scholarly journals Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Adam J. Dugan ◽  
Peter T. Nelson ◽  
Yuriko Katsumata ◽  
Lincoln M. P. Shade ◽  
Kevin L. Boehme ◽  
...  
Keyword(s):  
Association Studies ◽  
Hippocampal Sclerosis ◽  
Genome Wide Association Studies ◽  
Research Subjects ◽  
Single Nucleotide Variants ◽  
Risk Alleles ◽  
Age Related ◽  
Genome Wide ◽  
Significant Gene ◽  
Using Data

AbstractLimbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer’s Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer’s pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer’s-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.

scholarly journals MORFEE: a new tool for detecting and annotating single nucleotide variants creating premature ATG codons from VCF files

2020 ◽  
Author(s):  
Dylan Aïssi ◽  
Omar Soukarieh ◽  
Carole Proust ◽  
Beatrice Jaspard-Vinassa ◽  
Pierre Fautrad ◽  
...  
Keyword(s):  
Stop Codon ◽  
Association Studies ◽  
Premature Stop Codon ◽  
Open Reading Frames ◽  
Strong Impact ◽  
Genome Wide Association Studies ◽  
Single Nucleotide Variants ◽  
Functional Variants ◽  
Genome Wide ◽  
Upstream Open Reading Frames

AbstractSummaryVariants in 5’UTR regions that create upstream translation initiation AUG codons are a class of neglected non coding variations. When they associate with a premature stop codon and create upstream open reading frames (uORFs) whose translation competes with that of natural proteins, they can have strong impact on human diseases. We here describe MORFEE, a new bioinformatics tool that detects, annotates and predicts, from a standard VCF file, the creation of uORF by any 5’UTR variants on uORF creation. MORFEE was applied to two genomic resources and identified candidate functional variants that could explain statistical association signals observed in the context of Genome Wide Association Studies or could be responsible for rare forms of diseases. In conclusion MORFEE is an easy-to-use tool complementary to existing ones that can help resolving genetic investigations that remained so far unfruitful.Availability and implementationMORFEE is written in R with code and package available at https://github.com/daissi/[email protected]; [email protected]

scholarly journals Impact of Pre and Post Variant Filtration Strategies on Imputation

2020 ◽  
Author(s):  
Celine Charon ◽  
Rodrigue Allodji ◽  
Vincent Meyer ◽  
Jean-François Deleuze
Keyword(s):  
Quality Control ◽  
Rare Variants ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Direct Effects ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Conservative Post

Abstract Quality control methods for genome-wide association studies and fine mapping are commonly used for imputation, however, they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1,031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1,089 NCBI recorded individuals for additional validation.Without variant pre-filtration based on quality control (QC), we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E-04-1E-03) and rare variants (1E-03-5E-03) (p < 1E-04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs) <0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E-04). As a result, to maintain confidence and enough SNVs, we propose here a 2-step post-filtration approach to increase the number of very rare and rare variants compared to conservative post-filtration methods.

scholarly journals CONVERGENT AGING LOCI: PATHWAYS THAT TRANSCEND INDIVIDUAL DISEASES

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S221-S221
Author(s):  
Luke C Pilling ◽  
Luigi Ferrucci ◽  
David Melzer
Keyword(s):  
Disease Risk ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Telomere Shortening ◽  
Chronic Disease Risk ◽  
Trade Offs ◽  
Age Related ◽  
Genome Wide ◽  
Artery Disease

Abstract Thousands of loci across the genome have been identified for specific diseases in genome-wide association studies (GWAS), yet very few are associated with lifespan itself. We hypothesized that specific biological pathways transcend individual diseases and affect health and lifespan more broadly. Using the published results for the most recent GWAS for 10 key age-related diseases (including coronary artery disease, type-2 diabetes, and several cancers) we identified 22 loci with a strong genetic association with at least three of the diseases. These multi-trait aging loci include known genes affecting multiple diverse health end points, such as CDKN2A/B (9p21.3) and APOE. There are also novel multi-trait genes including SH2B3 and CASC8, likely involved in hallmark pathways of aging biology, including telomere shortening and inflammation. Several of these loci involve trade-offs between chronic disease risk and cancer.

scholarly journals Estimation of heritability for nine common cancers using data from genome-wide association studies in Chinese population

2016 ◽  
Vol 140 (2) ◽  
pp. 329-336 ◽  
Author(s):  
Juncheng Dai ◽  
Wei Shen ◽  
Wanqing Wen ◽  
Jiang Chang ◽  
Tongmin Wang ◽  
...  
Keyword(s):  
Chinese Population ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Using Data

scholarly journals Birth Cohort, Age, and Sex Strongly Modulate Effects of Lipid Risk Alleles Identified in Genome-Wide Association Studies

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0136319 ◽  
Author(s):  
Alexander M. Kulminski ◽  
Irina Culminskaya ◽  
Konstantin G. Arbeev ◽  
Liubov Arbeeva ◽  
Svetlana V. Ukraintseva ◽  
...  
Keyword(s):  
Birth Cohort ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Genome Wide ◽  
Age And Sex

scholarly journals Novel genetic determinants of telomere length from a trans-ethnic analysis of 109,122 whole genome sequences in TOPMed

2019 ◽  
Author(s):  
Margaret A Taub ◽  
Matthew P Conomos ◽  
Rebecca Keener ◽  
Kruthika R Iyer ◽  
Joshua S Weinstock ◽  
...  
Keyword(s):  
Telomere Length ◽  
Association Studies ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genetic Determinants ◽  
Age Related ◽  
Genome Wide ◽  
Variant Genotype ◽  
Effect Heterogeneity

ABSTRACTTelomeres shorten in replicating somatic cells, and telomere length (TL) is associated with age-related diseases 1,2. To date, 17 genome-wide association studies (GWAS) have identified 25 loci for leukocyte TL 3–19, but were limited to European and Asian ancestry individuals and relied on laboratory assays of TL. In this study from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of TL in n=109,122 trans-ethnic (European, African, Asian and Hispanic/Latino) individuals. We identified 59 sentinel variants (p-value <5×10−9) from 36 loci (20 novel, 13 replicated in external datasets). There was little evidence of effect heterogeneity across populations, and 10 loci had >1 independent signal. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). We further identified two novel genes, DCLRE1B (SNM1B) and PARN, using a multi-variant gene-based approach.

scholarly journals Evaluating the Potential of Younger Cases and Older Controls Cohorts to Improve Discovery Power in Genome-wide Association Studies of Late-onset Diseases

2019 ◽  
Author(s):  
Roman Teo Oliynyk
Keyword(s):  
Cumulative Incidence ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Cerebral Stroke ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Genome Wide ◽  
Artery Disease

AbstractFor more than a decade, genome-wide association studies have been making steady progress in discovering the causal gene variants that contribute to late-onset human diseases. Polygenic late-onset diseases in an aging population display the risk allele frequency decrease at older ages, caused by individuals with higher polygenic risk scores becoming ill proportionately earlier and bringing about a change in the distribution of risk alleles between new cases and the as-yet-unaffected population. This phenomenon is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes, while for late-onset diseases with relatively lower prevalence and heritability, exemplified by cancers, the effect is significantly lower. Computer simulations have determined that genome-wide association studies of the late-onset polygenic diseases showing high cumulative incidence together with high initial heritability will benefit from using the youngest possible age-matched cohorts. Moreover, rather than using age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.

scholarly journals Cascading epigenomic analysis for identifying disease genes from the regulatory landscape of GWAS variants

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009918
Author(s):  
Bernard Ng ◽  
William Casazza ◽  
Nam Hee Kim ◽  
Chendi Wang ◽  
Farnush Farhadi ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Target Genes ◽  
Association Studies ◽  
Disease Genes ◽  
Genome Wide Association Studies ◽  
Cascading Effects ◽  
Risk Alleles ◽  
Gene Sets ◽  
Genome Wide ◽  
Regulatory Landscape

The majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, comprises two types of models: one for linking cis genetic effects to epigenomic variation and another for linking cis epigenomic variation to gene expression. Applying these models in cascade to GWAS summary statistics generates gene level statistics that reflect genetically-driven epigenomic effects. We show on sixteen brain-related GWAS that CEWAS provides higher gene detection rate than related methods, and finds disease relevant genes and gene sets that point toward less explored biological processes. CEWAS thus presents a novel means for exploring the regulatory landscape of GWAS variants in uncovering disease mechanisms.

scholarly journals Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Viñuela ◽  
Arushi Varshney ◽  
Martijn van de Bunt ◽  
Rashmi B. Prasad ◽  
Olof Asplund ◽  
...  
Keyword(s):  
Large Scale ◽  
Association Studies ◽  
Cell Types ◽  
Genome Wide Association ◽  
Regulatory Sequences ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Gwas Signal ◽  
Using Data

Abstract Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.

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