Discerning the ancestry of European Americans in genetic association studies

Abstract

European Americans are often treated as a homogeneous group, but in fact form a structured population due to historical immigration of diverse source populations. Discerning the ancestry of European Americans genotyped in association studies is important in order to prevent false-positive or false-negative associations due to population stratification and to identify genetic variants whose contribution to disease risk differs across European ancestries. Here, we investigate empirical patterns of population structure in European Americans, analyzing 4,198 samples from four genome-wide association studies to show that components roughly corresponding to northwest European, southeast European, and Ashkenazi Jewish ancestry are the main sources of European American population structure. Building on this insight, we constructed a panel of 300 validated markers that are highly informative for distinguishing these ancestries. We demonstrate that this panel of markers can be used to correct for stratification in association studies that do not generate dense genotype data.

Identification of susceptibility genes for complex diseases using pooling-based genome-wide association scans

“…These statistical tests were then adjusted for possible population stratiWcation using the genomic control method (Devlin and Roeder 1999). BrieXy, a correction factor was calculated from a total of 100 ancestry informative markers previously described by Price et al (2008). These markers were typed using the SEQUENOM platform as previously described (Al-Shemari et al 2008).…”

Identifying modifier genes of monogenic disease: strategies and difficulties

“…An association between marker M and lung disease severity might then be found, not because marker M is indeed involved but because the subgroup of patients with the mild forms will have an excess number of individuals from center A where allele frequencies at marker M are diVerent. If this example could appear a bit unrealistic, the recent availability of large samples of individuals genotyped for hundreds of thousands of markers has demonstrated that allele frequency diVerences between populations are a concern even within populations previously considered relatively homogeneous (Price et al 2008;SteVens et al 2006).…”

“…New methods are currently being developed to account and correct for population stratiWcation in association studies (Epstein et al 2007;Luca et al 2008;Price et al 2006Price et al , 2008. These methods however have a cost in terms of power and might thus be diYcult to use when searching for modiWer genes.…”

A functional variant in the coding region of CAMTA2 is associated with left ventricular hypertrophy by affecting the activation of Nkx2.5-dependent transcription

“…In the two studies, both cases and controls were from the same city (Xinyang or Hongxinglong, which are not metropolitan cities). Although these strategies were selected to minimize population stratification, we cannot be sure that population stratification was completely ruled out, as the best strategies for ruling out population stratification, such as family-based studies and correction with principal components of ancestry determined using a very dense genotype data set [18,19], were not included in the present study; thus, this represents one of the limitations of the present study. It is also known that false-positive results caused by statistical fluctuation are common in casecontrol studies.…”