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Genetic variation of the type described in this paper are "experiments of nature," of a sort, that reveal when a specific gene is altered, disease risk can be affected. "This is direct evidence that if drugs can be designed to target these proteins, we have a chance to alter disease risk in people," said senior author Gerard Schellenberg, PhD, a professor of Pathology and Laboratory Medicine, and director of the Alzheimer Disease Genetics Consortium (ADGC) at the Perelman School of Medicine at the University of Pennsylvania. "It's been known for decades that microglia -- a first-line-of-defense cell we are born with -- surround amyloid plaque deposits associated with Alzheimer's. These multiple gene 'hits' all originating from microglia are the clearest demonstration that these cells are part of Alzheimer's pathology and, more importantly, provide clear protein targets where we can start to intervene with drugs." "The ADGC, supported by the National Institute on Aging (NIA) ..."
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The objective of this study is to examine the frequency, development, concomitants, and risk factors of falls in a population-based incident Parkinson's disease (PD) cohort. One hundred eighty-one drug-naïve patients with incident PD and 173 normal controls recruited from the Norwegian ParkWest study were prospectively monitored over 7 years. Information on falls was obtained biannually from patients, and at baseline and after 1, 3, 5, and 7 years of follow-up in control subjects. Generalized estimating equation models for correlated data were applied to investigate concomitant features of falls and risk factors for incident falls during 7 years of follow-up in PD. Overall, 64.1% of patients reported falling during the study period. The 7-year cumulative incidence of falls in non-falling patients at baseline (n = 153) was 57.5%, with a relative risk to controls of at least 3.1 (95% confidence interval 1.5-6.3; p < 0.002). Significant concomitants of falls in patients during the study period were higher age, Unified PD Rating Scale motor score, postural instability and gait difficulties (PIGD) phenotype, dementia, and follow-up time. Higher age at baseline, PIGD phenotype at 1-year visit, and follow-up time were independent risk factors for incident falls during follow-up. Nearly two-thirds of patients in the general PD population experience falls within 7 years of diagnosis, representing a more than threefold increased risk compared to age- and gender-matched controls. Patients with higher age at baseline and early PIGD have the greatest risk of falling and may, therefore, be the prime target of specialized assessment and treatment interventions.
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We study the thermodiffusion behavior of spherical polystyrene beads with a diameter of 25 nm by infrared thermal diffusion Forced Rayleigh Scattering (IR-TDFRS). Similar beads were used to investigate the radial dependence of the Soret coefficient by different authors. While Duhr and Braun (Proc. Natl. Acad. Sci. U.S.A. 104, 9346 (2007)) observed a quadratic radial dependence Braibanti et al. (Phys. Rev. Lett. 100, 108303 (2008)) found a linear radial dependence of the Soret coefficient. We demonstrated that special care needs to be taken to obtain reliable thermophoretic data, because the measurements are very sensitive to surface properties. The colloidal particles were characterized by transmission electron microscopy and dynamic light scattering (DLS) experiments were performed. We carried out systematic thermophoretic measurements as a function of temperature, buffer and surfactant concentration. The temperature dependence was analyzed using an empirical formula. To describe the Debye length dependence we used a theoretical model by Dhont. The resulting surface charge density is in agreement with previous literature results. Finally, we analyze the dependence of the Soret coefficient on the concentration of the anionic surfactant sodium dodecyl sulfate (SDS), applying an empirical thermodynamic approach accounting for chemical contributions.
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https://www.sciencedaily.com/releases/2017/07/170717110511.htm
[PLCG2; ABI3; TREM2] Newly discovered gene variants link innate immunity and Alzheimer's disease. Findings give neurologists fresh ideas for enlisting immune system to fight Alzheimer's [Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease]
Date: July 17, 2017
Source: University of Pennsylvania School of Medicine
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, cells that are part of the brain's injury response system. The study is an international collaboration of four AD research consortia that analyzed DNA from 85,000 subjects. The results are reported online this week in Nature Genetics. Studies of this type focus on identifying new therapeutic targets for treatment or prevention of AD, a goal of researchers world-wide. Genetic variation of the type described in this paper are "experiments of nature," of a sort, that reveal when a specific gene is altered, disease risk can be affected.
"This is direct evidence that if drugs can be designed to target these proteins, we have a chance to alter disease risk in people," said senior author Gerard Schellenberg, PhD, a professor of Pathology and Laboratory Medicine, and director of the Alzheimer Disease Genetics Consortium (ADGC) at the Perelman School of Medicine at the University of Pennsylvania. "It's been known for decades that microglia -- a first-line-of-defense cell we are born with -- surround amyloid plaque deposits associated with Alzheimer's. These multiple gene 'hits' all originating from microglia are the clearest demonstration that these cells are part of Alzheimer's pathology and, more importantly, provide clear protein targets where we can start to intervene with drugs." The ADGC, supported by the National Institute on Aging (NIA) at the National Institutes of Health, is one of the four consortia of the International Genomics of Alzheimer's Project on this study. The others are Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE), European Alzheimer's Disease Initiative (EADI), and Genetic and Environmental Risk in Alzheimer's Disease (GERAD).
The variants the team found -- PLCG2, ABI3, and TREM2 -- are all protein-coding mutations in genes that are highly expressed in microglia and are part of an immune cell protein network where multiple components contribute to AD risk. One of the genes, PLCG2, is an enzyme that is a potential drug target. Key questions remain in how microglia should be targeted and whether the injury response should be inhibited or activated and at what stage of disease. "Since prevention is a key goal of therapy, influencing microglial cells before onset of cognitive changes needs to be explored," Schellenberg said.
The three variants they identified are fairly rare and he accounts for their success in finding them to their three-stage study. In the first stage, the entire protein coding regions of 34,290 samples were sequenced. In the second and third stages, the team further refined the sequences of variants and verified the significant hits against untested samples from AD patients. "Our findings show that microglia and the innate immune system -- via microglia -- directly contribute to susceptibility of late-onset Alzheimer's disease, and are not just a down-stream 'after-the-fact' consequence of damage to the brain," Schellenberg said.
Reference: Gerard D Schellenberg et al. Genetics, 2017; DOI: 10.1038/ng.3916
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We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 x 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 x 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 x 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
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http://massgenomics.org/2015/04/rare-variants-complex-disease-abca7-alzheimers.html
RARE VARIANTS IN COMPLEX DISEASE: ABCA7 AND ALZHEIMER'S [LOSS-OF-FUNCTION VARIANTS IN ABCA7 CONFER RISK OF ALZHEIMER'S DISEASE]
[April 6, 2015] Although the cost of sequencing continues to fall precipitously (cue the NIH sequencing-versus-Moore's-Law figure), it's still expensive relative to high-throughput genotyping. Whole-genome sequencing on the X Ten costs around $2500 per sample by the time you account for basic analysis and data storage. This means that a well-powered genetic association study for complex disease (10,000 samples) would cost over $20 million just for data generation. The same cohort genotyped on a high-density SNP array might only cost about $1 million. Undoubtedly, that's why most large scale genome-wide association studies to date (>50,000 samples) have relied primarily on SNP array data.
There is a growing body of evidence, however, that rare variants (especially ones not present on SNP arrays) might confer a significant proportion of the genetic risk for complex disease. In age-related macular degeneration (AMD), for example, sequencing studies of moderate size (~5,000 samples) were able to identify rare coding variants in C3 and CFH associated with risk of disease. An important advantage of a sequencing approach is the ability to perform aggregation tests of private and rare coding variants (e.g. with the sequence kernel association test, SKAT) to boost the power to detect association.
A recent paper in Nature Genetics illustrates the feasibility of this approach for sequencing studies of complex disease. Stacy Steinberg and colleagues from deCODE Genetics conducted a search for rare functional variants in the known risk loci for Alzheimer's disease (AD) [http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3246.html] using a unique resource: whole-genome sequences of 2,636 Icelanders imputed into 104,220 long-range phased individuals and their relatives.
So here we have a rare variant association study (RVAS) that employs several strategies for an efficient design:
1. Studying an isolated population (Iceland), whose genetic structure enabled accurate genotype imputation of a large sample set (>100k individuals) with sequencing data for just 2,500.
2. Analyzing missense variants with SKAT, which aggregates rare variants (i.e. collapses them at the level of the gene) to boost power for association but allows for multiple directions of effect.
3. Examining only regions known to be associated with AD-which seem likely to harbor [rare] functional variants-to reduce the multiple testing penalty.
TARGETED ASSOCIATION STUDIES
There are, of course, disadvantages to limiting the scope of association testing to known regions. Obviously you won't be discovering any new associations, especially ones that sequencing (but not genotyping) might be able to uncover. Even so, you're stacking the deck in your favor because the known GWAS loci almost certainly harbor some functional variation that hasn't yet been fully interrogated.
Sometimes, sequencing will only serve to replicate the common variant association signal (i.e. not find anything new). Yet these targeted approaches might help narrow the boundaries of the associated region-which could encompass dozens or hundreds of genes-or, even better, identify disruptive variants whose LD with the lead SNP makes them good candidates for causal variants. Thirdly, one might uncover secondary independent association signals in GWAS loci, implicating that there are multiple haplotypes that influence disease risk.
VARIANT ANNOTATION AND AGGREGATION
As anyone who has done aggregation/burden testing in association studies can tell you, the analysis choices can have a significant impact on results. The annotation tool/source, MAF threshold, and variant mask (definition of what's deleterious and should be included) can introduce a lot of variability. In this case, the authors tried two variant masks:
1. Loss of function variants: nonsense, frameshift or canonical splice site variants. These are usually quite rare, and so the authors collapsed them to a single "meta variant" at the level of the gene.
2. Missense variants: nonsynonymous variants or splice region variants. This latter one is an interesting choice, and not necessarily one I'd have thought to make at the discovery stage.
The burden tests included only variants with MAF<1% and information (call rate) >0.80. The authors tested about 80 genes across the 17 loci, and the top-scoring hit was ABCA7 (p=0.00020).
SPLICE REGION VARIATION IN ABCA7
ABCA7 encodes ATP-binding cassette transporter A7, a member of ABC transporters that move lipids across membranes. The SKAT result was primarily driven by a single variant, c.5570+5G>C. Without it, the test had a p-value of 0.46. If you're familiar with the notation, then you know that c.5570+5 indicates a noncoding variant 5 bases into an intron. We call this the "splice region" and, unlike the canonical splice site (+/- 2bp) it's not clear that variants here affect splicing.
But the authors had another NGS tool to look at this: RNA-seq. When they looked at the transcript sequences of c.5570+5G>C carriers, they included a retained intron that eventually included a stop codon.
The image here is from Supplemental Figure 1 (the main text had no figures) and shows the intron retention in c.5570+5G>C carriers. Side note: according to the legend, the coordinates are on NCBI build 36, which practically a crime. But moving on, the RNA-seq results justified including the variant in the loss-of-function test (mask #1), which then yielded a p-value of 5.3e-10 with odds ratio of 1.97.
FOLLOW-UP AND REPLICATION OF ASSOCIATION
With a possible causal variant in hand, the authors next examined the long-range haplotypes to see if this variant was on the same background as rs4147929, the common variant previously associated with AD by GWAS. It was never on the same allele, which is a fascinating result; the common variant signal and this rare variant association appear to be independent. It's possible, therefore, that the mechanisms are different as well. To replicate the association, the authors genotyped ABCA7 loss-of-function variants in study groups from Europe and the United States, finding a p-value of 0.0056 with OR of 1.73. When combined with the Icelandic data by meta-analysis, the OR was 2.03 and the p-value 6.8e-15.
WHAT'S NEXT FOR AD AND COMMON DISEASE
ABCA7 certainly merits future studies, both in the genetics realm and in the laboratory for functional evaluation. It's strongly expressed in the brain, where it promotes the efflux of phospholipids and cholesterol to apoA-I and apoE. But the ortholog of ABCA7 in C. elegans and results from mouse models suggest that regulation of phagocytosis might be the primary function of the gene. The authors tested for correlation between variants in ABCA7 and two disease-associated alleles (in APOE and TREM2), but found none. Thus, the mechanism by which ABCA7 loss-of-function confers susceptibility to AD will need further investigation. Still, it's a promising start to detangling the etiology of a complex human disease, and a demonstration of the power of genome sequencing to uncover promising new leads.
REFERENCE: Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U, Kong A, Helisalmi S, Soininen H, Lah JJ, DemGene, Aarsland D, Fladby T, Ulstein ID, Djurovic S, Sando SB, White LR, Knudsen GP, Westlye LT, Selbæk G, Giegling I, Hampel H, Hiltunen M, Levey AI, Andreassen OA, Rujescu D, Jonsson PV, Bjornsson S, Snaedal J, & Stefansson K (2015). Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nature genetics PMID: 25807283 : http://www.ncbi.nlm.nih.gov/pubmed/25807283
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