| 1. |
|
|
| 2. |
- Bergstedt, Jacob
(författare)
-
Statistical Modeling and Learning of the Environmental and Genetic Drivers of Variation in Human Immunity
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During the last decade the variation in the human genome has been mapped in fine detail. Next generation sequencing has made it possible to cheaply and rapidly aquire vast amounts of biomolecular information on large cohorts of people. This have enabled large-scale epidemiological studies to investigate the relationships between environmental and genetic factors and human biomolecular traits. It is now possible to map variation in the genomic blueprint for human biology to variation in levels of epigenomic marks, gene expression levels and protein expression levels. This development has opened up the possibility of a "phenomic science": the data-driven study of the interactions between all levels of the relationship between the genotype, the environment, and the phenotype. The Milieu Intérieur study of Institut Pasteur, Paris, aims at bringing the techno-logical developments of modern biology to bear on the study of the human immune system in homeostasis. Deep phenotyping has been performed on 1,000 healthy, un-related people of Western European ancestry. The cohort is evenly stratified across sex, and across five decades of life, between 20 and 70 years of age. In this thesis, we combine the standardised flow cytometry of 173 parameters of innate and adaptive immune cells, genome-wide DNA genotyping, detailed information on life-style and environmental factors and MethylationEPIC array data of the Milieu Intérieur cohort, to identify the genetic and environmental drivers of variation in the human immune system. The increasing complexity of biological data requires the development of new statistical tools. In this work, we aim to integrate developments in machine learning, convex optimization, causal inference, and statistical methodology, to build robust and reliable tools for analysing the high-dimensional and highly complex biomolecular data of the Milieu Intérieur study. We construct a pipeline to perform genome-wide association studies on phenotypes with heterogenous distributions, while controlling for arbitrarily many environmental factors. The pipeline is applied to study the genetics of human immune system variation in homeostasis and the genetics of the function of the human thymus. Our pipeline identifies 15 loci that influence immunophenotypes. We show that these loci are enriched in disease-associated variants. We also report a commongenetic variant, situated within the T cell receptor locus, that increases the production of naive T cells within the human thymus. In addition, we find four key non-genetic factors that drive variation in the healthy human immune system: age, sex, latent cytomegalovirus infection and smoking. Age, sex, and smoking have a broad impact on the innate and the adaptive immune subsystems, while cytomegalovirus infection primarily seems to skew the T cell compartment of the adaptive immune subsystem towards inflammatory subsets. We also show that age and sex influence the function of the human thymus. Immunophenotypes are intimately connected to epigenetic markers in whole-blood. We leverage the >850,000 methylation sites probed in the MethylationEPIC array to build high-dimensional predictive models of 70 immune cell subsets and other traits such as age and smoking status. We employ elastic net regression and stability selection to build sparse, regularized models, and show that they are capable of estimating blood cell composition more accurately and cost-effectively than previous methods. The properties of elastic net regression and stability selection also enable us to investigate the relationship between DNA methylation and immune blood cell composition. This thesis develops methods for, and performs, the analysis of parts of the rich and multifaceted data of the Milieu Intérieur study. With the construction and analysis of this rich observational data we contribute to the young fields of population immunology and human phenomic science. We discover novel associations that will help in understanding the differences between people in vaccination efficacy and susceptibility to common autoimmune and infectious disesases. Finally, we present predictive models that will facilitate the application of immunological markers in the clinics
|
|
| 3. |
- Clave, Emmanuel, et al.
(författare)
-
Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus
- 2018
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 10:457
-
Tidskriftsartikel (refereegranskat)abstract
- The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.
|
|
| 4. |
- Daníelsdóttir, Hilda Björk, et al.
(författare)
-
Adverse Childhood Experiences and Adult Mental Health Outcomes
- 2024
-
Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 81:6, s. 586-594
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders.OBJECTIVE: To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding.DESIGN, SETTING, AND PARTICIPANTS: This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023.EXPOSURES: A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey.MAIN OUTCOMES AND MEASURES: Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register.RESULTS: Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11).CONCLUSIONS AND RELEVANCE: This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.
|
|
| 5. |
- Hu, Kejia, et al.
(författare)
-
Neuroendocrine pathways and breast cancer progression : a pooled analysis of somatic mutations and gene expression from two large breast cancer cohorts
- 2022
-
Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 22:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Experimental studies indicate that neuroendocrine pathways might play a role in progression of breast cancer. We aim to test the hypothesis that somatic mutations in the genes of neuroendocrine pathways influence breast cancer prognosis, through dysregulated gene expression in tumor tissue.METHODS: We conducted an extreme case-control study including 208 breast cancer patients with poor invasive disease-free survival (iDFS) and 208 patients with favorable iDFS who were individually matched on molecular subtype from the Breast Cancer Cohort at West China Hospital (WCH; N = 192) and The Cancer Genome Atlas (TCGA; N = 224). Whole exome sequencing and RNA sequencing of tumor and paired normal breast tissues were performed. Adrenergic, glucocorticoid, dopaminergic, serotonergic, and cholinergic pathways were assessed for differences in mutation burden and gene expression in relation to breast cancer iDFS using the logistic regression and global test, respectively.RESULTS: In the pooled analysis, presence of any somatic mutation (odds ratio = 1.66, 95% CI: 1.07-2.58) of the glucocorticoid pathway was associated with poor iDFS and a two-fold increase of tumor mutation burden was associated with 17% elevated odds (95% CI: 2-35%), after adjustment for cohort membership, age, menopausal status, molecular subtype, and tumor stage. Differential expression of genes in the glucocorticoid pathway in tumor tissue (P = 0.028), but not normal tissue (P = 0.701), was associated with poor iDFS. Somatic mutation of the adrenergic and cholinergic pathways was significantly associated with iDFS in WCH, but not in TCGA.CONCLUSION: Glucocorticoid pathway may play a role in breast cancer prognosis through differential mutations and expression. Further characterization of its functional role may open new avenues for the development of novel therapeutic targets for breast cancer.
|
|
| 6. |
- Olofsson, Björn, et al.
(författare)
-
Sensor Fusion for Robotic Workspace State Estimation
- 2016
-
Ingår i: IEEE/ASME Transactions on Mechatronics. - 1083-4435. ; 21:5, s. 2236-2248
-
Tidskriftsartikel (refereegranskat)abstract
- We consider the problem of tool position and orientation state estimation for robot manipulators in workspace by sensor fusion of the internal robot joint measurements with inertial measurement unit data. A prerequisite for this to be successful is accurate calibration of the sensors used. Therefore, we discuss a method for calibration of the sensor with respect to the robot end-effector, which is straightforward to apply on an arbitrary industrial manipulator. We also consider two different workspace state-estimation algorithms requiring a minimum of robot modeling; the first is based on the extended Kalman filter and the second is based on the Rao-Blackwellized particle filter. The calibration procedure and the state-estimation algorithms were evaluated and compared in extensive experiments. Both state-estimation algorithms exhibited an accuracy improvement compared to estimates provided by the forward kinematics of the robot. Moreover, both algorithms were shown to satisfy the constraints of real-time execution at 4-ms sampling period. To further evaluate and compare the robustness of the methods, the algorithms were investigated with respect to the sensitivity of the filter parameters and the noise modeling.
|
|
| 7. |
- Pasman, Joëlle A., et al.
(författare)
-
Epidemiological overview of major depressive disorder in Scandinavia using nationwide registers
- 2023
-
Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 29
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Major depressive disorder (MDD) is a common psychiatric disorder associated with a high disease burden. This study gives a comprehensive overview of the prevalence, outcomes, treatment, and genetic epidemiology of MDD within and across the Scandinavian countries.METHODS: This study has aimed to assess and compare across Norway, Denmark, and Sweden 1) the prevalence and trajectories of MDD and comorbidity, 2) outcomes and treatment, and 3) heritability (Denmark and Sweden only). The analyses leveraged data on 272,944 MDD cases (and 6.2 million non-cases) from Norway, Sweden, and Denmark in specialist care in national longitudinal health registers covering 1975-2013. Relying on harmonized public data global comparisons of socioeconomic and health metrics were performed to assess to what extent findings are generalizable.FINDINGS: MDD ranked among the most prevalent psychiatric disorders. For many cases, the disorder trajectory was severe, with varying proportions experiencing recurrence, developing comorbid disorders, requiring inpatient treatment, or dying of suicide. Important country differences in specialist care prevalence and treatment were observed. Heritability estimates were moderate (35-48%). In terms of socioeconomic and health indices, the Scandinavian nations were comparable to one another and grouped with other Western nations.INTERPRETATION: The Scandinavian countries were similar with regards to MDD epidemiological measures, but we show that differences in health care organization need to be taken into consideration when comparing countries. This study demonstrates the utility of using comprehensive population-wide registry data, outlining possibilities for other applications. The findings will be of use to policy makers for developing better prevention and intervention strategies.
|
|
| 8. |
- Patin, Etienne, et al.
(författare)
-
Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors
- 2018
-
Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 19, s. 302-314
-
Tidskriftsartikel (refereegranskat)abstract
- The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.
|
|
| 9. |
- Piasecka, Barbara, et al.
(författare)
-
Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges
- 2017
-
Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:3, s. 488-497
-
Tidskriftsartikel (refereegranskat)abstract
- The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.
|
|
| 10. |
- Scepanovic, Petar, et al.
(författare)
-
A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals
- 2019
-
Ingår i: Microbiome. - : Springer Science and Business Media LLC. - 2049-2618. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20-69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. RESULTS: Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. CONCLUSION: In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01699893.
|
|
