Insilico Functional Analysis of Genome-Wide Dataset From 17,000 Individuals Identifies Candidate Malaria Resistance Genes Enriched in Malaria Pathogenic Pathways.
Insilico Functional Analysis of Genome-Wide Dataset From 17,000 Individuals Identifies Candidate Malaria Resistance Genes Enriched in Malaria Pathogenic Pathways.
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DOI：
10.3389/fgene.2021.676960
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发表时间：
2021
影响因子：
3.7
通讯作者：
Chimusa ER
中科院分区：
文献类型：
--
作者：
Damena D;Agamah FE;Kimathi PO;Kabongo NE;Girma H;Choga WT;Golassa L;Chimusa ER
最近对严重疟疾的全基因组关联研究（GWASs）已经确定了几种关联变异。然而，许多潜在的生物学功能尚未被发现。本文通过对疟疾流行地区11个人群的GWAS综合统计（N = 17000）荟萃分析，系统地预测了可能的候选基因和途径。我们应用定位定位、表达数量性状位点（eQTL）、染色质相互作用定位和基于基因的关联分析来鉴定候选的严重疟疾抗性基因。我们进一步对肯尼亚、马拉维和冈比亚三个疟疾流行人群的原始GWAS数据集（N = 11000）进行罕见变异分析，并对三个人群和全球人群中鉴定的基因进行了不同的群体遗传结构分析。我们通过网络和通路分析来研究它们共同的生物学功能。我们的功能定位分析鉴定了57个位于已知疟疾基因组位点的基因，而我们基于基因的GWAS分析鉴定了基因组中另外125个基因。所鉴定的基因在疟疾致病途径中显著富集，包括红细胞相关功能、血液凝固、离子通道、粘附分子、膜信号元件和神经元系统的多个重叠途径。我们的群体遗传分析显示，与全球人群相比，三个疟疾流行人群中所鉴定基因的单核苷酸多态性（snp）的次要等位基因频率（MAF）普遍较高。总之，我们的研究结果表明，严重的疟疾抗性性状归因于多个基因，这突出了利用新的疟疾治疗方法同时靶向多种疟疾保护宿主分子途径的可能性。
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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2.1
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Dudbridge F
通讯作者：
Dudbridge F
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Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
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Snyder M
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