Background
While genome wide association studies (GWASs) of Alzheimer’s Disease (AD) in European ancestry cohorts (EUR) have identified >70 potentially independent AD risk loci, progress in ...non‐European populations has lagged. In this study, data from US Veterans of African ancestry (AFR) from the Million Veteran Program (MVP) biorepository were used to identify genetic factors associated with AD and related dementias (ADRD).
Method
Using the VA electronic medical record, 4,012 AFR ADRD cases (algorithm includes codes for AD and dementias such as vascular dementia) and 18,435 dementia‐free AFR controls were identified for inclusion in the GWAS. A GWAS was also performed using proxy dementia based on survey‐reported AFR participant parental history of AD or other dementia that included 4,385 maternal cases, 2,256 paternal cases, and 45,970 controls. Meta‐analysis of the case control and proxy results for was performed and then subsequently combined with results from a AFR AD GWAS conducted by the Alzheimer Disease Genetics Consortium (ADGC; Kunkle et al., 2021).
Result
The AFR MVP GWAS (case‐control + proxy) yielded genome‐wide significant associations with several loci including APOE (p=2.48x10‐101), ROBO1 (rs11919682, p=1.63x10‐8), and RP11‐340A13.2 (rs148433063, p=8.56x10‐9. The ROBO1 and RP11‐240A13.2 SNPs were not replicated in the ADGC sample (missing or not significant). The meta‐analysis of MVP and ADGC GWAS results (Table 1) additionally identified genome significant SNPs near known AD risk genes TREM2 (rs73427293, p=2.95x10‐9), CD2AP (rs7738720, p=1.14x10‐9), and ABCA7 (rs73505251, p=3.26x10‐10). Comparison of expression of genes near variants with suggestive evidence of association (p<5x10‐7) in the brains of EUR AD cases and controls from Framingham Heart Study, Religious Orders Study/Rush Memory and Aging Project, Mayo‐Mount Sinai Brain Bank, and Boston University Brain Bank (Panitch et al.) identified several differentially expressed genes including EML6.
Conclusion
The AFR dementia GWAS presented here is the largest to date. It increased the number of genome wide significant common‐variant dementia loci reported in AFR cohorts from two to six, including genes previously implicated in EUR cohorts. Increasing representation of AFRs is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.
The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation ...signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2–5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.
Display omitted
•Inverted triplications cause genomic disorders through alterations in gene dosage•Pairs of homologous inverted repeats generate varying structural haplotypes•Breakpoint junction mapping reveals template switches within repeats•Combining methodologies enhance the analysis of complex genomic aberrations
Analysis of 24 individuals harboring inverted triplications show surprising structural variant haplotype diversity and underlie the importance of inverted repeats acting as points of genomic instability leading to genomic disorders.
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a working group in June 2011 to examine alternative institutional review board (IRB) models. The ...working group was held in response to proposed changes in the regulations for government-supported research and the proliferation of multicenter clinical trials where multiple individual reviews may be inefficient. Group members included experts in heart, lung, and blood research, research oversight, bioethics, health economics, regulations, and information technology (IT). The group discussed alternative IRB models, ethical concerns, metrics for evaluating IRBs, IT needs, and economic considerations. Participants noted research gaps in IRB best practices and in metrics. The group arrived at recommendations for process changes, such as defining specific IRB performance requirements in funding announcements, requiring funded researchers to use more efficient alternative IRB models, and developing IT systems to facilitate information sharing and collaboration among IRBs. Despite the success of the National Cancer Institute's central IRB (CIRB), the working group, concerned about the creation costs and unknown cost-efficiency of a new CIRB, and about the risk of shifting the burden of dealing with multiple IRBs from sponsors to research institutions, did not recommend the creation of an NHLBI-funded CIRB.
Measurement has a special role in quantum theory: by collapsing the wavefunction it can enable phenomena such as teleportation and thereby alter the "arrow of time" that constrains unitary evolution. ...When integrated in many-body dynamics, measurements can lead to emergent patterns of quantum information in space-time that go beyond established paradigms for characterizing phases, either in or out of equilibrium. On present-day NISQ processors, the experimental realization of this physics is challenging due to noise, hardware limitations, and the stochastic nature of quantum measurement. Here we address each of these experimental challenges and investigate measurement-induced quantum information phases on up to 70 superconducting qubits. By leveraging the interchangeability of space and time, we use a duality mapping, to avoid mid-circuit measurement and access different manifestations of the underlying phases -- from entanglement scaling to measurement-induced teleportation -- in a unified way. We obtain finite-size signatures of a phase transition with a decoding protocol that correlates the experimental measurement record with classical simulation data. The phases display sharply different sensitivity to noise, which we exploit to turn an inherent hardware limitation into a useful diagnostic. Our work demonstrates an approach to realize measurement-induced physics at scales that are at the limits of current NISQ processors.
In the present study of astrometric, photometric, and spectrophotometric data for the low luminosity carbon star G77-61, radial velocity variations are detected which have a binary period of 245 ...days. The unseen companion is probably a cool white dwarf of much higher mass than the visible object. The most straightforward evolutionary hypothesis is that this star has an extremely metal-poor composition, and that it accreted a small amount of carbon-rich material when the now-unseen primary was at maximum radius. This may have inverted the C/O abundance of the secondary without achieving common envelope evolution and a sorter period.
By using A-frame instrumentation and direct distraction force, an exceptional correction can be obtained in patients with severe spondylolisthesis. Adolescent progressive spondylolisthesis should be ...considered as an entity separate from the lumbosacral anomalies such as spondylolysis and grades 0 and 1 spondylolisthesis without progression. An aplastic relationship appears to exist between the sacrum and the posterior superior wing of the ilium in the adolescent with progressive spondylolisthesis. Complications have been minimal but long-term observations of patients are necessary to evaluate the contribution of instrumentation in the treatment for severe progressive spondylolisthesis.
PDF
