Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Effects of endurance racing on horse plasma extracellular particle miRNA.

BACKGROUND: Physical exercise is an essential factor in preventing and treating metabolic diseases by promoting systemic benefits throughout the body. The molecular factors involved in this process are poorly understood. Micro RNAs (miRNAs) are small non-coding RNAs that inhibit mRNA transcription. MiRNAs, which can participate in the benefits of exercise to health, circulate in plasma in extracellular particles (EP). Horses that undergo endurance racing are an excellent model to study the impact of long-duration/low intensity exercise in plasma EP miRNAs. OBJECTIVES: To evaluate the effects of 160 km endurance racing on horse plasma extracellular particles and their miRNA population. STUDY DESIGN: Cohort study. METHODS: We collected plasma from five Arabian horses during five time-points of an endurance ride. Extracellular particles were purified from plasma and characterised by electron microscopy, resistive pulse sensing (qNano) and western blotting. Small RNAs were purified from horse plasma EP, and sequencing was performed. RESULTS: Endurance racing increased EP concentration and average diameter compared to before the race. Western blotting showed a high concentration of extracellular vesicles proteins 2 hours after the race, which returned to baseline 15 hours after the race. MicroRNA differential expression analysis revealed increasing levels of eca-miR-486-5p during and after the race, and decreasing levels of eca-miR-9083 after the end. CONCLUSIONS: This study adds new data about the variation in plasma EP concentrations after long-distance exercise and brings new insights about the roles of exercise-derived EP miRNAs during low-intensity endurance exercise.

Effects of Acute Aerobic Exercise on Rats Serum Extracellular Vesicles Diameter, Concentration and Small RNAs Content.

Physical exercise stimulates organs, mainly the skeletal muscle, to release a broad range of molecules, recently dubbed exerkines. Among them, RNAs, such as miRNAs, piRNAs, and tRNAs loaded in extracellular vesicles (EVs) have the potential to play a significant role in the way muscle and other organs communicate to translate exercise into health. Low, moderate and high intensity treadmill protocols were applied to rat groups, aiming to investigate the impact of exercise on serum EVs and their associated small RNA molecules. Transmission electron microscopy, resistive pulse sensing, and western blotting were used to investigate EVs morphology, size distribution, concentration and EVs marker proteins. Small RNA libraries from EVs RNA were sequenced. Exercise did not change EVs size, while increased EVs concentration. Twelve miRNAs were found differentially expressed after exercise: rno-miR-128-3p, 103-3p, 330-5p, 148a-3p, 191a-5p, 10b-5p, 93-5p, 25-3p, 142-5p, 3068-3p, 142-3p, and 410-3p. No piRNA was found differentially expressed, and one tRNA, trna8336, was found down-regulated after exercise. The differentially expressed miRNAs were predicted to target genes involved in the MAPK pathway. A single bout of exercise impacts EVs and their small RNA load, reinforcing the need for a more detailed investigation into EVs and their load as mediators of health-promoting exercise.

Supplementation with small-extracellular vesicles from ovarian follicular fluid during in vitro production modulates bovine embryo development.

Pregnancy success results from the interaction of multiple factors, among them are folliculogenesis and early embryonic development. Failure during these different processes can lead to difficulties in conception. Alternatives to overcome these problems are based on assisted reproductive techniques. Extracellular vesicles are cell-secreted vesicles present in different body fluids and contain bioactive materials, such as messenger RNA, microRNAs (miRNAs), and proteins. Thus, our hypothesis is that extracellular vesicles from follicular fluid from 3-6 mm ovarian follicles can modulate bovine embryo development in vitro. To test our hypothesis follicular fluid from bovine ovaries was aspirated and small-extracellular vesicles (<200 nm) were isolated for further analysis. Additionally, small-extracellular vesicles (EVs) were utilized for functional experiments investigating their role in modulating messenger RNA, microRNA as well as global DNA methylation and hydroxymethylation levels of bovine blastocysts. EVs from 3-6 mm follicles were used for RNA-seq and miRNA analysis. Functional annotation analysis of the EVs transcripts revealed messages related to chromatin remodeling and transcriptional regulation. EVs treatment during oocyte maturation and embryo development causes changes in blastocyst rates, as well as changes in the transcription levels of genes related to embryonic metabolism and development. Supplementation with EVs from 3-6 mm follicles during oocyte maturation and early embryo development (until the 4-cell stage) increased the levels of bta-miR-631 (enriched in EVs from 3-6 mm follicles) in embryos. Interestingly, the addition of EVs from 3-6 mm follicles induced changes in global DNA methylation and hydroxymethylation levels compared to embryos produced by the standard in vitro production system. Our results indicate that the supplementation of culture media with EVs isolated from the follicular fluid of 3-6 mm follicles during oocyte maturation and early embryo development can partially modify metabolic and developmental related genes as well as miRNA and global DNA methylation and hydroxymethylation, suggesting that EVs play an important role during oocyte maturation and early embryo development in vitro.

The Effects of Acute and Chronic Exercise on Skeletal Muscle Proteome.

Skeletal muscle plasticity and its adaptation to exercise is a topic that is widely discussed and investigated due to its primary role in the field of exercise performance and health promotion. Repetitive muscle contraction through exercise stimuli leads to improved cardiovascular output and the regulation of endothelial dysfunction and metabolic disorders such as insulin resistance and obesity. Considerable improvements in proteomic tools and data analysis have broth some new perspectives in the study of the molecular mechanisms underlying skeletal muscle adaptation in response to physical activity. In this sense, this review updates the main relevant studies concerning muscle proteome adaptation to acute and chronic exercise, from aerobic to resistance training, as well as the proteomic profile of natural inbred high running capacity animal models. Also, some promising prospects in the muscle secretome field are presented, in order to better understand the role of physical activity in the release of extracellular microvesicles and myokines activity. Thus, the present review aims to update the fast-growing exercise-proteomic scenario, leading to some new perspectives about the molecular events under skeletal muscle plasticity in response to physical activity. J. Cell. Physiol. 232: 257-269, 2017. © 2016 Wiley Periodicals, Inc.

Prediction of the impact of coding missense and nonsense single nucleotide polymorphisms on HD5 and HBD1 antibacterial activity against Escherichia coli.

Defensins confer host defense against microorganisms and are important for human health. Single nucleotide polymorphisms (SNPs) in defensin gene-coding regions could lead to less active variants. Using SNP data available at the dbSNP database and frequency information from the 1000 Genomes Project, two DEFA5 (L26I and R13H) and eight DEFB1 (C35S, K31T, K33R, R29G, V06I, C12Y, Y28* and C05*) missense and nonsense SNPs that are located within mature regions of the coded defensins were retrieved. Such SNPs are rare and population restricted. In order to assess their antibacterial activity against Escherichia coli, two linear regression models were used from a previous work, which models the antibacterial activity as a function of solvation potential energy, using molecular dynamics data. Regarding only the antibacterial predictions, for HD5, no biological differences between wild-type and its variants were observed; while for HBD1, the results suggest that the R29G, K31T, Y28* and C05* variants could be less active than the wild-type one. The data here reported could lead to a substantial improvement in knowledge about the impact of missense SNPs in human defensins and their world distribution. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 633-644, 2016.

Use of Targeted Exome Sequencing for Molecular Diagnosis of Skeletal Disorders.

Genetic disorders of the skeleton comprise a large group of more than 450 clinically distinct and genetically heterogeneous diseases associated with mutations in more than 300 genes. Achieving a definitive diagnosis is complicated due to the genetic heterogeneity of these disorders, their individual rarity and their diverse radiographic presentations. We used targeted exome sequencing and designed a 1.4 Mb panel for simultaneous testing of more than 4,800 exons in 309 genes involved in skeletal disorders. DNA from 69 individuals from 66 families with a known or suspected clinical diagnosis of a skeletal disorder was analyzed. Of 36 cases with a specific clinical hypothesis with a known genetic basis, mutations were identified for eight cases (22%). Of 20 cases with a suspected skeletal disorder but without a specific diagnosis, four causative mutations were identified. Also included were 11 cases with a specific skeletal disorder but for which there was at the time no known associated gene. For these cases, one mutation was identified in a known skeletal disease genes, and re-evaluation of the clinical phenotype in this case changed the diagnoses from osteodysplasia syndrome to Apert syndrome. These results suggest that the NGS panel provides a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in a highly genetically heterogeneous set of disorders such as genetic skeletal disorders. The data also stress the importance of a thorough clinical evaluation before DNA sequencing. The strategy should be applicable to other groups of disorders in which the molecular basis is largely known.

Exercise performed around MLSS decreases systolic blood pressure and increases aerobic fitness in hypertensive rats.

BACKGROUND: Exercise is a non-pharmacologic agent widely used for hypertension control, where low intensity is often associated with blood pressure reduction. Maximal lactate steady state (MLSS) was recently identified in spontaneously hypertensive rats (SHRs) as an important step in establishing secure intensities for prescribing exercise for hypertensive phenotypes. Here we verified the effects of training around MLSS, 20% below MLSS, and 15% above MLSS on aerobic fitness and blood pressure status of SHR. Eighteen-week-old SHRs (n = 5, ~ 172.4 ± 8.1 mm Hg systolic blood pressure) were trained on a treadmill for 4 weeks for 30 min/day, 5 days/week at a velocity of 20 m.min(-1). After training, a novel MLSS and incremental test was performed to evaluate the animals' aerobic fitness. Furthermore, ~ 22-week-old SHRs (n = 12, ~169.8 ± 13.8 mm Hg systolic blood pressure) were divided into non-exercised (CG, n = 4), low intensity (LIG, n = 4) and high intensity (HIG, n = 4) groups, where rats were trained at 16 m.min(-1) and 23 m.min(-1) respectively for 30 min/day, 5 days/week for 4 weeks. RESULTS: Exercise performed at MLSS enhanced aerobic fitness, leading to a novel MLSS, identified around 30 m.min(-1). Low and high intensity training reduced systolic blood pressure and only high intensity training led to improved aerobic fitness (28.1%, p < 0.01). CONCLUSIONS: Therefore, our data indicate a decrease in blood pressure due to low and high exercise intensity, and an increase in aerobic fitness provided by high-intensity exercise in SHRs.

NanoUPLC/MS(E) proteomic analysis reveals modulation on left ventricle proteome from hypertensive rats after exercise training.

NanoUPLC/MS(E) was used to verify the effects of 8weeks of low (SHR-LIT=4) and high (SHR-HIT=4) intensity training over the left ventricle proteome of hypertensive rats (SHR-C=4). Training enhanced the aerobic capacity and reduced the systolic blood pressure in all exercised rats. NanoUPLC/MS(E) identified 250 proteins, with 233 in common to all groups and 16 exclusive to SHR-C, 2 to SHR-LIT, and 2 to the SHR-HIT. Cardiac hypertrophy related proteins appeared only in SHR-C. The SHR-LIT enhanced the abundance of 30 proteins and diminished 6, while SHR-HIT enhanced the abundance of 39 proteins and reduced other 7. The levels of metabolic (ß and γ-enolase, adenine phosphoribosultransferase, and cytochrome b-c1), myofibril (myosin light chain 4, tropomyosin α and ß-chain), and transporter proteins (hemoglobin, serum albumin, and hemopexin) were increased by both intensities. Transcription regulator and histone variants were enhanced by SHR-LIT and SHR-HIT respectively. SHR-LIT reduced the concentration of myosin binding protein C, while desmin and membrane voltage dependent anion selective channel protein-3 were reduced only by SHR-HIT. In addition, polyubiquitin B and C, and transcription regulators decreased in both intensities. Exercise also increased the concentration of anti-oxidant proteins, peroxiredozin-6 and glutathione peroxidase-1. BIOLOGICAL SIGNIFICANCE: Pathologic left ventricle hypertrophy if one of the major outcomes of hypertension being a strong predictor of heart failure. Among the various risk factors for cardiovascular disorders, arterial hypertension is responsible for the highest rates of mortality worldwide. In this way, this present study contribute to the understanding of the molecular mechanisms involved in the attenuation of hypertension and the regression of pathological cardiac hypertrophy induced by exercise training.

Circulating miR-1, miR-133a, and miR-206 levels are increased after a half-marathon run.

CONTEXT: Circulating miRNAs are potential biomarkers that can be important molecules driving cell-to-cell communication. OBJECTIVE: To investigate circulating muscle-specific miRNAs in recreational athletes. MATERIALS AND METHODS: Three miRNAs from whole plasma before and after a half-marathon were analyzed by qPCR. RESULTS: MiR-1, -133a, and -206 significantly increased after the race. DISCUSSION: Increased levels of miRNAs after exercise point to potential biomarkers and to the possibility of being functional players following endurance training. CONCLUSION: These miRNAs are potential biomarkers of muscle damage or adaptation to exercise.

Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats.

BACKGROUND: Obesity is a multifactor disease associated with cardiovascular disorders such as hypertension. Recently, gut microbiota was linked to obesity pathogenesisand shown to influence the host metabolism. Moreover, several factors such as host-genotype and life-style have been shown to modulate gut microbiota composition. Exercise is a well-known agent used for the treatment of numerous pathologies, such as obesity and hypertension; it has recently been demonstrated to shape gut microbiota consortia. Since exercise-altered microbiota could possibly improve the treatment of diseases related to dysfunctional microbiota, this study aimed to examine the effect of controlled exercise training on gut microbial composition in Obese rats (n = 3), non-obese Wistar rats (n = 3) and Spontaneously Hypertensive rats (n = 3). Pyrosequencing of 16S rRNA genes from fecal samples collected before and after exercise training was used for this purpose. RESULTS: Exercise altered the composition and diversity of gut bacteria at genus level in all rat lineages. Allobaculum (Hypertensive rats), Pseudomonas and Lactobacillus (Obese rats) were shown to be enriched after exercise, while Streptococcus (Wistar rats), Aggregatibacter and Sutturella (Hypertensive rats) were more enhanced before exercise. A significant correlation was seen in the Clostridiaceae and Bacteroidaceae families and Oscillospira and Ruminococcus genera with blood lactate accumulation. Moreover, Wistar and Hypertensive rats were shown to share a similar microbiota composition, as opposed to Obese rats. Finally, Streptococcus alactolyticus, Bifidobacterium animalis, Ruminococcus gnavus, Aggregatibacter pneumotropica and Bifidobacterium pseudolongum were enriched in Obese rats. CONCLUSIONS: These data indicate that non-obese and hypertensive rats harbor a different gut microbiota from obese rats and that exercise training alters gut microbiota from an obese and hypertensive genotype background.

Modeling 3D facial shape from DNA.

Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.

Cytokine gene polymorphisms and Alzheimer's disease in Brazil.

BACKGROUND: Single-nucleotide polymorphisms in genes encoding immunological mediators can affect the biological activity of these molecules by regulating transcription, translation, or secretion, modulating the genetic risk of inflammatory damage in Alzheimer's disease (AD). Nonetheless, the Brazilian contingent is highly admixed, and few association trials performed herein with AD patients have considered genetic ancestry estimates as co-variables when investigating markers for this complex trait. METHODS: We analyzed polymorphisms in 10 inflammatory genes and compared the genotype distribution across outpatients with late-onset AD and noncognitively impaired subjects from Midwest Brazil under a strict criterion, and controlling for ancestry heritage and ApoE genotype. RESULTS: Our findings show an almost 40% lower chance of AD (p = 0.004) among homozygotes of the IL10 -1082A allele (rs1800896). Dichotomization to ApoE and mean ancestry levels did not affect protection, except among those with greater European or minor African heritage. CONCLUSION: The IL10 locus seems to affect the onset of AD in a context sensitive to the genetic ancestry of Brazilian older adults.

The complexity, function and applications of RNA in circulation.

Blood carries a wide array of biomolecules, including nutrients, hormones, and molecules that are secreted by cells for specific biological functions. The recent finding of stable RNA of both endogenous and exogenous origin in circulation raises a number of questions and opens a broad, new field: exploring the origins, functions, and applications of these extracellular RNA molecules. These findings raise many important questions, including: what are the mechanisms of export and cellular uptake, what is the nature and source of their stability, what molecules do they interact with in the blood, and what are the possible biological functions of the circulating RNA? This review summarizes some key recent developments in circulating RNA research and discusses some of the open questions in the field.

A Review of Computational Tools in microRNA Discovery.

Since microRNAs (miRNAs) were discovered, their impact on regulating various biological activities has been a surprising and exciting field. Knowing the entire repertoire of these small molecules is the first step to gain a better understanding of their function. High throughput discovery tools such as next-generation sequencing significantly increased the number of known miRNAs in different organisms in recent years. However, the process of being able to accurately identify miRNAs is still a complex and difficult task, requiring the integration of experimental approaches with computational methods. A number of prediction algorithms based on characteristics of miRNA molecules have been developed to identify new miRNA species. Different approaches have certain strengths and weaknesses and in this review, we aim to summarize several commonly used tools in metazoan miRNA discovery.

Association between polymorphisms in the TRHR gene, fat-free mass, and muscle strength in older women.

A previous genome-wide association study suggested that polymorphisms in the thyrotrophin-releasing hormone receptor (TRHR) gene contribute to fat-free mass (FFM) variation. The aim of the present study was to examine the association between polymorphisms in the TRHR gene with FFM and muscle strength in older women. Volunteers (n = 241; age = 66.65 ± 5.5 years) underwent quadriceps strength assessment using isokinetics and fat-free mass by dual-energy X-ray absorptiometry. TRHR polymorphisms and ancestry-informative markers were genotyped through standard procedures. No significant difference was observed for rs7832552. Regarding the rs16892496, ANCOVA revealed that appendicular fat-free mass (AFFM) and relative AFFM were significantly different between groups (p = 0.04 and p = 0.05, respectively). Individuals carrying A/A and A/C genotypes respectively showed, on average, an extra 1 kg and 900 g of AFFM when compared to C/C genotype carriers. Also, the C/C genotype group presented a significantly higher chance to have reduced muscle strength. The observations presented here provide further evidence that the rs16892496 polymorphism in the TRHR gene may play a role in FFM variation. Moreover, the results bring the novel insight that this genetic variant can present a modest contribution to muscle strength in older women.

Association of serum lipid components and obesity with genetic ancestry in an admixed population of elderly women.

The prevalence of metabolic disorders varies among ethnic populations and these disorders represent a critical health care issue for elderly women. This study investigated the correlation between genetic ancestry and body composition, metabolic traits and clinical status in a sample of elderly women. Clinical, nutritional and anthropometric data were collected from 176 volunteers. Genetic ancestry was estimated using 23 ancestry-informative markers. Pearsons correlation test was used to examine the relationship between continuous variables and an independent samples t-test was used to compare the means of continuous traits within categorical variables. Overall ancestry was a combination of European (57.49%), Native American (25.78%) and African (16.73%). Significant correlations were found for European ancestry with body mass index (r = 0.165; p = 0.037) and obesity (mean difference (MD) = 5.3%; p = 0.042). African ancestry showed a significant correlation with LDL (r = 0.159, p = 0.035), VLDL (r = -0.185; p = 0.014), hypertriglyceridemia (MD = 6.4%; p = 0.003) and hyperlipidemia (MD = 4.8%; p = 0.026). Amerindian ancestry showed a significant correlation with triglyceride levels (r = 0.150; p = 0.047) and hypertriglyceridemia (MD = 4.5%; p = 0.039). These findings suggest that genetic admixture may influence the etiology of lipid metabolism-related diseases and obesity in elderly women.

High molecular mass proteomics analyses of left ventricle from rats subjected to differential swimming training.

BACKGROUND: Regular exercises are commonly described as an important factor in health improvement, being directly related to contractile force development in cardiac cells.In order to evaluate the links between swimming exercise intensity and cardiac adaptation by using high molecular mass proteomics, isogenic Wistar rats were divided into four groups: one control (CG) and three training groups (TG's), with low, moderate and high intensity of exercises.In order to evaluate the links between swimming exercise intensity and cardiac adaptation by using high molecular mass proteomics, isogenic Wistar rats were divided into four groups: one control (CG) and three training groups (TG's), with low, moderate and high intensity of exercises. RESULTS: Findings here reported demonstrated clear morphologic alterations, significant cellular injury and increased energy supplies at high exercise intensities. α-MyHC, as well proteins associated with mitochondrial oxidative metabolism were shown to be improved. α-MyHC expression increase 1.2 fold in high intensity training group when compared with control group. α-MyHC was also evaluated by real-time PCR showing a clear expression correlation with protein synthesis data increase in 8.48 fold in high intensity training group. Other myofibrillar protein, troponin , appear only in high intensity group, corroborating the cellular injury data. High molecular masses proteins such as MRS2 and NADH dehydrogenase, involved in metabolic pathways also demonstrate increase expression, respectily 1.5 and 1.3 fold, in response to high intensity exercise. CONCLUSIONS: High intensity exercise demonstrated an increase expression in some high molecular masses myofibrilar proteins, α-MyHC and troponin. Furthermore this intensity also lead a significant increase of other high molecular masses proteins such as MRS2 and NADH dehydrogenase in comparison to low and moderate intensities. However, high intensity exercise also represented a significant degree of cellular injury, when compared with the individuals submitted to low and moderate intensities.

Amerindian genetic ancestry protects against Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide, and bears remarkable evidence for a differential prevalence among continental populations. In this scenario, estimating ancestry proportions in recently admixed populations is a strategy that can help increasing knowledge about the genetic structure of this complex trait. AIM/METHODS: Our purpose was to assess mean ancestry estimates for the three main parental contributors to the Brazilian contingent (European, African and Amerindian) using a panel of 12 ancestry informative markers. Outpatients with the late-onset form of AD (n = 120) were compared for ancestry levels with non-cognitively impaired subjects (n = 412) in the Midwest Brazil, controlling for classic clinical, social and anthropometric risk factors. RESULTS: Our findings show a 3-fold greater genetic Amerindian content among control subjects compared to AD patients (p < 0.001). CONCLUSION: Our results suggest that the allelic architecture of Native Americans can confer protection against the onset of the disease.

Lessons from genome-wide association studies findings in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder with a complex genetic background. Recent genome-wide association studies (GWAS) have placed important new contributors into the genetic framework of early- and late-onset forms of this dementia. Besides confirming the major role of classic allelic variants (e.g. apolipoprotein E) in the development of AD, GWAS have thus far implicated over 20 single nucleotide polymorphisms in AD. In this review, we summarize the findings of 16 AD-based GWAS performed to date whose public registries are available at the National Human Genome Research Institute, with an emphasis on understanding whether the polymorphic markers under consideration support functional implications to the pathophysiological role of the major genetic risk factors unraveled by GWAS.