Publications

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 individuals1. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample1,2 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.

'Polarization-Induced Effects in Heterostructures' published in 'Encyclopedia of Nanotechnology'

C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

Background: The relationship between sodium intake and cardiovascular disease (CVD) remains controversial, in part, due to inaccurate assessment of sodium intake. 24-hour urinary excretion over multiple days is considered the optimal method. Methods: We included individual participant data from 6 prospective cohorts among generally healthy adults with sodium and potassium excretion assessed by at least two 24-hour urine collections. Out of 10,709 participants (54% women; mean [SD] age, 51.5 [12.6] years), 571 incident CVD events (including myocardial infarction, coronary revascularization, and stroke) were ascertained during a median follow-up of 8.8 years. We analyzed each cohort using consistent methods and combined the results using random-effects meta-analysis. Results: Median 24-hour urinary sodium excretion (10 th -90 th percentile) was 3,270 (2,099-4,899) mg. Higher sodium excretion, lower potassium excretion and higher sodium-to-potassium ratio were all associated with higher risk of CVD events after controlling for confounding factors (all P values for trend≤0.02); there was no evidence of nonlinearity. The hazard ratio [HR] comparing top with bottom quartiles was 1.67 [95% confidence interval [CI]: 1.21-2.30] for sodium, 0.77 [0.57-1.02] for potassium and 1.72 [1.27-2.32] for sodium-to-potassium ratio. Each 1,000 mg/d increment in sodium excretion was associated with an 18% increase in CVD risk (95%CI: 5%-32%) and each 1,000 mg/d increment in potassium excretion was associated with 18% lower risk (95%CI: 6%-28%). Conclusions: Higher sodium and lower potassium intakes, measured in multiple 24-hour urine samples, were associated with higher risk of CVD in a dose-response manner. These findings support current recommendations to reduce sodium and increase potassium intakes.

This paper describes the behavior of bubbles suspended in a carrier liquid and moving within microfluidic networks of different connectivities. A single-phase continuum fluid, when flowing in a network of channels, partitions itself among all possible paths connecting the inlet and outlet. The flow rates along different paths are determined by the interaction between the fluid and the global structure of the network. That is, the distribution of flows depends on the fluidic resistances of all channels of the network. The movement of bubbles of gas, or droplets of liquid, suspended in a liquid can be quite different from the movement of a single-phase liquid, especially when they have sizes slightly larger than the channels, so that the bubbles (or droplets) contribute to the fluidic resistance of a channel when they are transiting it. This paper examines bubbles in this size range; in the size range examined, the bubbles are discrete and do not divide at junctions. As a consequence, a single bubble traverses only one of the possible paths through the network, and makes a sequence of binary choices ("left" or "right") at each branching intersection it encounters. We designed networks so that, at each junction, a bubble enters the channel into which the volumetric flow rate of the carrier liquid is highest. When there is only a single bubble inside a network at a time, the path taken by the bubble is, counter-intuitively, not necessarily the shortest or the fastest connecting the inlet and outlet. When a small number of bubbles move simultaneously through a network, they interact with one another by modifying fluidic resistances and flows in a time dependent manner; such groups of bubbles show very complex behaviors. When a large number of bubbles (sufficiently large that the volume of the bubbles occupies a significant fraction of the volume of the network) flow simultaneously through a network, however, the collective behavior of bubbles-the fluxes of bubbles through different paths of the network-can resemble the distribution of flows of a single-phase fluid.

OBJECTIVE— The aim of this article was to assess the association between the Alternate Healthy Eating Index (AHEI) and risk of type 2 diabetes in women. RESEARCH DESIGN AND METHODS— A total of 80,029 women aged 38–63 years in the Nurses’ Health Study were followed from 1984 to 2002. The AHEI score was computed from dietary information collected from five repeated food frequency questionnaires administered between 1984 and 1998. Relative risks (RRs) for type 2 diabetes were calculated using Cox proportional hazards models and adjusted for known diabetes risk factors. We also examined how changes in score in 4, 6–8, and 10–12 years are associated with diabetes risk. RESULTS— We ascertained 5,183 incident cases of type 2 diabetes during 18 years of follow-up. Women who scored high on the AHEI had a lower risk (RR comparing top to bottom score quintile 0.64 [95% CI 0.58–0.71], Ptrend < 0.0001) for diabetes. Women with consistently high AHEI scores throughout follow-up, compared with those with consistently low scores, had the lowest risk for diabetes. In addition, women whose AHEI scores improved during follow-up, even during recent years, had a lower risk of diabetes than did women whose (low) score did not change. CONCLUSIONS— A higher AHEI score is associated with a lower risk of type 2 diabetes in women. Therefore, the AHEI score may be a useful clinical tool to assess diet quality and to recommend for the prevention of diabetes.

Whereas moderate drinking may have health benefits, excessive alcohol consumption causes many important acute and chronic diseases and is the third leading contributor to preventable death in the United States. Twin studies suggest that alcohol-consumption patterns are heritable (50%); however, multiple genetic variants of modest effect size are likely to contribute to this heritable variation. Genome-wide association studies provide a tool for discovering genetic loci that contribute to variations in alcohol consumption. Opportunities exist to identify susceptibility loci with modest effect by meta-analyzing together multiple studies. However, existing studies assessed many different aspects of alcohol use, such as typical compared with heavy drinking, and these different assessments can be difficult to reconcile. In addition, many studies lack the ability to distinguish between lifetime and recent abstention or to assess the pattern of drinking during the week, and a variety of such concerns surround the appropriateness of developing a common summary measure of alcohol intake. Combining such measures of alcohol intake can cause heterogeneity and exposure misclassification, cause a reduction in power, and affect the magnitude of genetic association signals. In this review, we discuss the challenges associated with harmonizing alcohol-consumption data from studies with widely different assessment instruments, with a particular focus on large-scale genetic studies.

OBJECTIVE Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. RESEARCH DESIGN AND METHODS We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. RESULTS We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10−2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. CONCLUSIONS Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.

Abstract Social reward dependence (RD) in humans is a stable pattern of attitudes and behaviour hypothesized to represent a favourable disposition towards social relationships and attachment as a personality dimension. It has been theorized that this long‐term disposition to openness is linked to the capacity to process primary reward. Using brain structure measures from magnetic resonance imaging, and a measure of RD from Cloninger’s temperament and character inventory, a self‐reported questionnaire, in 41 male subjects sampled from a general population birth cohort, we investigated the neuro‐anatomical basis of social RD. We found that higher social RD in men was significantly associated with increased gray matter density in the orbitofrontal cortex, basal ganglia and temporal lobes, regions that have been previously shown to be involved in processing of primary rewards. These findings provide evidence for a brain structural disposition to social interaction, and that sensitivity to social reward shares a common neural basis with systems for processing primary reward information.

Abstract Background Globally, one in ten babies is born preterm (<37 weeks), and 1–2% preterm at very low birth weight (VLBW, <1500 g). As adults, they are at increased risk for a plethora of health conditions, e.g., cardiometabolic disease, which may partly be mediated by epigenetic regulation. We compared blood DNA methylation between young adults born at VLBW and controls. Methods 157 subjects born at VLBW and 161 controls born at term, from the Helsinki Study of Very Low Birth Weight Adults, were assessed for peripheral venous blood DNA methylation levels at mean age of 22 years. Significant CpG-sites (5’—C—phosphate—G—3’) were meta-analyzed against continuous birth weight in four independent cohorts (pooled n = 2235) with cohort mean ages varying from 0 to 31 years. Results In the discovery cohort, 66 CpG-sites were differentially methylated between VLBW adults and controls. Top hits were located in HIF3A , EBF4, and an intergenic region nearest to GLI2 (distance 57,533 bp). Five CpG-sites, all in proximity to GLI2 , were hypermethylated in VLBW and associated with lower birth weight in the meta-analysis. Conclusion We identified differentially methylated CpG-sites suggesting an epigenetic signature of preterm birth at VLBW present in adult life. Impact Being born preterm at very low birth weight has major implications for later health and chronic disease risk factors. The mechanism linking preterm birth to later outcomes remains unknown. Our cohort study of 157 very low birth weight adults and 161 controls found 66 differentially methylated sites at mean age of 22 years. Our findings suggest an epigenetic mark of preterm birth present in adulthood, which opens up opportunities for mechanistic studies.