scholarly journals Common variants in the transmembrane protease serine 6 (TMPRSS6) gene alter hepcidin but not plasma iron in response to oral iron in healthy Gambian adults: a recall-by-genotype study

2021 ◽  
Author(s):  
Momodou W Jallow ◽  
Susana Campino ◽  
Alasana Saidykhan ◽  
Andrew M Prentice ◽  
Carla Cerami
Keyword(s):  
Oral Dose ◽  
Iron Status ◽  
Association Studies ◽  
Oral Iron ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Plasma Iron ◽  
Risk Alleles ◽  
Genome Wide ◽  
Iron Parameters

Abstract Background The role of genetic determinants in mediating iron status in Africans is not fully understood. Genome-wide association studies in non-African populations have revealed genetic variants in the TMPRSS6 gene that are associated with the risk of anemia. Objectives To investigated the effects of risk alleles for low iron status from TMPRSS6 rs2235321, rs855791 and rs4820268, on responses to oral iron in healthy Gambian adults. Methods Using a recall-by-genotype design, participants were selected from a pre-genotype cohort of 3000 individuals in the Keneba Biobank (MRCG at LSHTM). Participants were invited to participate in the study based on nine genotype combinations obtained from three TMPRSS6 SNPs (rs2235321, rs855791 and rs4820268). The participants fasted overnight and then ingested a single oral dose of ferrous sulfate (130 mg elemental iron). Blood samples were collected prior to iron ingestion and at 2 and 5 hours after the oral iron dose. The effects of genotype on hepcidin and plasma iron parameters were assessed. Results A total of 251 individuals were enrolled. Homozygous carriers of the major TMPRSS6 alleles at each of the SNPs had higher plasma hepcidin at baseline (rs2235321: GG vs AA 9.50 vs 6.60ng/ml,  p = 0.035; rs855791: GG vs AG = 9.50 vs 4.96ng/mL,  p = 0.015; rs4820268: AA vs GG = 9.50 vs 3.27ng/mL,  p = 0.002) and at subsequent timepoints. There were no differences in delta plasma iron (a proxy for iron absorption) between genotypes. In most subjects, hepcidin levels increased following iron ingestion (overall group mean = 4.98 ± 0.98ng/ml at 5h,  p < 0.001),  but double heterozygotes at rs2235321 and rs855791 showed no increase (0.36 ± 0.40ng/ml at 5h,  p = 0.667). Conclusions This study revealed that common TMPRSS6 variants influence hepcidin concentrations, but not iron status indicators either at baseline or following a large oral dose of iron. These results suggest that genetic variations in the TMPRSS6 gene are unlikely to be important contributors to variations in iron status in Africans. This study was registered at ClinicalTrials.gov # NCT03341338.

GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

2019 ◽  
Vol 20 (10) ◽  
pp. 765-780 ◽  
Author(s):  
Diana Cruz ◽  
Ricardo Pinto ◽  
Margarida Freitas-Silva ◽  
José Pedro Nunes ◽  
Rui Medeiros
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Association Studies ◽  
Cardioembolic Stroke ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

scholarly journals Genome-Wide Association Study of Coronary Artery Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Naomi Ogawa ◽  
Yasushi Imai ◽  
Hiroyuki Morita ◽  
Ryozo Nagai
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Studies ◽  
Genome Wide Association ◽  
Candidate Gene Approach ◽  
International Hapmap Project ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Artery Disease

Coronary artery disease (CAD) is a multifactorial disease with environmental and genetic determinants. The genetic determinants of CAD have previously been explored by the candidate gene approach. Recently, the data from the International HapMap Project and the development of dense genotyping chips have enabled us to perform genome-wide association studies (GWAS) on a large number of subjects without bias towards any particular candidate genes. In 2007, three chip-based GWAS simultaneously revealed the significant association between common variants on chromosome 9p21 and CAD. This association was replicated among other ethnic groups and also in a meta-analysis. Further investigations have detected several other candidate loci associated with CAD. The chip-based GWAS approach has identified novel and unbiased genetic determinants of CAD and these insights provide the important direction to better understand the pathogenesis of CAD and to develop new and improved preventive measures and treatments for CAD.

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 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 Genome-wide association analysis reveals extensive genetic overlap between mood instability and psychiatric disorders but divergent patterns of genetic effects

2021 ◽  
Author(s):  
Guy Hindley ◽  
Kevin S O'Connell ◽  
Zillur Rahman ◽  
Oleksandr Frei ◽  
Shahram Bahrami ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Correlation ◽  
Association Studies ◽  
Single Gene ◽  
Genetic Effects ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Mood Instability ◽  
Genome Wide

Mood instability (MOOD) is a transdiagnostic phenomenon with a prominent neurobiological basis. Recent genome-wide association studies found significant positive genetic correlation between MOOD and major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. Summary statistics for schizophrenia (SCZ, n=105,318), bipolar disorder (BIP, n=413,466), DEP (n=450,619), attention-deficit hyperactivity disorder (ADHD, n=53,293) and MOOD (n=363,705), were analysed using the bivariate causal mixture model and conjunctional false discovery rate methods to estimate the proportion of shared variants influencing MOOD and each disorder, and identify jointly associated genomic loci. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg=0.10-0.62). Of 10.4K genomic variants influencing MOOD, 4K-9.4K were estimated to influence psychiatric disorders. MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25, with consistent genetic effects in independent samples. Fifty-three jointly associated loci were overlapping across two or more disorders (transdiagnostic), seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, synapse organization. The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions of shared loci suggest divergent effects on corresponding neurobiological mechanisms which may relate to differences in the core clinical features of each disorder.

scholarly journals Recent advances in the genetic association between osteoporotic fracture and sarcopenia

2021 ◽  
Vol 3 (1) ◽  
pp. 02-09
Author(s):  
Qiaocong Chen ◽  
◽  
Huiling Lou ◽  
Cheng Peng
Keyword(s):  
Fracture Risk ◽  
Osteoporotic Fracture ◽  
Musculoskeletal Diseases ◽  
Association Studies ◽  
Genetic Correlations ◽  
Osteoporotic Fractures ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide

The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Skeletal loads are dominated by muscle action. Recently, it has become clear that bone and muscle share genetic determinants. Involvement of the musculoskeletal system manifests as bone loss (osteoporosis) and muscle wasting (sarcopenia). There is clinical evidence that osteoporotic fractures are significantly associated with sarcopenia, and sarcopenia may be a potential predictive factor for fracture risk, which suggests that there may be shared genetic determinants between sarcopenia and osteoporotic fracture. In recent years, genome-wide association studies (GWASs) studies have found that both lean mass and hand grip strength are associated with fracture risk, which may provide a possible endophenotype for elucidating the potential genetic study of fracture risk. Our effort to understand the clinical and genetic correlations between osteoporotic fracture and sarcopenia is helpful to understand the interaction between muscle and bone, and to study the etiology of complex musculoskeletal diseases. Identifying potentially important genetic variations in bone and muscle, measuring these variations using state-of-the-art technology, and replicating these experiments in humans and large animals will provide potential drug or intervention targets for osteoporotic fracture valuable in the future. Keywords: Genetics, osteoporosis, fracture, sarcopenia, genome-wide association studies, single nucleotide polymorphism

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.

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