Osteochondrosis in the central and third tarsal bones of young horses

Recently, the central and third tarsal bones of 23 equine fetuses and foals were examined using micro-computed tomography. Radiological changes, including incomplete ossification and focal ossification defects interpreted as osteochondrosis, were detected in 16 of 23 cases. The geometry of the osteochondrosis defects suggested they were the result of vascular failure, but this requires histological confirmation. The study aim was to examine central and third tarsal bones from the 16 cases and to describe the tissues present, cartilage canals, and lesions, including suspected osteochondrosis lesions. Cases included 9 males and 7 females from 0 to 150 days of age, comprising 11 Icelandic horses, 2 standardbred horses, 2 warmblood riding horses, and 1 coldblooded trotting horse. Until 4 days of age, all aspects of the bones were covered by growth cartilage, but from 105 days, the dorsal and plantar aspects were covered by fibrous tissue undergoing intramembranous ossification. Cartilage canal vessels gradually decreased but were present in most cases up to 122 days and were absent in the next available case at 150 days. Radiological osteochondrosis defects were confirmed in histological sections from 3 cases and consisted of necrotic vessels surrounded by ischemic chondronecrosis (articular osteochondrosis) and areas of retained, morphologically viable hypertrophic chondrocytes (physeal osteochondrosis). The central and third tarsal bones formed by both endochondral and intramembranous ossification. The blood supply to the growth cartilage of the central and third tarsal bones regressed between 122 and 150 days of age. Radiological osteochondrosis defects represented vascular failure, with chondrocyte necrosis and retention, or a combination of articular and physeal osteochondrosis

Associations between arterial stiffness, depressive symptoms and cerebral small vessel disease: cross-sectional findings from the AGES-Reykjavik Study.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Arterial stiffness may contribute to depression via cerebral microvascular damage, but evidence for this is scarce. We therefore investigated whether arterial stiffness is associated with depressive symptoms and whether cerebral small vessel disease contributes to this association.This cross-sectional study included a subset of participants from the AGES-Reykjavik study second examination round, which was conducted from 2007 to 2011. Arterial stiffness (carotid-femoral pulse wave velocity [CFPWV]), depressive symptoms (15-item geriatric depression scale [GDS-15]) and cerebral small vessel disease (MRI) were determined. Manifestations of cerebral small vessel disease included higher white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces and lower total brain parenchyma volume.We included 2058 participants (mean age 79.6 yr; 59.0% women) in our analyses. Higher CFPWV was associated with a higher GDS-15 score, after adjustment for potential confounders (β 0.096, 95% confidence interval [CI] 0.005-0.187). Additional adjustment for white matter hyperintensity volume or subcortical infarcts attenuated the association between CFPWV and the GDS-15 score, which became nonsignificant (p > 0.05). Formal mediation tests showed that the attenuating effects of white matter hyperintensity volume and subcortical infarcts were statistically significant. Virchow-Robin spaces, cerebral microbleeds and cerebral atrophy did not explain the association between CFPWV and depressive symptoms.Our study was limited by its cross-sectional design, which precludes any conclusions about causal mediation. Depressive symptoms were assessed by a self-report questionnaire.Greater arterial stiffness is associated with more depressive symptoms; this association is partly accounted for by white matter hyperintensity volume and subcortical infarcts. This study supports the hypothesis that arterial stiffness leads to depression in part via cerebral small vessel disease.National Institutes of Health (NIH) N01-AG-12100 Intramural Research Program of the National Institute on Aging, USA Icelandic Heart Association Icelandic Parliament, Iceland National Institutes of Health, National Heart, Lung and Blood Institute HL094898 National Institute of Diabetes and Digestive and Kidney Diseases DK08244

Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesEpileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesA meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.Swedish Research Council Knut and Alice Wallenberg Foundation AFA Foundation Swedish Brain Foundatio

Sequence variants with large effects on cardiac electrophysiology and disease.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadFeatures of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease

Association Between Interstitial Lung Abnormalities and All-Cause Mortality.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.To investigate whether interstitial lung abnormalities are associated with increased mortality.Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).Interstitial lung abnormality status as determined by chest CT evaluation.All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.National Institutes of Health (NIH) T32 HL007633 Icelandic Research Fund 141513-051 Landspitali Scientific Fund A-2015-030 National Cancer Institute grant 1K23CA157631 NIH K08 HL097029 R01 HL113264 R21 HL119902 K25 HL104085 R01 HL116931 R01 HL116473 K01 HL118714 R01 HL089897 R01 HL089856 N01-AG-1-2100 HHSN27120120022C P01 HL105339 P01 HL114501 R01 HL107246 R01 HL122464 R01 HL111024 National Heart, Lung, and Blood Institute's Framingham Heart Study contract N01-HC-2519.5 GlaxoSmithKline NCT00292552 5C0104960 National Institute on Aging (NIA) grant 27120120022C NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament) NIA 27120120022

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.publishedVersio