A novel locus of resistance to severe malaria in a region of ancient balancing selection

The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum. We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60–0.76, P value = 9.5 × 10−11) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees. Taken together with previous observations on the malaria-protective role of blood group O, these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host–parasite interactions that are critical in determining the outcome of malaria infection.

• Publication year

  2015

• Venue

  Nature

• Publication date

  2015-09-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nature15390PMID 26416757PMCID 4629224
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Strong GWAS signals for severe malaria lie in or close to genes encoding the erythrocyte surface coat, including glycophorins and the region previously associated with blood group O.

  Confidence 0.85

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• The resistance locus is linked to polymorphisms showing features of ancient balancing selection based on haplotype sharing between humans and chimpanzees.

  Confidence 0.93

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• A haplotype at the locus provides 33% protection against severe malaria, with an odds ratio of 0.67.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• A multi-centre genome-wide association study in African children identified a novel malaria resistance locus near glycophorin genes.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

• ancient balancing selection

  evolutionary process

  An evolutionary process that maintains genetic diversity over long time spans.

  Aliases: balancing selection

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• blood group o

  blood group

  The ABO blood-group state lacking A and B antigens on red blood cells.

  Aliases: group O

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• genome-wide association study

  method

  A genome-wide scan for genetic variants associated with a phenotype across a large cohort.

  Aliases: GWAS

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• glycophorin genes

  gene cluster

  A cluster of genes encoding erythrocyte membrane glycoproteins that act as invasion receptors for Plasmodium falciparum.

  Aliases: glycophorins

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• haplotype

  genetic pattern

  A set of genetic variants inherited together at a genomic region.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• malaria resistance locus

  locus

  A genomic region in the human genome associated with resistance to malaria.

  Aliases: novel malaria resistance locus

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• severe malaria

  condition

  Life-threatening Plasmodium falciparum infection used as the disease phenotype in the association analysis.

  Aliases: life-threatening Plasmodium falciparum infection

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

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