Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa

Background: Tuberculosis (TB) is the most deadly infectious disease globally and highly prevalent in the developing world, especially sub-Saharan Africa. Even though a third of humans are exposed to Myocbacterium tuberculosis (Mtb), most infected immunocompetent individuals do not develop active TB. In contrast, for individuals infected with both TB and the human immunodeficiency virus (HIV), the risk of active disease is 10% or more per year. Previously, we identified in a genome-wide association study a region on chromosome 5 that was associated with resistance to TB. This region included epigenetic marks that could influence gene regulation so we hypothesized that HIV-infected individuals exposed to Mtb, who remain disease free, carry epigenetic changes that strongly protect them from active TB. To test this hypothesis, we conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania. Results: In 221 HIV-infected adults from Uganda and Tanzania, we identified 3 regions of interest that included markers that were differentially methylated between TB cases and LTBI controls, that also included methylation QTLs and associated SNPs: chromosome 1 (RNF220, p=4x10-5), chromosome 2 (between COPS8 and COL6A3 genes, p=2.7x10-5), and chromosome 5 (CEP72, p=1.3x10-5). These methylation results colocalized with associated SNPs, methylation QTLs, and methylation x SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung. Conclusion: Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.

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Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa785 ◽

2021 ◽

Author(s):

Catherine M Stein ◽

Penelope Benchek ◽

Jacquelaine Bartlett ◽

Robert P Igo ◽

Rafal S Sobota ◽

...

Keyword(s):

Genome Wide Association Study ◽

Chromosome 1 ◽

Chromosome 2 ◽

Chromosome 5 ◽

Epigenetic Marks ◽

Genome Wide ◽

A Genome ◽

Immunodeficiency Virus ◽

Disease Free ◽

Snp Interaction

Abstract Background Tuberculosis (TB) is the most deadly infectious disease globally and highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation. We hypothesized that HIV-infected individuals exposed to Mtb, who remain disease free, carry epigenetic changes that strongly protect them from active TB. Methods We conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania and integrated data from our GWAS. Results We identified 3 regions of interest that included markers that were differentially methylated between TB cases and LTBI controls: chromosome 1 (RNF220, p=4x10 -5), chromosome 2 (between COPS8 and COL6A3, p=2.7x10 -5), and chromosome 5 (CEP72, p=1.3x10 -5). These methylation results co-localized with associated SNPs, methylation QTLs, and methylation x SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung. Conclusion Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.

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A Genome-Wide Association Study Identifies SNP Markers for Virulence in Magnaporthe oryzae Isolates from Sub-Saharan Africa

10.1101/418509 ◽

2018 ◽

Cited By ~ 1

Author(s):

Veena Devi Ganeshan ◽

Stephen O. Opiyo ◽

Samuel K. Mutiga ◽

Felix Rotich ◽

David M. Thuranira ◽

...

Keyword(s):

Association Study ◽

Magnaporthe Oryzae ◽

Genome Wide Association Study ◽

Significant Snps ◽

Sub Saharan Africa ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome ◽

Sub Saharan ◽

Genomic Regions

ABSTRACTThe fungal phytopathogen Magnaporthe oryzae causes blast disease in cereals such as rice and finger millet worldwide. In this study, we assessed genetic diversity of 160 isolates from nine sub-Saharan Africa (SSA) and other principal rice producing countries and conducted a genome-wide association study (GWAS) to identify the genomic regions associated with virulence of M. oryzae. GBS of isolates provided a large and high-quality 617K single nucleotide polymorphism (SNP) dataset. Disease ratings for each isolate was obtained by inoculating them onto differential lines and locally-adapted rice cultivars. Genome-wide association studies were conducted using the GBS dataset and sixteen disease rating datasets. Principal Component Analysis (PCA) was used an alternative to population structure analysis for studying population stratification from genotypic data. A significant association between disease phenotype and 528 SNPs was observed in six GWA analyses. Homology of sequences encompassing the significant SNPs was determined to predict gene identities and functions. Seventeen genes recurred in six GWA analyses, suggesting a strong association with virulence. Here, the putative genes/genomic regions associated with the significant SNPs are presented.

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Admixture into and within sub-Saharan Africa

eLife ◽

10.7554/elife.15266 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 57

Author(s):

George BJ Busby ◽

Gavin Band ◽

Quang Si Le ◽

Muminatou Jallow ◽

Edith Bougama ◽

...

Keyword(s):

Gene Flow ◽

Geographic Region ◽

Sub Saharan Africa ◽

Genome Wide ◽

A Genome ◽

Depth Analysis ◽

Shared Ancestry ◽

Sub Saharan ◽

Linguistic Groups ◽

Insight Into

Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology.

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The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitamer Levels in CSF and Plasma

Genes ◽

10.3390/genes10010008 ◽

2018 ◽

Vol 10 (1) ◽

pp. 8 ◽

Cited By ~ 3

Author(s):

Loes Loohuis ◽

Monique Albersen ◽

Simone de Jong ◽

Timothy Wu ◽

Jurjen Luykx ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Vitamin B6 ◽

Pyridoxal Phosphate ◽

Genome Wide Association Study ◽

Active Form ◽

Minor Allele ◽

Chromosome 1 ◽

Joint Analysis ◽

Genome Wide ◽

A Genome

The active form of vitamin B6, pyridoxal phosphate (PLP), is essential for human metabolism. The brain is dependent on vitamin B6 for its neurotransmitter balance. To obtain insight into the genetic determinants of vitamin B6 homeostasis, we conducted a genome-wide association study (GWAS) of the B6 vitamers pyridoxal (PL), PLP and the degradation product of vitamin B6, pyridoxic acid (PA). We collected a unique sample set of cerebrospinal fluid (CSF) and plasma from the same healthy human subjects of Dutch ancestry (n = 493) and included concentrations and ratios in and between these body fluids in our analysis. Based on a multivariate joint analysis of all B6 vitamers and their ratios, we identified a genome-wide significant association at a locus on chromosome 1 containing the ALPL (alkaline phosphatase) gene (minimal p = 7.89 × 10−10, rs1106357, minor allele frequency (MAF) = 0.46), previously associated with vitamin B6 levels in blood. Subjects homozygous for the minor allele showed a 1.4-times-higher ratio between PLP and PL in plasma, and even a 1.6-times-higher ratio between PLP and PL in CSF than subjects homozygous for the major allele. In addition, we observed a suggestive association with the CSF:plasma ratio of PLP on chromosome 15 (minimal p = 7.93 × 10−7, and MAF = 0.06 for rs28789220). Even though this finding is not reaching genome-wide significance, it highlights the potential of our experimental setup for studying transport and metabolism across the blood–CSF barrier. This GWAS of B6 vitamers identifies alkaline phosphatase as a key regulator in human vitamin B6 metabolism in CSF as well as plasma. Furthermore, our results demonstrate the potential of genetic studies of metabolites in plasma and CSF to elucidate biological aspects underlying metabolite generation, transport and degradation.

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Genome-wide association study reveals 14 new SNPs and confirms two structural variants highly associated with the horned/polled phenotype in goats

BMC Genomics ◽

10.1186/s12864-021-08089-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jiazhong Guo ◽

Rui Jiang ◽

Ayi Mao ◽

George E. Liu ◽

Siyuan Zhan ◽

...

Keyword(s):

Association Study ◽

Mixed Model ◽

Genome Wide Association Study ◽

Insertion Site ◽

Genome Wide Association ◽

Chromosome 1 ◽

Structural Variants ◽

Diagnostic Pcr ◽

Genome Wide ◽

A Genome

Abstract Background There is a long-term interest in investigating the genetic basis of the horned/polled phenotype in domestic goats. Here, we report a genome-wide association study (GWAS) to detect the genetic loci affecting the polled phenotype in goats. Results We obtained a total of 13,980,209 biallelic SNPs, using the genotyping-by-sequencing data from 45 Jintang Black (JT) goats, which included 32 female and nine male goats, and four individuals with the polled intersex syndrome (PIS). Using a mixed-model based GWAS, we identified two association signals, which were located at 150,334,857–150,817,260 bp (P = 5.15 × 10− 119) and 128,286,704–131,306,537 bp (P = 2.74 × 10− 15) on chromosome 1. The genotype distributions of the 14 most significantly associated SNPs were completely correlated with horn status in goats, based on the whole-genome sequencing (WGS) data from JT and two other Chinese horned breeds. However, variant annotation suggested that none of the detected SNPs within the associated regions were plausible causal mutations. Via additional read-depth analyses and visual inspections of WGS data, we found a 10.1-kb deletion (CHI1:g. 129424781_129434939del) and a 480-kb duplication (CHI1:150,334,286–150,818,098 bp) encompassing two genes KCNJ15 and ERG in the associated regions of polled and PIS-affected goats. Notably, the 10.1-kb deletion also served as the insertion site for the 480-kb duplication, as validated by PCR and Sanger sequencing. Our WGS genotyping showed that all horned goats were homozygous for the reference alleles without either the structural variants (SVs), whereas the PIS-affected goats were homozygous for both the SVs. We also demonstrated that horned, polled, and PIS-affected individuals among 333 goats from JT and three other Chinese horned breeds can be accurately classified via PCR amplification and agarose gel electrophoresis of two fragments in both SVs. Conclusion Our results revealed that two genomic regions on chromosome 1 are major loci affecting the polled phenotypes in goats. We provided a diagnostic PCR to accurately classify horned, polled, and PIS-affected goats, which will enable a reliable genetic test for the early-in-life prediction of horn status in goats.

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Abstract 18116: Genetic Associations With Atherosclerotic Abdominal Aortic Calcification

Circulation ◽

10.1161/circ.132.suppl_3.18116 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Rajeev Malhotra ◽

Andreas C Mauer ◽

Jie Yao ◽

Xiuqing Guo ◽

Albert V Smith ◽

...

Keyword(s):

Genome Wide Association Study ◽

The United States ◽

Aortic Calcification ◽

Chromosome 1 ◽

Abdominal Aortic Calcification ◽

European Descent ◽

Genome Wide ◽

Abdominal Aortic ◽

A Genome ◽

Replication Analysis

Background: There is limited information regarding genetic contributions to atherosclerotic aortic calcification, an important predictor of cardiovascular disease. Methods: We conducted a genome-wide association study (GWAS) meta-analysis with subsequent replication analysis to define single nucleotide polymorphisms (SNPs) associated with abdominal (AAC) or thoracic aortic calcification (TAC). AAC and TAC were quantified using multi-detector computed tomography. SNPs were assayed by Illumina or Affymetrix arrays and imputation at the cohort level was performed using data from the 1000 Genomes project. Results: 9417 individuals of European descent from four cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortium were included in the AAC discovery analysis and 8422 individuals from five cohorts in the TAC discovery analysis. SNPs achieving genome-wide significance were tested for replication in four additional cohorts with Hispanic-American (HA) and African-American (AA) participants. Two regions contained SNPs associated at a genome-wide level for AAC (p<5.0x10 -8 , Table), the HDAC9 (chromosome 7, 6 SNPs) and RAP1GAP (chromosome 1, 2 SNPs) genetic loci. All six HDAC9 SNPs were associated with AAC in HA. Among these, rs2107595 was associated with AAC both in HA (p=2.8x10 -6 ) and in AA (p=0.01). SNPs in RAP1GAP were not associated with AAC in the replication analysis. No SNPs were associated with TAC at the genome-wide threshold. SNPs in the HDAC9 locus were associated with other forms of calcification (coronary artery calcification) as well as clinically apparent coronary heart disease (p<0.05). Conclusions: SNPs in the HDAC9 locus are associated with the presence of AAC in participants of European descent. This association was replicated in other ethnic groups in the United States. These findings suggest a novel role for HDAC9 in the development of abdominal aortic calcification.

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A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries)

Scientific Reports ◽

10.1038/srep21111 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 7

Author(s):

Xue Ren ◽

Guang-Li Yang ◽

Wei-Feng Peng ◽

Yong-Xin Zhao ◽

Min Zhang ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Close Association ◽

Significant Snps ◽

Genomic Region ◽

Ovis Aries ◽

Genome Wide Association ◽

Chromosome 2 ◽

Genome Wide ◽

A Genome

Abstract Horns are a cranial appendage found exclusively in Bovidae, and play important roles in accessing resources and mates. In sheep (Ovies aries), horns vary from polled to six-horned, and human have been selecting polled animals in farming and breeding. Here, we conducted a genome-wide association study on 24 two-horned versus 22 four-horned phenotypes in a native Chinese breed of Sishui Fur sheep. Together with linkage disequilibrium (LD) analyses and haplotype-based association tests, we identified a genomic region comprising 132.0–133.1 Mb on chromosome 2 that contained the top 10 SNPs (including 4 significant SNPs) and 5 most significant haplotypes associated with the polycerate phenotype. In humans and mice, this genomic region contains the HOXD gene cluster and adjacent functional genes EVX2 and KIAA1715, which have a close association with the formation of limbs and genital buds. Our results provide new insights into the genetic basis underlying variable numbers of horns and represent a new resource for use in sheep genetics and breeding.

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Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes

Scientific Reports ◽

10.1038/s41598-020-79515-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ya-Ching Chou ◽

Ming-Jer Chen ◽

Pi-Hua Chen ◽

Ching-Wen Chang ◽

Mu-Hsien Yu ◽

...

Keyword(s):

Association Study ◽

Quantitative Trait ◽

Genome Wide Association Study ◽

Chromosome 9 ◽

Genome Wide Association ◽

Chromosome 1 ◽

Eqtl Analysis ◽

Taiwanese Population ◽

Genome Wide ◽

A Genome

AbstractTo determine whether genetic predisposition to endometriosis varies depending on ethnicity and in association with expression quantitative trait loci (eQTL) in a Taiwanese population. We conducted a genome-wide association study (GWAS) and replicated it in 259 individuals with laparoscopy-confirmed stage III or IV endometriosis (cases) and 171 women without endometriosis (controls). Their genomic DNA was extracted from blood and evaluated by the GWAS of Taiwan Biobank Array. Novel genetic variants that predispose individuals to endometriosis were identified using GWAS and replication, including rs10739199 (P = 6.75 × 10−5) and rs2025392 (P = 8.01 × 10−5) at chromosome 9, rs1998998 (P = 6.5 × 10−6) at chromosome 14, and rs6576560 (P = 9.7 × 10−6) at chromosome 15. After imputation, strong signals were exhibited by rs10822312 (P = 1.80 × 10−7) at chromosome 10, rs58991632 (P = 1.92 × 10−6) and rs2273422 (P = 2.42 × 10−6) at chromosome 20, and rs12566078 (P = 2.5 × 10−6) at chromosome 1. We used the Genotype-Tissue Expression (GTEx) database to observe eQTL. Among these SNPs, the cis-eQTL rs13126673 of inturned planar cell polarity protein (INTU) showed significant association with INTU expression (P = 5.1 × 10–33). Moreover, the eQTL analysis was performed on endometriotic tissues from women with endometriosis. The expression of INTU in 78 endometriotic tissue of women with endometriosis is associated with rs13126673 genotype (P = 0.034). To our knowledge, this is the first GWAS to link endometriosis and eQTL in a Taiwanese population.

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