Functional neuroimaging and brain lesion studies demonstrate that secondary motor areas of the frontal lobe play a crucial role in the cortical control of hand movements. However, no study so far has examined frontal white matter connections of the secondary motor network, namely the frontal aslant tract, connecting the supplementary motor complex and the posterior inferior frontal regions, and the U-shaped dorsal and ventral premotor fibers running through the middle frontal gyrus. The aim of the current study is to explore the involvement of the short frontal lobe connections in reaching and reach-to-grasp movements in 32 right-handed healthy subjects by correlating tractography data based on spherical deconvolution approach with kinematical data. We showed that individual differences in the microstructure of the bilateral frontal aslant tract, bilateral ventral and left dorsal premotor tracts were associated with kinematic features of hand actions. Furthermore, bilateral ventral premotor connections were also involved in the closing grip phase necessary for determining efficient and stable grasping of the target object. This work suggests for the first time that hand kinematics and visuomotor processing are associated with the anatomy of the short frontal lobe connections.

We address the problem of testing whether a possibly high-dimensional vector may act as a mediator between some exposure variable and the outcome of interest. We propose a global test for mediation, which combines a global test with the intersection-union principle. We discuss theoretical properties of our approach and conduct simulation studies that demonstrate that it performs equally well or better than its competitor. We also propose a multiple testing procedure, Screen-Min, that provides asymptotic control of either familywise error rate or false discovery rate when multiple groups of potential mediators are tested simultaneously. We apply our approach to data from a large Norwegian cohort study, where we look at the hypothesis that smoking increases the risk of lung cancer by modifying the level of DNA methylation. KEYWORDSfalse discovery rate, familywise error rate, high-dimensional data, multiple mediators 3346

A growing amount of evidence in literature suggests that germline sequence variants and somatic mutations in non-coding distal regulatory elements may be crucial for defining disease risk and prognostic stratification of patients, in genetic disorders as well as in cancer. Their functional interpretation is challenging because genome-wide enhancer–target gene (ETG) pairing is an open problem in genomics. The solutions proposed so far do not account for the hierarchy of structural domains which define chromatin three-dimensional (3D) architecture. Here we introduce a change of perspective based on the definition of multi-scale structural chromatin domains, integrated in a statistical framework to define ETG pairs. In this work (i) we develop a computational and statistical framework to reconstruct a comprehensive map of ETG pairs leveraging functional genomics data; (ii) we demonstrate that the incorporation of chromatin 3D architecture information improves ETG pairing accuracy and (iii) we use multiple experimental datasets to extensively benchmark our method against previous solutions for the genome-wide reconstruction of ETG pairs. This solution will facilitate the annotation and interpretation of sequence variants in distal non-coding regulatory elements. We expect this to be especially helpful in clinically oriented applications of whole genome sequencing in cancer and undiagnosed genetic diseases research.

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020.

Ultraviolet radiation (UVR) exposure is a leading cause of skin cancers and an ubiquitous environmental exposure. However, the molecular mechanisms relating UVR exposure to melanoma is not fully understood. We aimed to investigate if lifetime UVR exposure could be robustly associated to DNA methylation (DNAm). We assessed DNAm in whole blood in three data sets (n = 183, 191, and 125) from the Norwegian Woman and Cancer cohort, using Illumina platforms. We studied genome-wide DNAm, targeted analyses of CpG sites indicated in the literature, global methylation, and accelerated aging. Lifetime history of UVR exposure (residential ambient UVR, sunburns, sunbathing vacations and indoor tanning) was collected by questionnaires. We used one data set for discovery and the other two for replication. One CpG site showed a genome-wide significant association to cumulative UVR exposure (cg01884057) (p nominal = 3.96e-08), but was not replicated in any of the two replication sets (p nominal ≥ 0.42). Two CpG sites (cg05860019, cg00033666) showed suggestive associations with the other UVR exposures. We performed extensive analyses of the association between long-term UVR exposure and DNAm. There was no indication of a robust effect of past UVR exposure on DNAm. Solar radiation is the major source of human exposure to ultraviolet radiation (UVR) 1 , and the major risk factor for cutaneous melanoma and keratinocyte skin cancers 2,3. Exposure to artificial UVR (indoor tanning) also increases skin cancer risk, and is classified as carcinogenic to humans 4. Identification of biomarkers indicating past exposures is important in the study of chronic diseases and their etiology. In epidemiological studies, DNA methylation has been a strong marker of environmental exposure 5,6. Exposure to smoking, air pollution, and heavy metals have consistently been linked to epigenetic changes, mainly to DNA methylation 7,8. UVR exposure has also been linked to DNA methylation, as UVR exposure has been demonstrated to change the epigenetic profile of the epidermis 9. An assessment of ambient UVR exposure and DNA methylation in CD4 + T-cells in European American individuals 10 demonstrated an epigenome-wide significant association for cg26930596 (PRKCZ), but failed to replicate in an independent sample. An Australian study found an association between UVR exposure and total LINE-1 hypomethylation 11. LINE-1 has often been used as a marker of genomic integrity, and a loss of methylation in LINE-1 is associated with global hypomethylation and with structural instability of the genome. Global hypomethylation has been associated with multiple cancers, including bladder, liver, breast, kidney, colon and melanoma 12. With UVR exposure as the main risk factor for melanoma, it is of interest to investigate if UVR exposure can affect epigenetic profiles, and if DNA methylation mediates the association between UVR exposure and the risk of melanoma. Our aim was to assess the former, i.e., whether DNA methylation in blood leucocytes is associated with life histo...