Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, ...with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.
We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron.
Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
ABSTRACT
The 2021 Women in Combat (WIC) Symposium brought together hundreds of service members, researchers, and multidisciplinary leaders for 3 days of virtual education and interactive discussion ...regarding female leadership, operational performance, and physical health and well-being. Three days of presentations were followed by virtual face-to-face breakout room sessions that aimed to identify gaps currently impacting military servicewomen, mirroring the inaugural WIC Symposium held in 2014. Keynote speakers revisited old recommendations and redefined these in the context of new research and policy changes within the Department of Defense (DoD), making it apparent that although much work has been done, policy and practice are yet to fully integrate the research recommendations that will improve the health and wellness of servicewomen. Originally planned as an in-person meeting, the WIC Symposium was held completely online because of the sustained threat of the COVID-19 pandemic. This event was collectively attended by nearly 10,000 people, reflecting an attendance of over ten times the number of registered attendees. The 2021 WIC Symposium was successful in part because of the groundwork laid by previous researchers who laid out virtual meeting best practices and in part because of the increased accessibility of an online event.
Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, ...the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.
To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.
We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.
A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.
With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.
We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.
Abstract Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common ...neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50–$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.
ABSTRACT
Introduction
The Women in Combat Summit 2021 “Forging the Future: How Women Enhance the Fighting Force” took place during February 9-11, 2021, via a virtual conference platform. The third ...and final day of the Summit regarded the physical health and well-being of military women and included the topics of urogenital health, nutrition and iron-deficiency anemia, unintended pregnancy and contraception, and traumatic brain injury.
Materials and methods
After presentations on the topics earlier, interested conference attendees were invited to participate in focus groups to discuss and review policy recommendations for physical health and well-being in military women. Discussions centered around the topics discussed during the presentations, and suggestions for future Women in Combat Summits were noted. Specifics of the methods of the Summit are presented elsewhere in this supplement.
Results
We formulated research and policy recommendations for urogenital health, nutrition and iron-deficiency anemia, contraception and unintended pregnancy, and traumatic brain injury.
Conclusions
In order to continue to develop the future health of military women, health care providers, researchers, and policymakers should consider the recommendations made in this supplement as they continue to build on the state of the science and forge the future.
Abstract The concept of a pathological overlap between neurodegenerative disorders is gaining momentum. We sought to determine the contribution of C9orf72 repeat expansions, recently discovered as a ...cause of frontotemporal dementia and amyotrophic lateral sclerosis, in a large number of Parkinson's disease patients. No large expansions were identified in our cohort.
ABSTRACT
Introduction
The modern female soldier has yet to be fully characterized as she steps up to fill new combat roles that have only recently been opened to women. Both U.S. and U.K. military ...operational research efforts are supporting a science-based evolution of physical training and standards for female warfighters. The increasing representation of women in all military occupations makes it possible to discover and document the limits of female physiological performance.
Method
An informal Delphi process was used to synthesize an integrated concept of current military female physiological research priorities and emerging findings using a panel of subject matter experts who presented their research and perspectives during the second Women in Combat Summit hosted by the TriService Nursing Research Program in February 2021.
Results
The physical characteristics of the modern soldier are changing as women train for nontraditional military roles, and they are emerging as stronger and leaner. Capabilities and physique will likely continue to evolve in response to new Army standards and training programs designed around science-based sex-neutral requirements. Strong bones may be a feature of the female pioneers who successfully complete training and secure roles traditionally reserved for men. Injury risk can be reduced by smarter, targeted training and with attention directed to female-specific hormonal status, biomechanics, and musculoskeletal architecture. An “estrogen advantage” appears to metabolically support enhanced mental endurance in physically demanding high-stress field conditions; a healthy estrogen environment is also essential for musculoskeletal health. The performance of female soldiers can be further enhanced by attention to equipment that serves their needs with seemingly simple solutions such as a suitable sports bra and personal protective equipment that accommodates the female anatomy.
Conclusions
Female physiological limits and performance have yet to be adequately defined as women move into new roles that were previously developed and reserved for men. Emerging evidence indicates much greater physical capacity and physiological resilience than previously postulated.
Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional ...risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.
PDF
