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Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects.

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 258 genes that have been reported to modulate fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. Notably, at least 40 genes that are known to regulate embryonic neurogenesis were dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or downregulated by VPA in the fetal brain and (b) associated with autism and/or known to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The genes meeting these criteria provide potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.

To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not \"a priori\" be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/ TNS3 , P  = 4.35 × 10 −8 ). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 ( NOC2L , P  = 8.36 × 10 −14 ), rs2941471 at 8q21.11 ( HNF4G , P  = 6.60 × 10 −10 ), rs4795218 at 17q12 ( HNF1B , P  = 1.32 × 10 −8 ), and rs1517037 at 18q21.32 ( GRP , P  = 3.28 × 10 −8 ). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene. Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n  = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments ( n  = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1 . Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.

Background A multiplicity of study designs such as gene candidate analysis, genome wide search (GWS) and, recently, whole genome association studies have been employed for the identification of the genetic components of essential hypertension (EH). Several genome-wide linkage studies of EH and blood pressure-related phenotypes demonstrate that there is no single locus with a major effect while several genomic regions likely to contain EH-susceptibility loci were validated by multiple studies. Methods We carried out the clinical assessment of the entire adult population in a Sardinian village (Talana) and we analyzed 16 selected families with 62 hypertensive subjects out of 267 individuals. We carried out a double GWS using a set of 902 uniformly spaced microsatellites and a high-density SNPs map on the same group of families. Results Three loci were identified by both microsatellites and SNP scans and the obtained linkage results showed a remarkable degree of similarity. These loci were identified on chromosome 2q24, 11q23.1–25 and 13q14.11–21.33. Further support to these findings is their broad description present in literature associated to EH or related phenotypes. Bioinformatic investigation of these loci shows several potential EH candidate genes, several of whom already associated to blood pressure regulation pathways. Conclusion Our search for major susceptibility EH genetic factors evidences that EH in the genetic isolate of Talana is due to the contribution of several genes contained in loci identified and replicated by earlier findings in different human populations.

Background and Objectives: Cancer‐related fatigue is a multifactorial condition that affects most people undergoing chemotherapy. To elucidate potential biological underpinnings of fatigue, this study tested correlations between patient‐reported fatigue and (1) functional measures and (2) transcriptomics of whole blood. Methods: Women undergoing chemotherapy were recruited to a cross‐sectional study. Participants reported subjective fatigue on the Functional Assessment for Chronic Illness Therapy‐Fatigue (FACIT‐F) and Brief Fatigue Inventory (BFI) questionnaires. Participants completed upper‐ and lower‐body functional assessments as an objective fatigability measure. Fasted blood samples were analyzed for complete blood counts (CBCs) to quantify cell type, and RNA‐Seq on whole blood was investigated for a distinct transcriptional signature in patients with high vs. low fatigue. Principal component analysis revealed that transcriptomic profiles clustered based on the neutrophil level, lymphocyte level, and several other clinical factors, which were accounted for when assessing differentially expressed genes. Results: Participants had breast ( n  = 29) or uterine ( n  = 1) cancer, were 53.4 ± 13.5 years old, and identified as Black/African American (56%) or White (44%). Hand grip strength, static fatigue index, and sit‐to‐stand assessments were not associated with FACIT‐F fatigue subscale responses. From RNA‐Seq data, higher fatigue was associated with fewer SH3RF1 transcripts ( p = 4.1 e ‐3) and more CAPRIN2 transcripts ( p = 8.2 e ‐3). Unbiased gene ontology/pathway analyses revealed perturbed biological processes in mitochondrial function, chiefly aerobic respiration (normalized effect size [ES] = −2.1), electron transport chain (ES = −1.9), generation of precursor metabolites and energy (ES = −1.8), and fatty acid oxidation (ES = −2.0), which tended to be downregulated among participants with more fatigue. Cellular components analyses consistently showed downregulation of mitochondrial proteins among those with higher fatigue (ESs = −1.7–−2.2). Future studies should investigate dietary, physical activity, and/or pharmaceutical interventions to optimize the efficiency of mitochondrial energy production during treatment to mitigate fatigue.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10−8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10−14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10−10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10−8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10−8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNAseq data ob-tained from E12.5 fetal mouse brains 3 hours after VPA administration revealed that VPA significant-ly increased or decreased the expression of approximately 7,300 genes. No significant sex differ-ences in VPA-induced gene expression were observed. Expression of genes associated with neu-rodevelopmental disorders (NDDs) such as autism as well as neurogenesis, axon growth and syn-aptogenesis, GABAergic, glutaminergic and dopaminergic synaptic transmission, perineuronal nets, and circadian rhythms was dysregulated by VPA. Moreover, expression of 399 autism risk genes was significantly altered by VPA as was expression of 252 genes that have been reported to play fundamental roles in the development of the nervous system but are not otherwise linked to autism. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity in the postnatal and adult brain. The set of genes meeting these criteria pro-vides potential targets for future hypothesis-driven approaches to elucidating the proximal underly-ing causes of defective brain connectivity in NDDs such as autism.

Pancreatic cancer is currently the seventh leading cause of cancer death worldwide. Age is the most significant risk factor for the disease and as the population in many developed countries ages, the absolute incidence of pancreatic cancer is expected to increase as well. The survival rates for pancreatic cancer are the poorest of any of the major tumor sites. The majority of cases are diagnosed at an advanced stage, with only about 20% of patients presenting with local disease. In recent years, a slight, but significant increase in survival rates has been reported in the United States from 4–5% to as high at 8%. Of the modifiable risk factors associated with pancreatic cancer, cigarette smoking, diabetes, and obesity are the most prevalent at the population level and thereby, have the largest attributable fraction. Diabetes and pancreatitis are both associated with an increased risk for pancreatic cancer in the case of longstanding disease. However, a recent onset of diabetes or pancreatitis can often be an early manifestation of the cancer itself. Family history of pancreatic cancer is an important predictor of future risk with up to 10% of newly diagnosed pancreatic cancer patients reporting a family history of disease. The goal of this chapter is review the epidemiology of pancreatic cancer along with the evidence supporting the role of established risk factors in the development of this disease.