Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Undifferentiated Spondyloarthropathies In Brazilians: Importance Of Hla-b27 And The B7-creg Alleles In Characterization And Disease Progression.

To analyze the profile of the HLA-B27 and B7 cross-reactive group (CREG) alleles and the role of these markers in disease characterization and progression in patients with undifferentiated spondyloarthropathies (uSpA). A total of 80 patients with a diagnosis of uSpA (40 HLA-B27 positive and 40 HLA-B27 negative) were prospectively studied for 2 years. The control group consisted of 66 HLA-B27 positive and 112 HLA-B27 negative individuals without a history of seronegative SpA. HLA-B alleles were typed at low (B7-CREG alleles, i.e., B*7, B*54, B*55, B*56, B*40, B*42) or high resolution (B*27 alleles) using polymerase chain reaction-amplified DNA hybridized with sequence-specific oligonucleotide probes. HLA-B*2705 was the most frequent allele, observed in 92.5% of the patients and in 77% of the controls, followed by the HLA-B*2702, observed in 5% of the patients and in 12% of the controls. HLA-B*2704 was observed in only one patient (2.5%), and was absent in the control population. HLA-B*2703 (6%) and HLA-B*2707 (5%) alleles were observed only in controls. No associations between HLA-B*27 alleles or B7-CREG alleles and any specific manifestation of uSpA were observed. HLA-B27 positive patients more frequently presented juvenile onset SpA (p = 0.002) and progression to ankylosing spondylitis (AS) (p = 0.03) than did HLA-B27 negative patients. The B7-CREG alleles were observed in 5% of the HLA-B27 positive uSpA group, in 25% of the HLA-B27 negative uSpA group, in 7% of the HLA-B27 positive controls, and in 13% of the HLA-B27 negative controls; a significant association was observed between the presence of the B7-CREG and the HLA-B27 negative uSpA group (p = 0.012). The frequency of the HLA-B*2705 allele among the B27 positive uSpA patients of this series was closely similar to that reported for patients with ankylosing spondylitis (AS). The presence of HLA-B*27 alleles was associated with the progression to AS, and the presence of B7-CREG was associated with uSpA in the HLA-B27 negative group.302632-

2002-900.dec

ABSTRACT. Objective. To analyze the profile of the HLA-B27 and B7 cross-reactive group (CREG) alleles and the role of these markers in disease characterization and progression in patients with undifferentiated spondyloarthropathies (uSpA). Methods. A total of 80 patients with a diagnosis of uSpA (40 HLA-B27 positive and 40 HLA-B27 negative) were prospectively studied for 2 years. The control group consisted of 66 HLA-B27 positive and 112 HLA-B27 negative individuals without a history of seronegative SpA. HLA-B alleles were typed at low (B7-CREG alleles, i.e., B*7, B*54, B*55, B*56, B*40, B*42) or high resolution (B*27 alleles) using polymerase chain reaction-amplified DNA hybridized with sequence-specific oligonucleotide probes. Results. HLA-B*2705 was the most frequent allele, observed in 92.5% of the patients and in 77% of the controls, followed by the HLA-B*2702, observed in 5% of the patients and in 12% of the controls. HLA-B*2704 was observed in only one patient (2.5%), and was absent in the control population. HLA-B*2703 (6%) and HLA-B*2707 (5%) alleles were observed only in controls. No associations between HLA-B*27 alleles or B7-CREG alleles and any specific manifestation of uSpA were observed. HLA-B27 positive patients more frequently presented juvenile onset SpA (p = 0.002) and progression to ankylosing spondylitis (AS) (p = 0.03) than did HLA-B27 negative patients. The B7-CREG alleles were observed in 5% of the HLA-B27 positive uSpA group, in 25% of the HLA-B27 negative uSpA group, in 7% of the HLA-B27 positive controls, and in 13% of the HLA-B27 negative controls; a significant association was observed between the presence of the B7-CREG and the HLA-B27 negative uSpA group (p = 0.012). Conclusio