Abstract
Previous genetic studies have identified local population structure within the Netherlands; however their resolution is limited by use of unlinked markers and absence of external reference data. Here we apply advanced haplotype sharing methods (ChromoPainter/fineSTRUCTURE) to study fine-grained population genetic structure and demographic change across the Netherlands using genome-wide single nucleotide polymorphism data (1,626 individuals) with associated geography (1,422 individuals). We identify 40 haplotypic clusters exhibiting strong north/south variation and fine-scale differentiation within provinces. Clustering is tied to country-wide ancestry gradients from neighbouring lands and to locally restricted gene flow across major Dutch rivers. North-south structure is temporally stable, with west-east differentiation more transient, potentially influenced by migrations during the middle ages. Despite superexponential population growth, regional demographic estimates reveal population crashes contemporaneous with the Black Death. Within Dutch and international data, GWAS incorporating fine-grained haplotypic covariates are less confounded than standard methods.
Highlights
Previous genetic studies have identified local population structure within the Netherlands; their resolution is limited by use of unlinked markers and absence of external reference data
These observations suggest that the demographic past of the Dutch population has left residual signatures in its present regional genetic structure; this has not been fully explained in the context of neighbouring populations and far the use of unlinked genetic markers have limited the resolution at which this structure can be described
Clusters at this level were robustly defined by total variation distance (TVD; p < 0.001) and fixation index (FST; Fig. 1a); remarkably, some FST values between differentiated Dutch clusters were comparable in magnitude to estimates between European countries
Summary
Previous genetic studies have identified local population structure within the Netherlands; their resolution is limited by use of unlinked markers and absence of external reference data. Despite its small geographical size, previous genetic studies of the people of the Netherlands have demonstrated coarse population structure that correlates with its geography, as well as apparent heterogeneity in effective population sizes across provinces[1,2] These observations suggest that the demographic past of the Dutch population has left residual signatures in its present regional genetic structure; this has not been fully explained in the context of neighbouring populations and far the use of unlinked genetic markers have limited the resolution at which this structure can be described. We show that the complex genetic structure observed demonstrably confounds GWAS; through analysis of the Netherlands and more extensive international data[19], we demonstrate that using shared haplotypes as GWAS covariates significantly reduces this confounding over standard single-marker methods
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