Dutch population structure across space, time and GWAS design

Byrne, Ross P.; Rheenen, Wouter van; Berg, Leonard H van den; Veldink, Jan H.; McLaughlin, Russell L.

doi:10.1038/s41467-020-18418-4

Cited by 34 publications

(21 citation statements)

References 43 publications

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“…This still leaves the question of exactly which frequency of variants (or length of IBD segments) to use. The structure in most studies exists on multiple time scales, even in relatively homogeneous populations ( Byrne et al, 2020 ). In such cases, sets of PCs derived from variants in different frequency bins, or from IBD segments of different lengths, may be needed.…”

Section: Discussionmentioning

confidence: 99%

“…Large GWAS in relatively homogeneous populations, such as the UK Biobank (UKB) ( Bycroft et al, 2018 ), should alleviate many of these concerns. However, such populations still exhibit fine-scale population structure ( Leslie et al, 2015 ; Karakachoff et al, 2015 ; Kerminen et al, 2017 ; Haworth et al, 2019 ; Raveane et al, 2019 ; Bycroft et al, 2019 ; Byrne et al, 2020 ). The extent to which this fine structure impacts GWAS inference in practice is largely unknown, and it is not clear whether existing methods adequately correct for it.…”

Section: Introductionmentioning

confidence: 99%

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Demographic history mediates the effect of stratification on polygenic scores

Zaidi

Mathieson

2020

eLife

108

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Population stratification continues to bias the results of genome-wide association studies (GWAS). When these results are used to construct polygenic scores, even subtle biases can cumulatively lead to large errors. To study the effect of residual stratification, we simulated GWAS under realistic models of demographic history. We show that when population structure is recent, it cannot be corrected using principal components of common variants because they are uninformative about recent history. Consequently, polygenic scores are biased in that they recapitulate environmental structure. Principal components calculated from rare variants or identity-by-descent segments can correct this stratification for some types of environmental effects. While family-based studies are immune to stratification, the hybrid approach of ascertaining variants in GWAS but reestimating effect sizes in siblings reduces but does not eliminate stratification. We show that the effect of population stratification depends not only on allele frequencies and environmental structure but also on demographic history.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Demographic history mediates the effect of stratification on polygenic scores

Zaidi

Mathieson

2020

eLife

108

View full text Add to dashboard Cite

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“…SOURCEFIND is a software tool that works directly on the output of the haplotype-based methods ChromoPainter and FineSTRUCTURE[ 9 ]. It has been previously utilized to capture genetic ancestry within Europe [ 12 , 16 , 40 ] and in Latin America[ 18 ]. We have previously shown that ChromoPainter and FineSTRUCTURE work well in our target population[ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Changes in the fine-scale genetic structure of Finland through the 20th century

et al. 2021

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Information about individual-level genetic ancestry is central to population genetics, forensics and genomic medicine. So far, studies have typically considered genetic ancestry on a broad continental level, and there is much less understanding of how more detailed genetic ancestry profiles can be generated and how accurate and reliable they are. Here, we assess these questions by developing a framework for individual-level ancestry estimation within a single European country, Finland, and we apply the framework to track changes in the fine-scale genetic structure throughout the 20th century. We estimate the genetic ancestry for 18,463 individuals from the National FINRISK Study with respect to up to 10 genetically and geographically motivated Finnish reference groups and illustrate the annual changes in the fine-scale genetic structure over the decades from 1920s to 1980s for 12 geographic regions of Finland. We detected major changes after a sudden, internal migration related to World War II from the region of ceded Karelia to the other parts of the country as well as the effect of urbanization starting from the 1950s. We also show that while the level of genetic heterogeneity in general increases towards the present day, its rate of change has considerable differences between the regions. To our knowledge, this is the first study that estimates annual changes in the fine-scale ancestry profiles within a relatively homogeneous European country and demonstrates how such information captures a detailed spatial and temporal history of a population. We provide an interactive website for the general public to examine our results.

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“…We next performed PCA with prcomp function in R base [ 29 ] with the sum of IBD pairwise lengths computed separately using IBD segments with 1–2 cM and 5–7 cM to gain insights on the temporal population structure. To approximate the expected age of the IBD segments in these two bins (1-2 cM; 5-7 cM), we applied the formula described previously by Byrne et al [ 41 ], assuming a generation time of 25 years. Although the length of IBD segments represents wide time distributions, these expected values are point estimates that can be used as a reference.…”

Section: Methodsmentioning

confidence: 99%

The genetic scenario of Mercheros: an under-represented group within the Iberian Peninsula

et al. 2021

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Background The general picture of human genetic variation has been vastly depicted in the last years, yet many populations remain broadly understudied. In this work, we analyze for the first time the Merchero population, a Spanish minority ethnic group that has been scarcely studied and historically persecuted. Mercheros have been roughly characterised by an itinerant history, common traditional occupations, and the usage of their own language. Results Here, we examine the demographic history and genetic scenario of Mercheros, by using genome-wide array data, whole mitochondrial sequences, and Y chromosome STR markers from 25 individuals. These samples have been complemented with a wide-range of present-day populations from Western Eurasia and North Africa. Our results show that the genetic diversity of Mercheros is explained within the context of the Iberian Peninsula, evidencing a modest signal of Roma admixture. In addition, Mercheros present low genetic isolation and intrapopulation heterogeneity. Conclusions This study represents the first genetic characterisation of the Merchero population, depicting their fine-scale ancestry components and genetic scenario within the Iberian Peninsula. Since ethnicity is not only influenced by genetic ancestry but also cultural factors, other studies from multiple disciplines are needed to further explore the Merchero population. As with Mercheros, there is a considerable gap of underrepresented populations and ethnic groups in publicly available genetic data. Thus, we encourage the consideration of more ethnically diverse population panels in human genetic studies, as an attempt to improve the representation of human populations and better reconstruct their fine-scale history.

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Dutch population structure across space, time and GWAS design

Cited by 34 publications

References 43 publications

Demographic history mediates the effect of stratification on polygenic scores

Demographic history mediates the effect of stratification on polygenic scores

Changes in the fine-scale genetic structure of Finland through the 20th century

The genetic scenario of Mercheros: an under-represented group within the Iberian Peninsula

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