Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium.

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

Physical function and its response to exercise: associations with cytokine gene variation in older adults with knee osteoarthritis.

BACKGROUND: We determined whether physical function and its response to exercise training are associated with polymorphisms in cytokine genes (interleukin-6 [IL-6] -174 G/C; tumor necrosis factor alpha [TNFalpha] -308 G/A and -238 G/A; and TNFalpha receptors [TNFR]1 +36 A/G, TNFR2 +676 T/G, and TNFR2 +1663 A/G), in 214 older (> or =60 years), overweight (body mass index > or =28 kg/m(2)) individuals with knee osteoarthritis. METHODS: Physical function (walking distance, stair-climb time, self-reported disability) was measured before and after an 18-month randomized, controlled exercise trial involving walking and weight lifting 3 days/week. RESULTS: In cross-sectional analyses, baseline walking distance was greater in individuals homozygous for the major G allele at IL-6 -174 compared to individuals with at least one C allele (p = .05). Both walking distance (p =.02) and stair-climb time (p = .003) were better in individuals homozygous for the major G allele of the TNFalpha -308 polymorphism compared to those with at least one A allele. Walking distance was better (p = .02), and stair-climb time tended to be better (p = .06), in individuals homozygous for the major T allele of the TNFR2 +676 polymorphism. No associations were seen with self-reported physical disability nor with the other polymorphisms. In response to exercise, there was a significant interaction between TNFalpha -308 genotype and exercise treatment on 6-month changes in stair-climb time (p = .007), and on 18-month changes in self-reported physical disability (p = .01), such that individuals with an A allele showed greater improvement in response to exercise. CONCLUSIONS: Walking distance and stair climbing speed are partly influenced by genetic variation in the IL-6 and TNFalpha genes in older individuals with knee osteoarthritis.