Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP

Germline mutations in cellular-energy associated genes have been shown to lead to various monogenic disorders. Notably, mitochondrial disorders often impact skeletal muscle, brain, liver, heart, and kidneys, which are the body’s top energy-consuming organs. However, energy-related dysfunctions have not been widely seen as causes of common diseases, although evidence points to such a link for certain disorders. During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption. AMP deaminase deficient subjects experience some negative effects like decreased muscle power output, but also positive effects such as decreased diabetes and improved prognosis for chronic heart failure patients. That may reflect decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since de novo IMP synthesis requires burning seven ATPs. Similarly, beneficial effects have been seen in heart, skeletal muscle, or brain after treatment with allopurinol or febuxostat to inhibit xanthine oxidoreductase, which catalyzes hypoxanthine -> xanthine and xanthine -> urate reactions. Some disorders of those organs may reflect dysfunction in energy-consumption/production, and the observed beneficial effects related to reinforcement of ATP re-synthesis due to increased hypoxanthine levels in the blood and tissues. Recent clinical studies indicated that treatment with xanthine oxidoreductase inhibitors plus inosine had the strongest impact for increasing the pool of salvageable purines and leading to increased ATP levels in humans, thereby suggesting that this combination is more beneficial than a xanthine oxidoreductase inhibitor alone to treat disorders with ATP deficiency

Silicon isotopes in an EMIC's ocean: Sensitivity to runoff, iron supply, and climate

The isotopic composition of Si in biogenic silica (BSi), such as opal buried in the oceans' sediments, has changed over time. Paleorecords suggest that the isotopic composition, described in terms of δ30Si, was generally much lower during glacial times than today. There is consensus that this variability is attributable to differing environmental conditions at the respective time of BSi production and sedimentation. The detailed links between environmental conditions and the isotopic composition of BSi in the sediments remain, however, poorly constrained. In this study, we explore the effects of a suite of offset boundary conditions during the Last Glacial Maximum (LGM) on the isotopic composition of BSi archived in sediments in an Earth System Model of intermediate complexity (EMIC). Our model results suggest that a change in the isotopic composition of Si supply to the glacial ocean is sufficient to explain the observed overall low(er) glacial δ30Si in BSi. All other processes explored trigger model responses of either wrong sign or magnitude or are inconsistent with a recent estimate of bottom water oxygenation in the Atlantic Sector of the Southern Ocean. Caveats, mainly associated with generic uncertainties in today's pelagic biogeochemical modules, remain.publishedVersio

Imputation of KIR Types from SNP Variation Data.

Large population studies of immune system genes are essential for characterizing their role in diseases, including autoimmune conditions. Of key interest are a group of genes encoding the killer cell immunoglobulin-like receptors (KIRs), which have known and hypothesized roles in autoimmune diseases, resistance to viruses, reproductive conditions, and cancer. These genes are highly polymorphic, which makes typing expensive and time consuming. Consequently, despite their importance, KIRs have been little studied in large cohorts. Statistical imputation methods developed for other complex loci (e.g., human leukocyte antigen [HLA]) on the basis of SNP data provide an inexpensive high-throughput alternative to direct laboratory typing of these loci and have enabled important findings and insights for many diseases. We present KIR∗IMP, a method for imputation of KIR copy number. We show that KIR∗IMP is highly accurate and thus allows the study of KIRs in large cohorts and enables detailed investigation of the role of KIRs in human disease.This work was supported by the Australian National Health and Medical Research Council (NHMRC), Career Development Fellowship ID 1053756 (S.L.); by a Victorian Life Sciences Computation Initiative (VLSCI) grant number VR0240 on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia (S.L.); by the UK Multiple Sclerosis Society, grant 894/08 (S.S.); and by the Wellcome Trust and the MRC with partial funding from the National Institute of Health Cambridge Biomedical Research Centre (J.T., J.A.T.). Research at the Murdoch Childrens Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2015.09.00

A Genome-Wide Association Study of Nephrolithiasis in the Japanese Population Identifies Novel Susceptible Loci at 5q35.3, 7p14.3, and 13q14.1

Nephrolithiasis is a common nephrologic disorder with complex etiology. To identify the genetic factor(s) for nephrolithiasis, we conducted a three-stage genome-wide association study (GWAS) using a total of 5,892 nephrolithiasis cases and 17,809 controls of Japanese origin. Here we found three novel loci for nephrolithiasis: RGS14-SLC34A1-PFN3-F12 on 5q35.3 (rs11746443; P = 8.51×10−12, odds ratio (OR) = 1.19), INMT-FAM188B-AQP1 on 7p14.3 (rs1000597; P = 2.16×10−14, OR = 1.22), and DGKH on 13q14.1 (rs4142110; P = 4.62×10−9, OR = 1.14). Subsequent analyses in 21,842 Japanese subjects revealed the association of SNP rs11746443 with the reduction of estimated glomerular filtration rate (eGFR) (P = 6.54×10−8), suggesting a crucial role for this variation in renal function. Our findings elucidated the significance of genetic variations for the pathogenesis of nephrolithiasis

Elucidating the genetic architecture of reproductive ageing in the Japanese population.

Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10-8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches

Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis

To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10−49); however, these variants which are most likely to impact on risk, are rare (MAFT, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10−4 for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10−3, for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10−6). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Genome-Wide Association Study in a Lebanese Cohort Confirms PHACTR1 as a Major Determinant of Coronary Artery Stenosis

The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57×10−5). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85×10−6), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02×10−10). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD

Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits