Genetic Variants Associated with Complex Human Diseases Show Wide Variation across Multiple Populations

Abstract

Background: The wide use of genome wide association studies (GWAS) has led to the successful identification of multiple genetic susceptibility variants to several complex human diseases. Given the limited amount of data on genetic variation at these loci in populations of non-European origin, we investigated population variation among 11 population groups for loci showing strong and consistent association from GWAS with several complex human diseases. Methods: Data from the International HapMap Project Phase 3, comprising 11 population groups, were used to estimate allele frequencies at loci showing strong and consistent association from GWAS with any of 26 complex human diseases and traits. Allele frequency summary statistics and F_ST at each locus were used to estimate population differentiation. Results: There is wide variation in allele frequencies and F_ST across the 11 population groups for susceptibility loci to these complex human diseases and traits. Allele frequencies varied widely across populations, often by as much as 20- to 40-fold. F_ST, as a measure of population differentiation, also varied widely across the loci studied (for example, 0.019 to 0.201 for type 2 diabetes, 0.022 to 0.520 for prostate cancer loci, and 0.006 to 0.520 for serum lipid levels). Conclusions: The public health risk posed by any of these risk alleles is likely to show wide variation across populations simply as a function of its frequency, and this risk difference may be amplified by gene-gene and gene-environment interactions. These analyses offer compelling reasons for including multiple human populations from different parts of the world in the international effort to use genomic tools to understand disease etiology and differential distribution of diseases across ethnic groups.

Genome-wide scan with nearly 700 000 SNPs in two Sardinian sub-populations suggests some regions as candidate targets for positive selection

“…It is therefore possible to speculate, on the basis of the high differentiation between the two examined samples, that these could have a role in the susceptibility to common complex diseases. 52,53 These results could have a predictive value for incoming association studies focused on multifactorial diseases in the same sub-populations.…”

“…52 In fact, examination of allele frequencies in 11 HapMap phase III populations has demonstrated high levels of variation for the markers already associated with complex diseases and traits in genome-wide scans. 53 It is then plausible that a similar phenomenon could occur also in a limited geographical area such as Sardinia, especially according to the heterogeneity found among its examined groups.…”

Estimating the contribution of genetic variants to difference in incidence of disease between population groups

“…Most of these GWAS have been conducted in populations of European ancestry. 3 Allele frequencies at loci showing strong and consistent association from GWAS with any of five common complex human conditions -type 2 diabetes, obesity, Crohn's disease, prostate cancer and breast cancer have shown wide variation across the 11 populations in the phase III of the International HapMap Project. 3 Another study of 25 single-nucleotide polymorphisms (SNPs), which show robust GWAS-derived associations with six complex human diseases (Crohn's disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, coronary artery disease and obesity) using individuals from 53 populations worldwide resulted in substantial variation in risk allele frequencies among populations.…”

The pursuit of genome-wide association studies: where are we now?

“…In fact, one study has shown a wide variation in allele frequencies across different populations for the SNPs identified by GWAS for several complex diseases and traits. 141 A new risk allele for breast cancer was also identified by a GWAS carried out in a Chinese population and this was replicated in women of European ancestry. As in the T2D case, the risk allele has gone undetected by several European GWAS of breast cancer.…”