Corrigendum to: Genome-wide heritability analysis of severe malaria resistance reveals evidence of polygenic inheritance

ABSTRACTObjectiveEstimating SNP-heritability (h2g) of severe malaria/resistance and its distribution across the genome might shed new light in to the underlying biology.MethodWe investigated h2g of severe malaria susceptibility and resistance from genome-wide association study (GWAS) dataset (sample size =11, 657). We partitioned the h2g in to chromosomes, allele frequencies and annotations. We further examined none-cell type specific and cell type specific enrichments from GWAS-summary statistics.ResultsWe estimated the h2g of severe malaria at 0.21 (se=0.05, p=2.7×10−5), 0.20 (se =0.05, p=7.5×10−5) and 0.17 (se =0.05, p= 7.2×10−4) in Gambian, Kenyan and Malawi populations, respectively. The h2g attributed to the GWAS significant SNPs and the well-known sickle cell (HbS) variant was approximately 0.07 and 0.03, respectively. We prepared African population reference panel and obtained comparable h2g estimate (0.21 (se = 0.02, p< 1×10−5)) from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in protein coding genic SNPs while summary statistics analysis suggests pattern of enrichment in multiple categories.ConclusionWe report for the first time that the heritability of malaria susceptibility and resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Overall, our results suggest that malaria susceptibility and resistance is a polygenic trait. Further studies with larger sample sizes are needed to better understand the underpinning genetics of resistance and susceptibility to severe malaria.

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Genome-wide heritability analysis of severe malaria resistance reveals evidence of polygenic inheritance

Human Molecular Genetics ◽

10.1093/hmg/ddz258 ◽

2019 ◽

Vol 29 (1) ◽

pp. 168-176

Author(s):

Delesa Damena ◽

Emile R Chimusa

Keyword(s):

Severe Malaria ◽

Genome Wide Association Study ◽

Allelic Frequency ◽

Relationship Matrix ◽

Summary Statistics ◽

Cell Type ◽

Polygenic Inheritance ◽

Genome Wide ◽

A Genome ◽

Cell Type Specific

Abstract Background: Estimating single nucleotide polymorphism (SNP)-heritability (h2g) of severe malaria resistance and its distribution across the genome might shed new light in to the underlying biology. Method: We investigated h2g of severe malaria resistance from a genome-wide association study (GWAS) dataset (sample size = 11 657). We estimated the h2g and partitioned in to chromosomes, allele frequencies and annotations using the genetic relationship-matrix restricted maximum likelihood approach. We further examined non-cell type-specific and cell type-specific enrichments from GWAS-summary statistics. Results: The h2g of severe malaria resistance was estimated at 0.21 (se = 0.05, P = 2.7 × 10−5), 0.20 (se = 0.05, P = 7.5 × 10−5) and 0.17 (se = 0.05, P = 7.2 × 10−4) in Gambian, Kenyan and Malawi populations, respectively. A comparable range of h2g [0.21 (se = 0.02, P < 1 × 10−5)] was estimated from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in genic SNPs while summary statistics analysis suggests evidences of enrichment in multiple categories. Supporting the polygenic inheritance, the h2g of severe malaria resistance is distributed across the chromosomes and allelic frequency spectrum. However, the h2g is disproportionately concentrated on three chromosomes (chr 5, 11 and 20), suggesting cost-effectiveness of targeting these chromosomes in future malaria genomic sequencing studies. Conclusion: We report for the first time that the heritability of malaria resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Further studies with larger sample sizes are needed to better understand the underpinning genetics of severe malaria resistance.

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Genome-wide association study indicates two novel resistance loci for severe malaria

Nature ◽

10.1038/nature11334 ◽

2012 ◽

Vol 489 (7416) ◽

pp. 443-446 ◽

Cited By ~ 148

Author(s):

Christian Timmann ◽

Thorsten Thye ◽

Maren Vens ◽

Jennifer Evans ◽

Jürgen May ◽

...

Keyword(s):

Association Study ◽

Severe Malaria ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide

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Eating behavior in the Old Order Amish: heritability analysis and a genome-wide linkage analysis

American Journal of Clinical Nutrition ◽

10.1093/ajcn/75.6.1098 ◽

2002 ◽

Vol 75 (6) ◽

pp. 1098-1106 ◽

Cited By ~ 90

Author(s):

Nanette I Steinle ◽

Wen-Chi Hsueh ◽

Soren Snitker ◽

Toni I Pollin ◽

Hakan Sakul ◽

...

Keyword(s):

Linkage Analysis ◽

Eating Behavior ◽

Old Order Amish ◽

Old Order ◽

Genome Wide ◽

A Genome ◽

Heritability Analysis

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Genome Wide Association Mapping of Root Traits in the Andean Genepool of Common Bean (Phaseolus vulgaris L.) Grown With and Without Aluminum Toxicity

Frontiers in Plant Science ◽

10.3389/fpls.2021.628687 ◽

2021 ◽

Vol 12 ◽

Author(s):

Daniel Ambachew ◽

Matthew W. Blair

Keyword(s):

Common Bean ◽

Candidate Genes ◽

Aluminum Toxicity ◽

Root Traits ◽

Al Toxicity ◽

Genome Wide Association ◽

Soil Conditions ◽

Polygenic Inheritance ◽

Genome Wide ◽

Significant Difference

Common bean is one of the most important grain legumes for human diets but is produced on marginal lands with unfavorable soil conditions; among which Aluminum (Al) toxicity is a serious and widespread problem. Under low pH, stable forms of Al dissolve into the soil solution and as phytotoxic ions inhibit the growth and function of roots through injury to the root apex. This results in a smaller root system that detrimentally effects yield. The goal of this study was to evaluate 227 genotypes from an Andean diversity panel (ADP) of common bean and determine the level of Al toxicity tolerance and candidate genes for this abiotic stress tolerance through root trait analysis and marker association studies. Plants were grown as seedlings in hydroponic tanks at a pH of 4.5 with a treatment of high Al concentration (50 μM) compared to a control (0 μM). The roots were harvested and scanned to determine average root diameter, root volume, root surface area, number of root links, number of root tips, and total root length. Percent reduction or increase was calculated for each trait by comparing treatments. Genome wide association study (GWAS) was conducted by testing phenotypic data against single nucleotide polymorphism (SNP) marker genotyping data for the panel. Principal components and a kinship matrix were included in the mixed linear model to correct for population structure. Analyses of variance indicated the presence of significant difference between genotypes. The heritability of traits ranged from 0.67 to 0.92 in Al-treated and reached similar values in non-treated plants. GWAS revealed significant associations between root traits and genetic markers on chromosomes Pv01, Pv04, Pv05, Pv06, and Pv11 with some SNPs contributing to more than one trait. Candidate genes near these loci were analyzed to explain the detected association and included an Al activated malate transporter gene and a multidrug and toxic compound extrusion gene. This study showed that polygenic inheritance was critical to aluminum toxicity tolerance in common beans roots. Candidate genes found suggested that exudation of malate and citrate as organic acids would be important for Al tolerance. Possible cross-talk between mechanisms of aluminum tolerance and resistance to other abiotic stresses are discussed.

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First genome-wide association study of non-severe malaria in two birth cohorts in Benin

Human Genetics ◽

10.1007/s00439-019-02079-5 ◽

2019 ◽

Vol 138 (11-12) ◽

pp. 1341-1357 ◽

Cited By ~ 3

Author(s):

Jacqueline Milet ◽

Anne Boland ◽

Pierre Luisi ◽

Audrey Sabbagh ◽

Ibrahim Sadissou ◽

...

Keyword(s):

Association Study ◽

Severe Malaria ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Birth Cohorts ◽

Genome Wide

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Genetics of psoriasis: a basis for precision medicine

Precision Clinical Medicine ◽

10.1093/pcmedi/pbz011 ◽

2019 ◽

Vol 2 (2) ◽

pp. 120-130 ◽

Cited By ~ 3

Author(s):

Delin Ran ◽

Minglong Cai ◽

Xuejun Zhang

Keyword(s):

Genetic Variation ◽

Precision Medicine ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Direct Sequencing ◽

Disease Prediction ◽

Inflammatory Skin Disease ◽

Polygenic Inheritance ◽

Genome Wide

AbstractPsoriasis is an inflammatory skin disease with a background of polygenic inheritance. Both environmental and genetic factors are involved in the etiology of the disease. In the last two decades, numerous studies have been conducted through linkage analysis, genome-wide association study (GWAS), and direct sequencing to explore the role of genetic variation in disease pathogenesis and progression. To date, >80 psoriasis susceptibility genes have been identified, including HLA-Cw6, IL12B, IL23R, and LCE3B/3C. Some genetic markers have been applied in disease prediction, clinical diagnosis, treatment, and new drug development, which could further explain the pathogenesis of psoriasis and promote the development of precision medicine. This review summarizes related research on genetic variation in psoriasis and explores implications of the findings in clinical application and the promotion of a personalized medicine project.

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Insilico Functional Analysis of Genome-Wide Dataset From 17,000 Individuals Identifies Candidate Malaria Resistance Genes Enriched in Malaria Pathogenic Pathways

Frontiers in Genetics ◽

10.3389/fgene.2021.676960 ◽

2021 ◽

Vol 12 ◽

Author(s):

Delesa Damena ◽

Francis E. Agamah ◽

Peter O. Kimathi ◽

Ntumba E. Kabongo ◽

Hundaol Girma ◽

...

Keyword(s):

Functional Analysis ◽

Severe Malaria ◽

Resistance Genes ◽

Population Genetic ◽

Association Studies ◽

Chromatin Interaction ◽

Genome Wide Association Studies ◽

Biological Functions ◽

Population Genetic Analysis ◽

Genome Wide

Recent genome-wide association studies (GWASs) of severe malaria have identified several association variants. However, much about the underlying biological functions are yet to be discovered. Here, we systematically predicted plausible candidate genes and pathways from functional analysis of severe malaria resistance GWAS summary statistics (N = 17,000) meta-analysed across 11 populations in malaria endemic regions. We applied positional mapping, expression quantitative trait locus (eQTL), chromatin interaction mapping, and gene-based association analyses to identify candidate severe malaria resistance genes. We further applied rare variant analysis to raw GWAS datasets (N = 11,000) of three malaria endemic populations including Kenya, Malawi, and Gambia and performed various population genetic structures of the identified genes in the three populations and global populations. We performed network and pathway analyses to investigate their shared biological functions. Our functional mapping analysis identified 57 genes located in the known malaria genomic loci, while our gene-based GWAS analysis identified additional 125 genes across the genome. The identified genes were significantly enriched in malaria pathogenic pathways including multiple overlapping pathways in erythrocyte-related functions, blood coagulations, ion channels, adhesion molecules, membrane signalling elements, and neuronal systems. Our population genetic analysis revealed that the minor allele frequencies (MAF) of the single nucleotide polymorphisms (SNPs) residing in the identified genes are generally higher in the three malaria endemic populations compared to global populations. Overall, our results suggest that severe malaria resistance trait is attributed to multiple genes, highlighting the possibility of harnessing new malaria therapeutics that can simultaneously target multiple malaria protective host molecular pathways.

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Quantitative Genetic Analysis of the Maize Leaf Microbiome

10.1101/268532 ◽

2018 ◽

Cited By ~ 2

Author(s):

Jason G. Wallace ◽

Karl A. Kremling ◽

Edward S. Buckler

Keyword(s):

Community Diversity ◽

Exact Nature ◽

Common Environment ◽

Operational Taxonomic Units ◽

Metabolic Functions ◽

Genome Wide ◽

Significant Enrichment ◽

Heritability Analysis ◽

Founder Events ◽

Diversity Metrics

AbstractThe degree to which an organism can affect its associated microbial communities (“microbiome”) varies by organism and habitat, and in many cases is unknown. We address this question by analyzing the metabolically active bacteria of the maize phyllosphere across 300 diverse maize lines growing in a common environment. We performed comprehensive heritability analysis for 49 community diversity metrics, 380 bacterial clades (individual operational taxonomic units and higher-level groupings), and 9042 predicted metagenomic functions. We find that only a few few bacterial clades (5) and diversity metrics (2) are significantly heritable, while a much larger number of metabolic functions (200) are. Many of these associations appear to be driven by the amount of Methylobacteria present in each sample, and we find significant enrichment for traits relating to short-chain carbon metabolism, secretion, and nitrotoluene degradation. Genome-wide association analysis identifies a small number of associated loci for these heritable traits, including two loci (on maize chromosomes 7 and 10) that affect a large number of traits even after correcting for correlations among traits. This work is among the most comprehensive analyses of the maize phyllosphere to date. Our results indicate that while most of the maize phyllosphere composition is driven by environmental factors and/or stochastic founder events, a subset of bacterial taxa and metabolic functions is nonetheless significantly impacted by host plant genetics. Additional work will be needed to identify the exact nature of these interactions and what effects they may have on the phenotype of host plants.

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Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Circulation Research ◽

10.1161/circresaha.120.317107 ◽

2021 ◽

Author(s):

Doris Skoric-Milosavljevic ◽

Rafik Tadros ◽

Fernanda M Bosada ◽

Federico Tessadori ◽

Jan Hendrik van Weerd ◽

...

Keyword(s):

Genome Wide Association Study ◽

Regulatory Element ◽

Susceptibility Locus ◽

Mouse Heart ◽

Polygenic Risk Score ◽

Polygenic Inheritance ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome

Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

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