to gene flow.

genetics↗
bioRxiv2019

Long read sequencing of 1,817 Icelanders provides insight into the role of structural variants in human disease

Long-read sequencing (LRS) promises to improve characterization of structural variants (SVs), a major source of genetic diversity. We generated LRS data on 3,622 Icelanders using Oxford Nanopore Technologies, and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions), spanning a median of 10 Mb per haploid genome. We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association with a rare (AF = 0.037%) deletion of the first exon of PCSK9. Carriers of this deletion have 0.93 mmol/L (1.31 SD) lower LDL cholesterol levels than the population average (p-value = 7.0{middle dot}10-20). We also discovered an association with a multi-allelic SV inside a large repeat region, contained within single long reads, in an exon of ACAN. Within this repeat region we found 11 alleles that differ in the number of a 57 bp-motif repeat, and observed a linear relationship (0.016 SD per motif inserted, p = 6.2{middle dot}10-18) between the number of repeats carried and height. These results show that SVs can be accurately characterized at population scale using long read sequence data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.

genetics↗
bioRxiv2019

CCR5-del32 is not deleterious in the homozygous state in humans

Recently, Wei and Nielsen1 reported an analysis of UK Biobank data which suggested that the well-known HIV-protective variant CCR5-del32 is associated with a 21% increase in all-cause mortality. We demonstrate, using two well-powered population samples in Iceland and Finland with extensive health data and death information, neither an effect on mortality nor increase in risk of any disease. Further reexamination of the UK Biobank (UKBB) data suggests that the very modest association was with a SNP of poor genotyping quality - at a nearby proxy SNP, no statistically significant impact on mortality nor deviation from Hardy-Weinberg equilibrium exists in the UKBB sample. We thus find no evidence of any meaningful risk of increased mortality from homozygosity of CCR5-del32.

genetics↗
bioRxiv2019

PopDel identifies medium-size deletions jointly in tens of thousands of genomes

Thousands of genomic structural variants segregate in the human population and can impact phenotypic traits and diseases. Their identification in whole-genome sequence data of large cohorts is a major computational challenge. We describe a novel approach, PopDel, which jointly identifies deletions of about 500 to at least 10,000 bp in length in many genomes together. PopDel scales to tens of thousands of genomes as we demonstrate in evaluations on up to 49,962 genomes. We show that PopDel reliably reports common, rare and de novo deletions. On genomes with available high-confidence reference call sets PopDel shows excellent recall and precision. Genotype inheritance patterns in up to 6,794 trios indicate that genotypes predicted by PopDel are more reliable than those of previous SV callers. Furthermore, PopDels running time is competitive with the fastest tested previous tools. The demonstrated scalability and accuracy of PopDel enables routine scans for deletions in large-scale sequencing studies.

bioinformatics↗