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- Mishra, A, et al.
(author)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Journal article (peer-reviewed)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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- Butler-Laporte, G, et al.
(author)
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
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Journal article (peer-reviewed)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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- Clark, DW, et al.
(author)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Journal article (peer-reviewed)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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- Czamara, D, et al.
(author)
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Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2548-
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Journal article (peer-reviewed)abstract
- Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
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- de Jong, S, et al.
(author)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Journal article (peer-reviewed)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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- Langeback, A, et al.
(author)
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CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 19384-
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Journal article (peer-reviewed)abstract
- The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies.
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- Meier, Ralph, et al.
(author)
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Comparison of dynamical states of random networks with human EEG
- 2007
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In: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 70:10-12, s. 1843-1847
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Journal article (peer-reviewed)abstract
- Existing models of EEG have mainly focused on relations to network dynamics characterized by firing rates [L. de Arcangelis, H.J. Herrmann, C. Perrone-Capano, Activity-dependent brain model explaining EEG spectra, arXiv:q-bio.NC/0411043 v1, 23 Nov 2004; D.T. Liley, D.M. Alexander, J.J. Wright, M.D. Aldous, Alpha rhythm emerges from large-scale networks of realistically coupled multicompartmental model cortical neurons, Network 10(1) (1999) 79-92; O. David, J.K. Friston, A neural mass model for MEG/EEG: coupling and neuronal dynamics, NeuroImage 20 (2003) 1743-1755]. Generally, these models assume that there exists a linear mapping between network firing rates and EEG states. However, firing rate is only one of several descriptors for network activity states. Other relevant descriptors are synchrony and irregularity of firing patterns [N. Brunel, Dynamics of sparsely connected networks of excitatory and inhibitory spiking neurons, J. Comput. Neurosci. 8(3) (2000) 183-208]. To develop a better understanding of the EEG we need to relate these state descriptors to EEG states. Here, we try to go beyond the firing rate based approaches described in [D.T. Liley, D.M. Alexander, J.J. Wright, M.D. Aldous, Alpha rhythm emerges from large-scale networks of realistically coupled multicompartmental model cortical neurons, Network 10(1) (1999) 79-92; O. David, J.K. Friston, A neural mass model for MEG/EEG: coupling and neuronal dynamics, NeuroImage 20 (2003) 1743-1755] and relate synchronicity and irregularity in the network to EEG states. We show that the transformation between network activity and EEG can be approximately mediated by linear kernel with the shape of an α- or γ-function, allowing us a comparison between EEG states and network activity space. We find that the simulated EEG generated from asynchronous irregular type network activity is closely related to the human EEG recorded in the awake state, evaluated using power spectral density characteristics.
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