Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
复制标题
DOI：
10.1038/s41467-019-13480-z
复制
发表时间：
2019-12-16
影响因子：
16.6
通讯作者：
Kwiatkowski, Dominic P.
中科院分区：
文献类型：
--
作者：
Band, Gavin;Le, Quang Si;Kwiatkowski, Dominic P.
影响对传染病抵抗力的人类遗传因素知之甚少。在这里，我们报告了一项全基因组关联研究，研究对象是来自11个国家的17,000例严重疟疾病例和人口控制，通过对家庭三人组进行测序，并通过对另外15,000个样本中的候选基因进行直接分型而获得的信息。我们根据全基因组水平的证据确定了五个可复制的关联，其中包括6号染色体上新发现的一个变异。这些变异加在一起，约占严重疟疾遗传力的十分之一，使用全基因组基因型别，我们估计遗传率为-23%。我们询问了现有的功能数据，发现了ATP2B4中已知关联的红系特异性转录起始点，但无法确定6号染色体上可能的因果机制。此前报道的人类白细胞抗原相关性在这些样本中不会复制。这一大型数据集将为进一步研究不同人群中疟疾耐药性的遗传决定因素提供基础。
The 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 thegenetic determinants of malaria resistance in diverse populations.