scholarly journals Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African–American youth

2019 ◽  
Vol 56 (8) ◽  
pp. 557-566 ◽  
Author(s):  
Dongnhu Thuy Truong ◽  
Andrew Kenneth Adams ◽  
Steven Paniagua ◽  
Jan C Frijters ◽  
Richard Boada ◽  
...  
Keyword(s):  
African American ◽  
Reading Disability ◽  
Genetic Factors ◽  
African American Youth ◽  
Genome Wide Association ◽  
Hispanic American ◽  
Biological Mechanisms ◽  
Genome Wide ◽  
The Brain ◽  
Shared Genetic

BackgroundRapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms.ObjectiveTo identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach.MethodsWe conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African–American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted.ResultsGenome-wide significant effects were observed at rs1555839 (p=4.03×10−8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer–promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule.ConclusionThis study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene–brain–behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

scholarly journals Multivariate genome-wide association study of rapid automatized naming and rapid alternating stimulus in Hispanic and African American youth

2017 ◽  
Author(s):  
Dongnhu T. Truong ◽  
Andrew K. Adams ◽  
Richard Boada ◽  
Jan C. Frijters ◽  
Dina Hill ◽  
...  
Keyword(s):  
African American ◽  
Reading Disability ◽  
Reading Fluency ◽  
Genetic Factors ◽  
Word Reading ◽  
African American Youth ◽  
Rapid Automatized Naming ◽  
Genome Wide ◽  
The Brain ◽  
Shared Genetic

ABSTRACTReading disability is a complex neurodevelopmental disorder that is characterized by difficulties in reading despite educational opportunity and normal intelligence. Performance on rapid automatized naming (RAN) and rapid alternating stimulus (RAS) tests gives a reliable predictor of reading outcome. These tasks involve the integration of different neural and cognitive processes required in a mature reading brain. Most studies examining the genetic factors that contribute to RAN and RAS performance have focused on pedigree-based analyses in samples of European descent, with limited representation of groups with Hispanic or African ancestry. In the present study, we conducted a multivariate genome-wide association analysis to identify shared genetic factors that contribute to performance across RAN Objects, RAN Letters, and RAS Letters/Numbers in a sample of Hispanic and African American youth (n=1,331). We then tested whether these factors also contribute to variance in reading fluency and word reading. Genome-wide significant, pleiotropic, effects across RAN Objects, RAN Letters, and RAS Letters/Numbers were observed for SNPs located on chromosome 10q23.31 (rs1555839, multivariate association, p=2.23 × 10−8), which also showed significant association with reading fluency and word reading performance (p <0.001). Bioinformatic analysis of this region using epigenetic data from the NIH Roadmap Epigenomics Mapping Consortium indicates active transcription of the gene RNLS in the brain. Neuroimaging genetic analysis of fourteen cortical regions in an independent sample of typically developing children across multiple ethnicities (n=690) showed that rs1555839 was associated with variation in volume of the right inferior parietal cortex—a region of the brain that processes numerical information and has been implicated in reading disability. This study provides support for a novel locus on chromosome 10q23.31 associated with RAN, RAS, and reading-related performance.AUTHOR SUMMARYReading disability has a strong genetic component that is explained by multiple genes and genetic factors. The complex genetic architecture along with diverse cognitive impairments associated with reading disability, poses challenges in identifying novel genes and variants that confer risk. One method to begin parsing genetic and neurobiological mechanisms that contribute to reading disability is to take advantage of the high correlation among reading-related cognitive traits like rapid automatized naming (RAN) and rapid alternating stimulus (RAS) to identify shared genetic factors that contribute to common biological mechanisms. In the present study, we used a multivariate genome-wide analysis approach that identified a region of chromosome 10q23.31 associated with variation in RAN Objects, RAN Letters, and RAS Letters/Numbers performance in a sample of 1,331 Hispanic and African American youth in the Genes, Reading, and Dyslexia (GRaD) Study. Genetic variants in this region were also associated with reading fluency in GRaD, and differences in brain structures implicated in reading disability in a separate sample of 690 children. The gene, RNLS, is located within the implicated region of chromosome 10q23.31 and plays a role in breaking down a class of chemical messengers known to affect attention, learning, and memory in the brain. These findings provide a basis to inform our understanding of the biological basis of reading disability.

scholarly journals Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

2019 ◽  
Author(s):  
Joanna von Berg ◽  
Sander W. van der Laan ◽  
Patrick F. McArdle ◽  
Rainer Malik ◽  
Steven J. Kittner ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Sample Size ◽  
Genetic Risk ◽  
Genetic Factors ◽  
Stroke Risk ◽  
Genome Wide Association ◽  
Small Vessel ◽  
Genome Wide ◽  
Ischemic Stroke Risk ◽  
The Brain

AbstractStroke causes approximately 1 in every 20 deaths in the United States. Most strokes are ischemic, caused by a blockage of blood flow to the brain. While neurologists agree on the delineation of ischemic stroke (IS) into the three most common subtypes (cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS)), several different subtyping systems exist. The two most commonly-used clinical subtyping systems are TOAST (Trial of Org 10172 in Acute Stroke Treatment) and CCS (Causative Classification System for Stroke), but agreement between these two systems is only moderate. Here, we have compared two approaches to combining the existing subtyping systems for a phenotype suited for a genome-wide association study (GWAS).We used the NINDS Stroke Genetics Network dataset (SiGN, 13,390 cases and 28,026 controls), which includes cases with both CCS and TOAST subtypes. We defined two new phenotypes: 1) the intersect, for which an individual must be assigned the same subtype by CCS and TOAST; and 2) the union, for which an individual must be assigned a subtype by either CCS or TOAST. The union yields the largest sample size while the intersect may yield a phenotype with less potential misclassification.We performed GWAS for all subtypes, using the original subtyping systems, the intersect, and the union as phenotypes. In each subtype, heritability was higher for the intersect phenotype compared to the union, CCS (alone), and TOAST (alone) phenotypes. We observed stronger effects at known IS variants with the intersect compared to the other phenotype definitions. In GWAS of the intersect, we identify rs10029218 as an associated variant with small vessel stroke. We conclude that in the absence of a golden standard for phenotyping, taking this alternate approach yields more power to detect genetic associations in ischemic stroke.Author summaryAround one in five people will have a stroke at some point in their life. Most strokes (~80%) are ischemic, caused by a blockage of blood supply to the brain. Ischemic stroke risk is partly influenced by lifestyle, and partly by genetics. There are different ischemic stroke subtypes, and genome-wide association studies (GWAS) indicate that the genetic risk for these subtypes is influenced by different genetic factors. Genetic studies of ischemic stroke are therefore typically performed by analyzing each subtype separately. There are several methods to determine someone’s subtype based on clinical features. To find more genetic factors that influence ischemic stroke risk, we aimed to find a group of patients that are phenotypically similar by using information from all subtyping methods. We compared a group of patients assigned the same subtype by all subtyping methods (the intersect) to a group of patients assigned that subtype by at least one subtyping method (the union). Even though the intersect sample size is smaller, we find genetic factors in the intersect GWAS have stronger genetic effects, likely explained by the fact that we are more certain of the subtype in the intersect. Using the intersect, we find new risk-associated genetic factors.

scholarly journals Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel L. McCartney ◽  
Josine L. Min ◽  
Rebecca C. Richmond ◽  
Ake T. Lu ◽  
Maria K. Sobczyk ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Biological Aging ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Biomarkers Of Aging ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Abstract TP134: Genome Wide Association Studies in Han Chinese Populations Identify Novel Susceptibility Loci for Specific Ischemic Stroke Subtypes

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Tai-Ming Ko ◽  
Tsong-Hai Lee Lee ◽  
Chien-Hsiun Chen ◽  
Yuan-Tsong Chen ◽  
Jer-Yuarn Wu
Keyword(s):  
Ischemic Stroke ◽  
Chinese Population ◽  
Genetic Factors ◽  
Han Chinese ◽  
Genome Wide Association ◽  
Papillary Thyroid ◽  
Susceptibility Loci ◽  
Han Chinese Population ◽  
Chinese Populations ◽  
Genome Wide

Introduction: Although family history studies in ischemic stroke support that genetic factors may be involved in the pathogenesis of two major subtypes of ischemia stroke: large-artery atherosclerosis (LAA) and small-vessel occlusion (SVO), it is still unclear which particular genetic factors contribute to LAA or SVO. Hypothesis: Because the etiology of ischemic stroke is heterogeneous, we hypothesize that genetic factors may vary by etiologic subtypes or ethnicities. Thus, we aim to identify genetic factors that contribute to LAA or SVO based on two independent Han Chinese populations. Methods: Novel genetic variants that predispose individuals to LAA and SVO were identified by genome-wide association study comprising of 824 individuals (including 444 LAA cases and 380 SVO cases) and 1,727 controls in a Han Chinese population residing in Taiwan. The LAA study was replicated in an independent Han Chinese population comprising of an additional 319 LAA cases and 1,802 controls. Results: In LAA cases, from two independent populations, we identified five single-nucleotide polymorphisms (SNPs), including SNP-1 (P = 3.10 х 10–8), SNP-2 (P = 4.00 х 10–9), SNP-3 (P = 3.57 х 10–8), SNP-4 (P = 1.76 х 10–8), and SNP-5 (P = 2.92 х 10–8), at one novel locus on chromosome 14q13.3 within PTCSC3 (encoding papillary thyroid carcinoma susceptibility candidate 3). In SVO cases, from the discovery stage, we identified two novel candidate susceptibility loci on chromosome 3p25.3 (SNP-6, P = 3.24 х 10–5) and chromosome 14 q31.1 (SNP-7, P = 2.58 х 10–4). Conclusions: For LAA, the newly identified SNPs within PTCSC3 gene were found to have genome-wide statistical significance (P < 5 х 10–8) and were shown to be located in a risk locus correlated with papillary thyroid carcinoma. Moreover, the genetic association between PTCSC3 gene and SVO was not identified, which suggested that PTCSC3 is a specific susceptibility locus for LAA. For SVO, we identified two novel candidate genetic loci which were valuable for replication by an independent population with SVO. In conclusion, our findings provide insights into the genetic basis of LAA and SVO, which may be applicable in the study of the pathogenesis of ischemic stroke and in the development of alternative therapeutic interventions.

Identification of Potential Pleiotropic Genes for Immune and Skeletal Diseases Using Multivariate MetaCCA Analysis

2021 ◽  
Vol 23 ◽  
Author(s):  
Pei He ◽  
Rong- Rong Cao ◽  
Fei- Yan Deng ◽  
Shu- Feng Lei
Keyword(s):  
Association Study ◽  
Canonical Correlation ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Summary Statistics ◽  
Immune Disease ◽  
Histocompatibility Complex ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
Shared Genetic

Background: Immune and skeletal systems physiologically and pathologically interact with each other. The immune and skeletal diseases may share potential pleiotropic genetics factors, but the shared specific genes are largely unknown Objective: This study aimed to investigate the overlapping genetic factors between multiple diseases (including rheumatoid arthritis (RA), psoriasis, osteoporosis, osteoarthritis, sarcopenia and fracture) Methods: The canonical correlation analysis (metaCCA) approach was used to identify the shared genes for six diseases by integrating genome-wide association study (GWAS)-derived summary statistics. Versatile Gene-based Association Study (VEGAS2) method was further applied to refine and validate the putative pleiotropic genes identified by metaCCA. Results: About 157 (p<8.19E-6), 319 (p<3.90E-6) and 77 (p<9.72E-6) potential pleiotropic genes were identified shared by two immune disease, four skeletal diseases, and all of the six diseases, respectively. The top three significant putative pleiotropic genes shared by both immune and skeletal diseases, including HLA-B, TSBP1 and TSBP1-AS1 (p<E-300) were located in the major histocompatibility complex (MHC) region. Nineteen of 77 putative pleiotropic genes identified by metaCCA analysis were associated with at least one disease in the VEGAS2 analysis. Specifically, majority (18) of these 19 putative validated pleiotropic genes were associated with RA. Conclusion: The metaCCA method identified some pleiotropic genes shared by the immune and skeletal diseases. These findings help to improve our understanding of the shared genetic mechanisms and signaling pathways underlying immune and skeletal diseases.

scholarly journals Genetic Determinants of Telomere Length in African American Youth

2018 ◽  
Author(s):  
Andrew M. Zeiger ◽  
Marquitta J. White ◽  
Sam S. Oh ◽  
Jonathan Witonsky ◽  
Maria G. Contreras ◽  
...  
Keyword(s):  
African American ◽  
Telomere Length ◽  
Genome Wide Association Study ◽  
African Ancestry ◽  
African American Youth ◽  
Genetic Associations ◽  
Disease States ◽  
Genome Wide ◽  
Pediatric Populations ◽  
Genetic And Environmental Factors

ABSTRACTTelomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

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