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It has been suggested that mitochondrial dysfunction plays a role in metabolic disorders including obesity, diabetes, and hypertension. The fact that mitochondrial defects can be accumulated over time as a normal part of aging may explain why some individuals can eat all sorts of foods and remain at normal weight while they are young. However, around the fourth decade of life there is a trend towards \"middle-age spread\" with weight gain and the body's decreasing ability to metabolize calories efficiently. To test the hypothesis that mitochondrial variants are associated with BMI in adults, we analyzed a total number of 984 mitochondrial single nucleotide polymorphisms (mtSNPs) in a sample of 6,528 individuals participating in the KORA studies. To assess mtSNP association while taking heteroplasmy into account we used the raw signal intensity values measured on the microarray and applied linear regression. Significant results were obtained for 2 mtSNPs located in the Cytochrome c oxidase subunit genes (MT-CO1: Padjusted = 0.0140 and MT-CO3: Padjusted = 0.0286) and 3 mtSNPs located in the NADH dehydrogenase subunit genes (MT-ND1, MT-ND2 and MT-ND4L: Padjusted = 0.0286). Polymorphisms located in the MT-CO3 and MT-ND4L genes have not been associated with BMI or related phenotypes in the past. Our results highlight the importance of the mitochondrial genome among the factors that contribute to the risk of high BMI. Focusing on mitochondrial variants may lead to further insights regarding effects of existing medications, or even to the development of innovative treatments.

Background Genome-wide association studies allow us to understand the genetics of complex diseases. Human metabolism provides information about the disease-causing mechanisms, so it is usual to investigate the associations between genetic variants and metabolite levels. However, only considering genetic variants and their effects on one trait ignores the possible interplay between different “omics” layers. Existing tools only consider single-nucleotide polymorphism (SNP)–SNP interactions, and no practical tool is available for large-scale investigations of the interactions between pairs of arbitrary quantitative variables. Results We developed an R package called pulver to compute p-values for the interaction term in a very large number of linear regression models. Comparisons based on simulated data showed that pulver is much faster than the existing tools. This is achieved by using the correlation coefficient to test the null-hypothesis, which avoids the costly computation of inversions. Additional tricks are a rearrangement of the order, when iterating through the different “omics” layers, and implementing this algorithm in the fast programming language C++. Furthermore, we applied our algorithm to data from the German KORA study to investigate a real-world problem involving the interplay among DNA methylation, genetic variants, and metabolite levels. Conclusions The pulver package is a convenient and rapid tool for screening huge numbers of linear regression models for significant interaction terms in arbitrary pairs of quantitative variables. pulver is written in R and C++, and can be downloaded freely from CRAN at https://cran.r-project.org/web/packages/pulver/ .

ABSTRACT Recent studies indicate that air pollutants not only increase the risk of cardiovascular and respiratory diseases but also have a negative impact on the developing brain. Exposure to airborne particulate matter (PM) and nitrogen dioxide (NO2) may lead to disruption of neural development by interfering with critical maturation processes. In this study, we assessed the impact of prenatal and early life PM10 and NO2 exposure on diffusion Magnetic Resonance Imaging (dMRI) structural measures: fractional anisotropy (FA), mean diffusivity (MD), and fixel‐based analysis (FBA) on a population of 425 10‐ to 13‐year‐old children with attention deficit hyperactivity disorder (ADHD, n = 116), a sensitive, at‐risk population, and typically developing children (TD, n = 309) from the NeuroSmog study. Unlike traditional voxel‐based methods, FBA allows identification of distinct fiber bundles within voxels. We show that early life exposure to NO2 was associated with lower global FA and higher MD measures. However, despite having a large sample size and using state‐of‐the‐art techniques, we found no significant fixel‐level associations. Notably, we found no evidence that individuals with ADHD are more susceptible to the effects of air pollution. Combined with other studies, our results suggest that dMRI measures are the brain outcomes most consistently affected by air pollution. We explored the association between air pollution and global brain measures and fixel‐specific white matter measures in Polish 10–13‐year‐s old children, with and without ADHD. Global measures were associated with NO2 and PM10 but an insignificant interaction between ADHD and pollutants. No associations between air pollution and fixel‐specific measures. Children and air pollution icons are created by Freepik—Flaticon. Brain icon was downloaded from Pixabay.

Exposure to airborne particulate matter (PM) may affect neurodevelopmental outcomes in children. The mechanisms underlying these relationships are not currently known. We aim to assess whether PM affects the developing brains of schoolchildren in Poland, a country characterized by high levels of PM pollution. Children aged from 10 to 13 years (n = 800) are recruited to participate in this case–control study. Cases (children with attention deficit hyperactivity disorder (ADHD)) are being recruited by field psychologists. Population-based controls are being sampled from schools. The study area comprises 18 towns in southern Poland characterized by wide-ranging levels of PM. Comprehensive psychological assessments are conducted to assess cognitive and social functioning. Participants undergo structural, diffusion-weighted, task, and resting-state magnetic resonance imaging (MRI). PM concentrations are estimated using land use regression models, incorporating information from air monitoring networks, dispersion models, and characteristics of roads and other land cover types. The estimated concentrations will be assigned to the prenatal and postnatal residential and preschool/school addresses of the study participants. We will assess whether long-term exposure to PM affects brain function, structure, and connectivity in healthy children and in those diagnosed with ADHD. This study will provide novel, in-depth understanding of the neurodevelopmental effects of PM pollution.

Introduction: Entry into adolescence, a key period for mental health development, is associated with a higher risk of psychopathology. Existing findings on the nature of the relationship between internalising behaviours and specific executive functions are inconsistent. This study aimed to determine whether internalising behaviours are risk factors for specific domains of executive functions – working memory, verbal fluency, and planning – in a stratified random sample of young adolescents. The study also aimed to investigate whether sex and age have a moderating role in the aforementioned association. Materials and methods: Participants were 477 adolescents (aged 10–13 years, including 223 girls and 254 boys) from southern Poland. To assess the independent variable of internalising behaviours, the Youth Self-Report (YSR) was used. The components of executive functions (including working memory, verbal fluency, and planning) were measured using a battery of neuropsychological tests known as PU1. Associations between internalising symptoms and executive functions were evaluated using quasi-Poisson regression models, adjusted for potential confounders. Results: The study did not confirm the impact of internalising behaviours on the efficiency of executive functions in the studied group of adolescents. However, significant associations not covered by the research hypotheses were discovered: variance in working memory and phonological and categorical fluency is explained by age, and variance in categorical verbal fluency is also explained by parental education. Conclusions: Future exploration of predictors of executive functions components may reveal psychological risk factors, such as individual emotional and behavioural functioning in adolescence or family bonds; this could provide practical benefits in working with adolescents.

We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P<10-14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKbIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961, chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.

It has been suggested that mitochondrial dysfunction plays a role in metabolic disorders including obesity, diabetes, and hypertension. The fact that mitochondrial defects can be accumulated over time as a normal part of aging may explain why some individuals can eat all sorts of foods and remain at normal weight while they are young. However, around the fourth decade of life there is a trend towards \"middle-age spread\" with weight gain and the body's decreasing ability to metabolize calories efficiently. To test the hypothesis that mitochondrial variants are associated with BMI in adults, we analyzed a total number of 984 mitochondrial single nucleotide polymorphisms (mtSNPs) in a sample of 6,528 individuals participating in the KORA studies. To assess mtSNP association while taking heteroplasmy into account we used the raw signal intensity values measured on the microarray and applied linear regression. Significant results were obtained for 2 mtSNPs located in the Cytochrome c oxidase subunit genes (MT-CO1: Padjusted = 0.0140 and MT-CO3: Padjusted = 0.0286) and 3 mtSNPs located in the NADH dehydrogenase subunit genes (MT-ND1, MT-ND2 and MT-ND4L: Padjusted = 0.0286). Polymorphisms located in the MT-CO3 and MT-ND4L genes have not been associated with BMI or related phenotypes in the past. Our results highlight the importance of the mitochondrial genome among the factors that contribute to the risk of high BMI. Focusing on mitochondrial variants may lead to further insights regarding effects of existing medications, or even to the development of innovative treatments.

Blindness has been shown to induce changes in the structural and functional organization of the brain. However, few studies have investigated the relationship between these structural and functional changes. In this study, we examined cortical thickness within occipital regions of interest in 38 early blind individuals and explored its relationship to functional activation during linguistic processing. Participants engaged in tactile Braille reading and auditory processing tasks involving words, pseudowords, and control conditions to assess various aspects of linguistic processing. Linear mixed models revealed a significant association between cortical thickness and functional activation in the occipital cortex during linguistic tasks. Specifically, lower cortical thickness in the middle occipital gyrus, the calcarine sulcus, and the parieto-occipital sulcus were linked to increased activation during orthographic processing in blind participants (Braille pseudowords vs. Braille nonsense-symbols). Similarly, lower cortical thickness in the calcarine sulcus and parieto-occipital sulcus was associated with greater functional activation during phonological processing (auditory pseudowords vs. auditory control). These findings align with prior research suggesting that structural and functional adaptations in the visual cortex of blind individuals may be influenced by developmental mechanisms such as pruning or myelination. This study highlights the interplay between cortical structure and functional reorganization in the blind brain.

Doc number: 44 Abstract Background: Congenital heart defects (CHD) is the most common cause of death from a congenital structure abnormality in newborns and is often associated with fetal loss. There are many types of CHD. Human genetic studies have identified genes that are responsible for the inheritance of a particular type of CHD and for some types of CHD previously thought to be sporadic. However, occasionally different members of the same family might have anatomically distinct defects -- for instance, one member with atrial septal defect, one with tetralogy of Fallot, and one with ventricular septal defect. Our objective is to identify susceptibility loci for CHD in families affected by distinct defects. The occurrence of these apparently discordant clinical phenotypes within one family might hint at a genetic framework common to most types of CHD. Results: We performed a genome-wide linkage analysis using MOD score analysis in families with diverse CHD. Significant linkage was obtained in two regions, at chromosome 15 (15q26.3, P empirical = 0.0004) and at chromosome 18 (18q21.2, P empirical = 0.0005). Conclusions: In these two novel regions four candidate genes are located: SELS, SNRPA1, and PCSK6 on 15q26.3, and TCF4 on 18q21.2. The new loci reported here have not previously been described in connection with CHD. Although further studies in other cohorts are needed to confirm these findings, the results presented here together with recent insight into how the heart normally develops will improve the understanding of CHD.

The epigenome has been shown to be influenced by biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption, and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here, we provide evidence on the associations between epigenetic modifications, in our case, CpG methylation and educational attainment (EA), a biologically distal environmental factor that is arguably among of the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals. While we find that 9 CpG probes are significantly associated with EA, only two remain associated when we restrict the sample to never-smokers. These two are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, their effect sizes on EA are far smaller than the known associations between CpG probes and biologically proximal environmental factors. Two analyses that combine the effects of many probes, polygenic methylation score and epigenetic-clock analyses, both suggest small associations with EA. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.