Genomic and molecular characterization of preterm birth.

Preterm birth (PTB) complications are the leading cause of long-term morbidity and mortality in children. By using whole blood samples, we integrated whole-genome sequencing (WGS), RNA sequencing (RNA-seq), and DNA methylation data for 270 PTB and 521 control families. We analyzed this combined dataset to identify genomic variants associated with PTB and secondary analyses to identify variants associated with very early PTB (VEPTB) as well as other subcategories of disease that may contribute to PTB. We identified differentially expressed genes (DEGs) and methylated genomic loci and performed expression and methylation quantitative trait loci analyses to link genomic variants to these expression and methylation changes. We performed enrichment tests to identify overlaps between new and known PTB candidate gene systems. We identified 160 significant genomic variants associated with PTB-related phenotypes. The most significant variants, DEGs, and differentially methylated loci were associated with VEPTB. Integration of all data types identified a set of 72 candidate biomarker genes for VEPTB, encompassing genes and those previously associated with PTB. Notably, PTB-associated genes RAB31 and RBPJ were identified by all three data types (WGS, RNA-seq, and methylation). Pathways associated with VEPTB include EGFR and prolactin signaling pathways, inflammation- and immunity-related pathways, chemokine signaling, IFN-γ signaling, and Notch1 signaling. Progress in identifying molecular components of a complex disease is aided by integrated analyses of multiple molecular data types and clinical data. With these data, and by stratifying PTB by subphenotype, we have identified associations between VEPTB and the underlying biology

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Deciphering Transcription and Methylation Specific to Late-Onset Alzheimer's Disease

Alzheimer disease (AD) is the most common form of dementia affecting approximately 13% of individuals 65 and older. Rare variants in the Amyloid precursor protein, Presenilin 1, or Presenilin 2 genes primarily cause Early-Onset Alzheimer disease and comprise 2% of AD cases. Conversely, Late-Onset Alzheimer disease (LOAD) is much more complex and accounts for greater than 90% of AD cases. Recent transcriptome studies have shed light on molecular functions altered in LOAD. Many of these studies have consistently observed alterations within several pathways: synaptic transmission, inflammation, energy metabolism, myelination, and signal transduction. While αβ plaques and neurofibrillary tangles (NFTs) are pathological hallmarks of Alzheimer disease, many clinical LOAD phenotypes are shared across other dementias, including cognitive decline and memory loss. Transcriptome studies have predominately compared Alzheimer samples to normal controls. Using this approach, it is often unclear if the observed disrupted processes in LOAD are specific to LOAD or are the result of non-specific general neurodegenerative effects. In this study, I deciphered the transcriptional and regulation changes observed in LOAD from those due to general neurodegeneration by using a disease control. In addition, two regulatory mechanisms that can influence transcription, ncRNAs and DNA methylation, were analyzed to determine their roles in the transcriptional changes specific to LOAD. This study revealed a wide disruption of transcription, splicing, and DNA methylation specific to LOAD and the general neurodegeneration process. In particular, LOAD specific changes were observed within cellular processes involved in myelination and the innate immune system. Further analysis revealed that strong LOAD specific disruptions of regulatory mechanisms of transcription (e.g. DNA methylation and ncRNAs) converged on cellular processes disrupted in LOAD, specifically processes involved in myelination. These results identified genes and processes specifically altered in LOAD, which could serve as potential avenues of treatment for LOAD. The use of additional types of neurodegenerative disease controls could allow the further honing in on genes specifically altered in LOAD and offers a very promising avenue for further investigations.</p

The physiological and fatigue responses associated with male and mixed-gender Ultimate Frisbee game-play

The aims of this study were to describe the physiological and fatigue responses associated with indoor Ultimate Frisbee game-play; compare exercise intensities attained to current activity guidelines; and compare responses between male and mixed-gender game formats. A between-subjects (game format) repeated measures (time points) observational experimental design was utilized. Subjects competed in male (n = 10; age: 26.3 ± 7.6 yr) or mixed-gender (males: n = 4; 28.5 ± 5.7 yr; females: n = 6; 28.3 ± 8.1 yr) indoor Ultimate Frisbee game-play. Games consisted of 10-min halves, with heart rate (HR), blood lactate concentration ([BLa-]), rating of perceived exertion, and 5- and 20-m sprint times measured. Durations spent in HR-derived intensity zones and sprint decrements were calculated across games. Mixed-gender game-play produced significantly (P < 0.05) higher relative HR (94.3 ± 5.1 vs.89.6 ± 4.8% HRmax) and [BLa-] (8.31 ± 2.22 vs. 4.68 ± 1.89 mmol•L-1) than male game-play. Significantly (P < 0.05) longer durations were spent at vigorous (male: 60.2 ± 26.1%; mixed-gender36.8 ± 34.8%) and near-maximal (male: 31.6 ± 27.6%; mixed-gender: 58.6 ± 37.7%) exercise intensities than moderate (3.9-7.2%), light (0.7-1.0%), and very light (0-0.1%) intensities in both formats. Limited physiological and sprint fatigue was apparent across games. Subjects primarily performed at vigorous and near-maximal intensities during Ultimate Frisbee. The greater physiological demands encountered during mixed-gender game-play might be attributed to underlying gender-mediated cardiovascular differences. These findings support the efficacy of Ultimate Frisbee as a prescriptive exercise tool for health benefit

The physiological and fatigue responses associated with male and mixed-gender Ultimate Frisbee game-play

The aims of this study were to describe the physiological and fatigue responses associated with indoor Ultimate Frisbee game-play; compare exercise intensities attained to current activity guidelines; and compare responses between male and mixed-gender game formats. A between-subjects (game format) repeated measures (time points) observational experimental design was utilized. Subjects competed in male (n = 10; age: 26.3 ± 7.6 yr) or mixed-gender (males: n = 4; 28.5 ± 5.7 yr; females: n = 6; 28.3 ± 8.1 yr) indoor Ultimate Frisbee game-play. Games consisted of 10-min halves, with heart rate (HR), blood lactate concentration ([BLa-]), rating of perceived exertion, and 5- and 20-m sprint times measured. Durations spent in HR-derived intensity zones and sprint decrements were calculated across games. Mixed-gender game-play produced significantly (P < 0.05) higher relative HR (94.3 ± 5.1 vs.89.6 ± 4.8% HRmax) and [BLa-] (8.31 ± 2.22 vs. 4.68 ± 1.89 mmol•L-1) than male game-play. Significantly (P < 0.05) longer durations were spent at vigorous (male: 60.2 ± 26.1%; mixed-gender36.8 ± 34.8%) and near-maximal (male: 31.6 ± 27.6%; mixed-gender: 58.6 ± 37.7%) exercise intensities than moderate (3.9-7.2%), light (0.7-1.0%), and very light (0-0.1%) intensities in both formats. Limited physiological and sprint fatigue was apparent across games. Subjects primarily performed at vigorous and near-maximal intensities during Ultimate Frisbee. The greater physiological demands encountered during mixed-gender game-play might be attributed to underlying gender-mediated cardiovascular differences. These findings support the efficacy of Ultimate Frisbee as a prescriptive exercise tool for health benefit