Wednesday, May 27, 2009

GWAS and fine mapping in Africans

Genome-wide and fine-resolution association analysis of malaria in West Africa.
Jallow M, Teo YY, Small KS et al.
Nat Genet. 2009 May 24. [Epub ahead of print]
Abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Tuesday, May 12, 2009

Geography and genetics of p53 in E. Asia

Winter Temperature and UV Are Tightly Linked to Genetic Changes in the p53 Tumor Suppressor Pathway in Eastern Asia
Hong Shi,Si-jie Tan,Hua Zhong,Wenwei Hu,Arnold Levine,Chun-jie Xiao,Yi Peng,Xue-bin Qi,Wei-hua Shou,Run-lin Z. Ma,Yi Li,Bing Su, andXin Lu
AJHG Volume 84, Issue 4, 534-541, 02 April 2009

Abstract: The tumor suppressor p53 is a master sensor of stress. Two human-specific polymorphisms, p53 codon 72 and MDM2 SNP309, influence the activities of p53. There is a tight association between cold winter temperature and p53 Arg72 and between low UV intensity and MDM2 SNP309 G/G in a cohort of 4029 individuals across Eastern Asia that suggests causative selection. Moreover, the two polymorphisms are not coselected. Haplotype-based selection analysis further suggests that this is a striking example of two functional polymorphisms being strongly selected for in human populations in response to environmental stresses.
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