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

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.

Download Full-text

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

10.1101/649095 ◽

2019 ◽

Author(s):

Delesa Damena ◽

Emile R. Chimusa

Keyword(s):

Severe Malaria ◽

Genome Wide Association Study ◽

Summary Statistics ◽

Cell Type ◽

Protein Coding ◽

Polygenic Inheritance ◽

Genome Wide ◽

Cell Type Specific ◽

Malaria Susceptibility ◽

Susceptibility And Resistance

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.

Download Full-text

Partitioning heritability by functional category using GWAS summary statistics

10.1101/014241 ◽

2015 ◽

Cited By ~ 9

Author(s):

Hilary Kiyo Finucane ◽

Brendan Bulik-Sullivan ◽

Alexander Gusev ◽

Gosia Trynka ◽

Yakir Reshef ◽

...

Keyword(s):

Association Studies ◽

Smoking Behavior ◽

Complex Diseases ◽

New Method ◽

Age At Menarche ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Cell Type ◽

Genome Wide ◽

Cell Type Specific

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.

Download Full-text

A compendium of uniformly processed human gene expression and splicing quantitative trait loci

Nature Genetics ◽

10.1038/s41588-021-00924-w ◽

2021 ◽

Vol 53 (9) ◽

pp. 1290-1299

Author(s):

Nurlan Kerimov ◽

James D. Hayhurst ◽

Kateryna Peikova ◽

Jonathan R. Manning ◽

Peter Walter ◽

...

Keyword(s):

Gene Expression ◽

Quantitative Trait ◽

Target Genes ◽

Genome Wide Association Study ◽

Cell Types ◽

Summary Statistics ◽

Genome Wide ◽

Cell Type Specific ◽

Trait Locus ◽

Complex Human Traits

AbstractMany gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and co-localization. However, technical differences between these datasets are a barrier to their widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals have still not been identified. In the present study, we present the eQTL Catalogue (https://www.ebi.ac.uk/eqtl), a resource of quality-controlled, uniformly re-computed gene expression and splicing QTLs from 21 studies. We find that, for matching cell types and tissues, the eQTL effect sizes are highly reproducible between studies. Although most QTLs were shared between most bulk tissues, we identified a greater diversity of cell-type-specific QTLs from purified cell types, a subset of which also manifested as new disease co-localizations. Our summary statistics are freely available to enable the systematic interpretation of human GWAS associations across many cell types and tissues.

Download Full-text

Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells

Frontiers in Immunology ◽

10.3389/fimmu.2020.607889 ◽

2021 ◽

Vol 11 ◽

Author(s):

Vikas Duhan ◽

Vishal Khairnar ◽

Simo Kitanovski ◽

Thamer A. Hamdan ◽

Andrés D. Klein ◽

...

Keyword(s):

Dendritic Cells ◽

Vesicular Stomatitis Virus ◽

Immune Activation ◽

Genome Wide Association Study ◽

Innate Immune ◽

Akt Phosphorylation ◽

Genome Wide ◽

A Genome ◽

Cell Type Specific ◽

Vesicular Stomatitis

Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection.

Download Full-text

Approximate conditional phenotype analysis based on genome wide association summary statistics

Scientific Reports ◽

10.1038/s41598-021-82000-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Peitao Wu ◽

Biqi Wang ◽

Steven A. Lubitz ◽

Emelia J. Benjamin ◽

James B. Meigs ◽

...

Keyword(s):

Large Scale ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Summary Statistics ◽

Phenotypic Data ◽

Individual Level ◽

Genome Wide ◽

Level Data ◽

A Genome ◽

Phenotype Analysis

AbstractBecause single genetic variants may have pleiotropic effects, one trait can be a confounder in a genome-wide association study (GWAS) that aims to identify loci associated with another trait. A typical approach to address this issue is to perform an additional analysis adjusting for the confounder. However, obtaining conditional results can be time-consuming. We propose an approximate conditional phenotype analysis based on GWAS summary statistics, the covariance between outcome and confounder, and the variant minor allele frequency (MAF). GWAS summary statistics and MAF are taken from GWAS meta-analysis results while the traits covariance may be estimated by two strategies: (i) estimates from a subset of the phenotypic data; or (ii) estimates from published studies. We compare our two strategies with estimates using individual level data from the full GWAS sample (gold standard). A simulation study for both binary and continuous traits demonstrates that our approximate approach is accurate. We apply our method to the Framingham Heart Study (FHS) GWAS and to large-scale cardiometabolic GWAS results. We observed a high consistency of genetic effect size estimates between our method and individual level data analysis. Our approach leads to an efficient way to perform approximate conditional analysis using large-scale GWAS summary statistics.

Download Full-text

Genome-Wide Association Study of lipid traits in youth with type 2 diabetes

Journal of the Endocrine Society ◽

10.1210/jendso/bvab139 ◽

2021 ◽

Author(s):

Nicola Santoro ◽

Ling Chen ◽

Jennifer Todd ◽

Jasmin Divers ◽

Amy S Shah ◽

...

Keyword(s):

Type 2 Diabetes ◽

Association Study ◽

Genome Wide Association Study ◽

Risk Allele ◽

Density Lipoprotein ◽

Genome Wide Association ◽

Relationship Matrix ◽

Genome Wide ◽

A Genome

Abstract Context Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. Objective To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study (GWAS). Design, participants and main outcome measures We genotyped 206,928 variants and imputed 17,642,824 variants in 1,076 youth (mean age 15.0 ±2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride, low-density lipoprotein (LDL-c) and high-density lipoprotein (HDL-c) concentrations adjusted for the genetic relationship matrix within each sub-study followed by meta-analyses for each trait. Results We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance (P=2.3×10 -8) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 (P=5.1×10 -9) between HERFUD1 and CETP associated with HDL-c, with carriers of one copy of the risk allele having twice higher HDL-c. Conclusions Our genetic analyses of lipid traits in youth with T2D have identified one novel and one previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.

Download Full-text

echolocatoR: an automated end-to-end statistical and functional genomic fine-mapping pipeline

10.1101/2020.10.22.351221 ◽

2020 ◽

Cited By ~ 2

Author(s):

Brian M. Schilder ◽

Jack Humphrey ◽

Towfique Raj

Keyword(s):

Linkage Disequilibrium ◽

Fine Mapping ◽

R Package ◽

Functional Genomic ◽

Summary Statistics ◽

Cell Type ◽

High Confidence ◽

Genome Wide ◽

Cell Type Specific ◽

End To End

AbstractSummaryecholocatoR integrates a diverse suite of statistical and functional fine-mapping tools in order to identify, test enrichment in, and visualize high-confidence causal consensus variants in any phenotype. It requires minimal input from users (a summary statistics file), can be run in a single R function, and provides extensive access to relevant datasets (e.g. reference linkage disequilibrium (LD) panels, quantitative trait loci (QTL) datasets, genome-wide annotations, cell type-specific epigenomics, thereby enabling rapid, robust and scalable end-to-end fine-mapping investigations.Availability and implementationecholocatoR is an open-source R package available through GitHub under the MIT license: https://github.com/RajLabMSSM/echolocatoR

Download Full-text

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.

Download Full-text

Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania

Nature Communications ◽

10.1038/s41467-019-13480-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 15

Author(s):

Keyword(s):

Severe Malaria ◽

Genome Wide Association Study ◽

Causal Mechanism ◽

Chromosome 6 ◽

Genetic Determinants ◽

Genome Wide ◽

A Genome ◽

Genome Wide Data ◽

Candidate Loci ◽

Population Controls

AbstractThe human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on the genetic determinants of malaria resistance in diverse populations.

Download Full-text

Concordance of Genetic Variation that Increases Risk for Tourette Syndrome and that Influences its Underlying Neurocircuitry

10.1101/366294 ◽

2018 ◽

Cited By ~ 2

Author(s):

Mary Mufford ◽

Josh Cheung ◽

Neda Jahanshad ◽

Celia van der Merwe ◽

Linda Ding ◽

...

Keyword(s):

Tourette Syndrome ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Brain Regions ◽

Genetic Variations ◽

Summary Statistics ◽

Brain Volumes ◽

Subcortical Brain ◽

Genome Wide ◽

A Genome

ABSTRACTBACKGROUNDThere have been considerable recent advances in understanding the genetic architecture of Tourette Syndrome (TS) as well as its underlying neurocircuitry. However, the mechanisms by which genetic variations that increase risk for TS - and its main symptom dimensions - influence relevant brain regions are poorly understood. Here we undertook a genome-wide investigation of the overlap between TS genetic risk and genetic influences on the volume of specific subcortical brain structures that have been implicated in TS.METHODSWe obtained summary statistics for the most recent TS genome-wide association study (GWAS) from the TS Psychiatric Genomics Consortium Working Group (4,644 cases and 8,695 controls) and GWAS of subcortical volumes from the ENIGMA consortium (30,717 individuals). We also undertook analyses using GWAS summary statistics of key symptom factors in TS, namely social disinhibition and symmetry behaviour. SNP Effect Concordance Analysis (SECA) was used to examine genetic pleiotropy - the same SNP affecting two traits - and concordance - the agreement in SNP effect directions across these two traits. In addition, a conditional false discovery rate (FDR) analysis was performed, conditioning the TS risk variants on each of the seven subcortical and the intracranial brain volume GWAS. Linkage Disequilibrium Score Regression (LDSR) was used as validation of SECA.RESULTSSECA revealed significant pleiotropy between TS and putaminal (p=2×10−4) and caudal (p=4×10−4) volumes, independent of direction of effect, and significant concordance between TS and lower thalamic volume (p=1×10−3). LDSR lent additional support for the association between TS and thalamic volume (p=5.85×10−2). Furthermore, SECA revealed significant evidence of concordance between the social disinhibition symptom dimension and lower thalamic volume (p=1×10−3), as well as concordance between symmetry behaviour and greater putaminal volume (p=7×10−4). Conditional FDR analysis further revealed novel variants significantly associated with TS (p<8×10−7) when conditioning on intracranial (rs2708146, q=0.046; and rs72853320, q=0.035 and hippocampal (rs1922786, q=0.001 volumes respectively.CONCLUSIONThese data indicate concordance for genetic variations involved in disorder risk and subcortical brain volumes in TS. Further work with larger samples is needed to fully delineate the genetic architecture of these disorders and their underlying neurocircuitry.

Download Full-text