The Impact of Divergence Time on the Nature of Population Structure: An Example from Iceland

Alkes L Price,David Reich,Hreinn Stefansson,Snaebjorn Palsson,Ole A Andreassen,Agnar Helgason,Augustine Kong,Kari Stefansson,David St Clair,Gil Mcvean

doi:10.1371/journal.pgen.1000505

Abstract

The Icelandic population has been sampled in many disease association studies, providing a strong motivation to understand the structure of this population and its ramifications for disease gene mapping. Previous work using 40 microsatellites showed that the Icelandic population is relatively homogeneous, but exhibits subtle population structure that can bias disease association statistics. Here, we show that regional geographic ancestries of individuals from Iceland can be distinguished using 292,289 autosomal single-nucleotide polymorphisms (SNPs). We further show that subpopulation differences are due to genetic drift since the settlement of Iceland 1100 years ago, and not to varying contributions from different ancestral populations. A consequence of the recent origin of Icelandic population structure is that allele frequency differences follow a null distribution devoid of outliers, so that the risk of false positive associations due to stratification is minimal. Our results highlight an important distinction between population differences attributable to recent drift and those arising from more ancient divergence, which has implications both for association studies and for efforts to detect natural selection using population differentiation.

Highlights

The Icelandic population has been sampled in many disease association studies [1,2,3,4,5,6,7,8]
The Icelandic population is a structured population, in that geographic regions of Iceland exhibit differences in allele frequencies of genetic markers. These differences are relatively small, previous work has shown that they can bias association statistics in disease studies if cases and controls are sampled in different proportions across the geographic regions
We further show that the allele frequency differences between regions of Iceland are due to genetic drift since the settling of Iceland, not to differences in contributions from ancestral populations

Summary

Introduction

The Icelandic population has been sampled in many disease association studies [1,2,3,4,5,6,7,8]. There is a strong motivation to understand the structure of this population and the ramifications for association studies. A recent study of 40 microsatellite markers showed that the Icelandic population is relatively homogeneous, but that subtle subpopulation differences exist, inflating disease association statistics in simulated case-control studies [9]. The availability of genotype data from a large number of Icelandic samples, based on densely distributed SNPs from all over the genome and collected in the course of genome-wide association studies, makes it possible to investigate Icelandic population structure in greater depth. We analyzed over 30,000 Icelandic samples that were genotyped using the Illumina 300 K chip

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Discussion

Conclusion