Genome-wide association study identifies 74 loci associated with educational attainment.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Directional dominance on stature and cognition in diverse human populations.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Residing near allergenic trees can increase risk of allergies later in life: LISA Leipzig study.

BACKGROUND: We investigated whether residing in places with higher greenness, more trees and more allergenic trees early in life increases the risk of allergic outcomes, and whether these associations differ depending on the concentration of air pollutants. METHODS: The analytic sample included 631 children from the German birth cohort LISA Leipzig. Asthma and allergic rhinitis, sensitization to aeroallergens and food allergens, as well as confounders, were collected prospectively up to 15 years. Greenness was assessed by Normalized Difference Vegetation Index (NDVI). A tree registry was used to derive information on trees, which were classified into allergenic and non-allergenic. Annual average concentrations of nitrogen dioxide (NO2) and ozone were also used. Geographic exposures were assigned to home addresses at birth. Longitudinal associations were analysed using generalized estimating equations. RESULTS: Medium and high numbers (tertiles) of trees and allergenic trees in a 500 m buffer around birth addresses were associated with increased odds of allergic rhinitis up to 15 years regardless of NDVI. These exposures were also related to higher odds of sensitization to aeroallergens. Associations with asthma and sensitization to food allergens were less consistent. Effect estimates for allergic rhinitis were stronger in the high tertile of NO2 compared to the low tertile, while an opposite tendency was observed for ozone. CONCLUSION: We observed that early life residence in places with many trees, and allergenic trees specifically, may increase the prevalence of allergic rhinitis later in life. This association and its modification by air pollution should be pursued in further studies.

pulver: an R package for parallel ultra-rapid p-value computation for linear regression interaction terms.

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/ .

Pathways linking greenspace to behavioural problems in Polish children.

Background: Previous cross-sectional studies have found a beneficial relationship between greenspace and children's behaviour. Nevertheless, evidence on the mechanisms underlying this association remains scant. We examined whether the availability of greenspace was related to fewer behavioural problems in Polish children and investigated potential mechanisms. Methods: Data were obtained from the case-control NeuroSmog study, in which children with and without attention deficit hyperactivity disorder (ADHD) were tested from October 2020 to September 2022. The analytic sample comprised 679 children aged 10-13 years. Parents reported internalizing, externalizing, and total behavioural problems using the Child Behaviour Check List (CBCL), as well as information about the presence of a domestic garden and potential mediators: greenspace perception, neighbourhood social cohesion, and physical activity. Tree and grass covers were extracted in 500 m and 1 km buffers around lifelong residences. Structural equation modelling (SEM) was used to examine the psychosocial pathways linking the greenspace metrics to behavioural problems. Results: Greenspace was only indirectly related to fewer behavioural problems. Specifically, tree cover was related to greater levels of physical activity which, in turn, was related to fewer internalizing and total behavioural problems. Tree cover and presence of garden were related to greenspace perception which, in turn, was associated with higher neighbourhood social cohesion which, in turn, was linked to fewer behavioural problems. The patterns of associations in children without ADHD were very similar to those in the full sample except that the associations from garden to greenspace perception and from physical activity to total behavioural problems were no longer significant. The only association persisted among girls was from neighbourhood social cohesion to behavioural problems and among boys were from tree cover to physical activity and tree cover and garden to greenspace perception. Conclusion: Trees and garden, but not grass, are linked to fewer behavioural problems through greenspace perception, neighbourhood social cohesion, and physical activity in Polish children.

Genome-wide linkage analysis of congenital heart defects using MOD score analysis identifies two novel loci.

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.

Family Functioning Style as a Predictor of the Quality of Cognitive Functioning of Primary School Students With ADHD.

OBJECTIVE: This study aimed to specify whether family communication and satisfaction are predictors of a child's executive functions and whether attention deficit hyperactivity disorder (ADHD) severity lies in the pathway between these variables. METHOD: Two hundred Polish children with ADHD, aged 10 to 13, were tested using Conners 3, the PU1 Battery of Cognitive Tests and Stanford-Binet Intelligence Scale, Fifth Edition (SB5). Parents filled out the FACES IV-SOR questionnaire. Structural equation modeling (SEM) was used to test the hypotheses. RESULTS: The quality of family communication and satisfaction did not predict executive functioning in children with ADHD, and ADHD severity did not play a mediating role neither in boys or in girls. Intelligent quotient was the only predictor of executive functioning in the group of boys. CONCLUSION: These results contrast with those of previous studies that have shown the existence of similar associations in other cultural contexts.

Does exposure to nature make children more intelligent? Analysis in Polish children with and without ADHD.

Previous studies have shown that exposure to nature and physical activity (PA) may be associated with higher intelligence in children. We examined whether there is an association between lifelong exposure to greenspace and bluespace and intelligence in children aged 10-13 with and without attention deficit hyperactivity disorder (ADHD), and whether PA mediates this association. The sample (N = 714) was collected within the NeuroSmog case-control study, where children with (N = 206) and without ADHD (N = 508) were recruited from 18 towns in Southern Poland. Nature exposure was estimated as the sum of the z-scores of the objective and perceived measures. Objective greenspace exposure was defined as the percentage of grass and tree cover in 500 m and 1 km buffers around lifelong residential addresses, respectively. Objective bluespace exposure was defined as the percentage of water cover in 500 m and 1 km buffers. Perceived greenspace/bluespace was measured as the parent-rated availability, quality, and use of greenspace/bluespace. Intelligence was assessed using the Polish version of the Stanford-Binet Intelligence Scales, 5th edition (SB5). SB5 Full Scale Intelligence Quotient (IQ), Nonverbal IQ, Verbal IQ, five factor and ten subtest scores were analysed as outcomes. The associations between nature and IQ scores were assessed by linear regressions separately for cases and controls, adjusting the models for sex, parental education, and urbanicity. Structural equation modeling was implemented to test whether PA mediated the association between nature and intelligence. None of the greenspace or bluespace measures were consistently associated with intelligence. PA was not found to be a mediator. We did not find evidence that higher lifelong nature exposure is associated with higher intelligence in Polish schoolchildren with or without ADHD. This casts doubts on whether exposure to nature has relevant influence on IQ.

Association of residential and school green- and bluespace with academic performance in 10-13-year-old Polish schoolchildren with and without attention deficit hyperactivity disorder.

BACKGROUND: Several studies, mostly based on the USA data, have reported that school greenspace was associated with better academic performance. However, nearly all of them were conducted on aggregated data. We are among the first individual data-based studies worldwide to examine whether exposure to school and residential green- and bluespace can boost academic performance. METHODS: NeuroSmog is an ongoing case-control study investigating the impact of air pollution on brain development in children with and without attention deficit hyperactivity disorder (ADHD). 658 children aged 10 to 13 years from 18 large and small towns in southern Poland constituted the analytical sample. Information about latest end-of-year school grades in Polish and maths was collected by the parent report while perceived academic performance in these subjects was collected by the Youth Self-Report. Tree, grass, and water cover, as well as overall vegetation, were abstracted in Euclidean buffers of 500 and 1000 m around concurrent school and residential addresses. Perceived green- and bluespace data were also collected. Adjusted for age, sex, parent education, financial situation, and urbanicity, logistic models were fitted to assess the associations between each exposure-outcome pair. RESULT: We found no consistent associations between academic performance and school or residential green- and bluespace. This held true for children with and without ADHD. CONCLUSIONS: Higher residential and school green- and bluespace do not seem to be sufficient for better academic performance.

Air pollution and attention in Polish schoolchildren with and without ADHD.

BACKGROUND: Development and functioning of attention-a key component of human cognition-can be affected by environmental factors. We investigated whether long- and short-term exposure to particulate matter with aerodynamic diameter < 10 µm (PM10) and nitrogen dioxide (NO2) are related to attention in 10- to 13-year-old children living in Polish towns recruited in the NeuroSmog case-control study. METHODS: We investigated associations between air pollution and attention separately in children with attention deficit hyperactivity disorder (ADHD, n = 187), a sensitive, at-risk population with impaired attention and in population-based typically developing children (TD, n = 465). Alerting, orienting, and executive aspects of attention were measured using the attention network test (ANT), while inhibitory control was measured with the continuous performance test (CPT). We assessed long-term exposure to NO2 and PM10 using novel hybrid land use regression (LUR) models. Short-term exposures to NO2 and PM10 were assigned to each subject using measurements taken at the air pollution monitoring station nearest to their home address. We tested associations for each exposure-outcome pair using adjusted linear and negative binomial regressions. RESULTS: We found that long-term exposures to both NO2 and PM10 were associated with worse visual attention in children with ADHD. Short-term exposure to NO2 was associated with less efficient executive attention in TD children and more errors in children with ADHD. It was also associated with shorter CPT response times in TD children; however, this effect was accompanied by a trend towards more CPT commission errors, suggestive of more impulsive performance in these subjects. Finally, we found that short-term PM10 exposure was associated with fewer omission errors in CPT in TD children. CONCLUSIONS: Exposure to air pollution, especially short-term exposure to NO2, may have a negative impact on attention in children. In sensitive populations, this impact might be different than in the general population.

Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.

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.

NeuroSmog: Determining the Impact of Air Pollution on the Developing Brain: Project Protocol.

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.

Depression and anxiety with exposure to ozone and particulate matter: An epidemiological claims data analysis.

BACKGROUND: Depression and anxiety have complex etiologies and are associated with a significant burden of disease. Although air pollution has been hypothesized as a possible risk factor of these disorders, the associations are still under-investigated. We aimed to analyze associations between long-term exposure to ambient ozone and particulate matter with diameter <10 µm (PM10) and diagnoses of depression and anxiety in a general population. METHODS: We utilized data from a large statutory health insurance company from Saxony, Germany. Information on outpatient clinical diagnoses of depression and anxiety was available for the years 2005-2014. We assigned ambient ozone and PM10 estimates to residential districts of 1.13 million individuals aged 16 and older. Depression and anxiety were defined as diagnoses counts. Associations with depression and anxiety were assessed using adjusted generalized estimating equations models. RESULTS: In the ten-year study period, the observed prevalences of depression and anxiety were 7.40% and 3.82%, respectively. In the two-pollutant model, 10 more days with a maximum 8-h average ozone concentration exceeding 120 µg/m³ resulted in a relative risk (RR) of 1.010 with 95% confidence interval (CI) (1.005, 1.014) for depression and an RR of 1.007 (95% CI (1.000, 1.014)) for anxiety. The effect estimates of PM10 for depression and anxiety were 1.180 (95% CI (1.160, 1.201)) and 1.176 (95% CI (1.148, 1.205)) per 10 µg/m³ increase in PM10 concentration, respectively. Age, sex, and access to healthcare of the individual were also associated with the diagnosis of the disorders. The associations were consistent across one- and two-pollutant models. CONCLUSIONS: Our findings indicate that increased levels of ambient ozone and PM10 may elevate the risk of a depression or anxiety diagnosis in the general population. However, given the lack of data on individual air pollutant exposure and socioeconomic status, our results should be interpreted with caution. Further well-designed epidemiological studies should replicate our findings.

Associations of autozygosity with a broad range of human phenotypes.

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.

Mitochondrial genetic variants identified to be associated with BMI in adults.

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.