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An Icelandic example of the impact of population structure on association studies


The impact of population structure on association studies undertaken to identify genetic variants underlying common human diseases is an issue of growing interest1,2,3,4. Spurious associations of alleles with disease phenotypes may be obtained or true associations overlooked when allele frequencies differ notably among subpopulations that are not represented equally among cases and controls. Population structure influences even carefully designed studies and can affect the validity of association results1,2. Most study designs address this problem by sampling cases and controls from groups that share the same nationality or self-reported ethnic background, with the implicit assumption that no substructure exists within such groups. We examined population structure in the Icelandic gene pool using extensive genealogical and genetic data. Our results indicate that sampling strategies need to take account of substructure even in a relatively homogenous5 genetic isolate6. This will probably be even more important in larger populations.

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Figure 1: The distribution of geographic ancestry in three cohorts of Icelanders.
Figure 2: Partitioning the total variance in geographic ancestry.
Figure 3: The effect of stratification on association studies as measured by the genomic control λ statistic in the three cohorts of genotyped individuals: (a) 1895–1935, (b) 1940–1955 and (c) 1960–2000.

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We thank P. Donnelly and D. Altshuler for comments on a previous version of this paper.

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Correspondence to Agnar Helgason.

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A.H., J.G. and K.S. have stocks or equity interests in deCODE Genetics.

Supplementary information

Supplementary Fig. 1

Genetic divergence measured by the c parameter among 11 subpopulations for three cohorts of genotypes. (PDF 268 kb)

Supplementary Table 1

Descriptive statistics for the 40 microsatellite loci used in the genetic analyses of population structure. (PDF 46 kb)

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Helgason, A., Yngvadóttir, B., Hrafnkelsson, B. et al. An Icelandic example of the impact of population structure on association studies. Nat Genet 37, 90–95 (2005).

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