The Genome-wide Patterns of Variation Expose Significant Substructure in a Founder Population

Department of Molecular Medicine, National Public Health Institute and Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2009; 83(6):787-94. DOI: 10.1016/j.ajhg.2008.11.005
Source: PubMed


Although high-density SNP genotyping platforms generate a momentum for detailed genome-wide association (GWA) studies, an offshoot is a new insight into population genetics. Here, we present an example in one of the best-known founder populations by scrutinizing ten distinct Finnish early- and late-settlement subpopulations. By determining genetic distances, homozygosity, and patterns of linkage disequilibrium, we demonstrate that population substructure, and even individual ancestry, is detectable at a very high resolution and supports the concept of multiple historical bottlenecks resulting from consecutive founder effects. Given that genetic studies are currently aiming at identifying smaller and smaller genetic effects, recognizing and controlling for population substructure even at this fine level becomes imperative to avoid confounding and spurious associations. This study provides an example of the power of GWA data sets to demonstrate stratification caused by population history even within a seemingly homogeneous population, like the Finns. Further, the results provide interesting lessons concerning the impact of population history on the genome landscape of humans, as well as approaches to identify rare variants enriched in these subpopulations.

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    • "The location of recombination hotspots and the length of LD blocks (genomic fragments inherited together) are population specific [1], [4], [5]. Interestingly, it has been shown that the Finnish population has distinctive population substructure compared with other Europeans [6]–[8]. "
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    ABSTRACT: The Major Histocompatibility Complex (MHC, 6p21) codes for traditional HLA and other host response related genes. The polymorphic HLA-DRB1 gene in MHC Class II has been associated with several complex diseases. In this study we focus on MHC haplotype structures in the Finnish population. We explore the variability of extended HLA-DRB1 haplotypes in relation to the other traditional HLA genes and a selected group of MHC class III genes. A total of 150 healthy Finnish individuals were included in the study. Subjects were genotyped for HLA alleles (HLA-A, -B, -DRB1, -DQB1, and -DPB1). The polymorphism of TNF, LTA, C4, BTNL2 and HLA-DRA genes was studied with 74 SNPs (single nucleotide polymorphism). The C4A and C4B gene copy numbers and a 2-bp silencing insertion at exon 29 in C4A gene were analysed with quantitative genomic realtime-PCR. The allele frequencies for each locus were calculated and haplotypes were constructed using both the traditional HLA alleles and SNP blocks. The most frequent Finnish A∼B∼DR -haplotype, uncommon in elsewhere in Europe, was A*03∼B*35∼DRB1*01∶01. The second most common haplotype was a common European ancestral haplotype AH 8.1 (A*01∼B*08∼DRB1*03∶01). Extended haplotypes containing HLA-B, TNF block, C4 and HLA-DPB1 strongly increased the number of HLA-DRB1 haplotypes showing variability in the extended HLA-DRB1 haplotype structures. On the contrary, BTNL2 block and HLA-DQB1 were more conserved showing linkage with the HLA-DRB1 alleles. We show that the use of HLA-DRB1 haplotypes rather than single HLA-DRB1 alleles is advantageous when studying the polymorphisms and LD patters of the MHC region. For disease association studies the HLA-DRB1 haplotypes with various MHC markers allows us to cluster haplotypes with functionally important gene variants such as C4 deficiency and cytokines TNF and LTA, and provides hypotheses for further assessment. Our study corroborates the importance of studying population-specific MHC haplotypes.
    PLoS ONE 11/2013; 8(11):e79690. DOI:10.1371/journal.pone.0079690 · 3.23 Impact Factor
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    • "Due to the relative historic isolation, the Finnish population bears characteristics of a founder population with the potential of reduced genetic heterogeneity [28]. However, the risk of population stratification brought about by inclusion of the Eastern Finland case cohort exists [28]. One weakness of our study is that it combines three retrospectively collected data sets in which the extent of coded information available varies. "
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    ABSTRACT: Pre-eclampsia/eclampsia is a common vascular pregnancy disorder associated with high maternal and infant mortality and morbidity worldwide. The role of Activin A and more recently type 2 Activin A receptor (ACVR2A) in the pathogenesis of pre-eclampsia has been the subject of genetic and biochemical research with controversial results. We genotyped a candidate pre-eclampsia-associated single nucleotide polymorphism rs1424954 in ACVR2A in three independent study populations of Finnish pre-eclamptic (total N = 485) and non-pre-eclamptic (total N = 449) women using pre-designed TaqMan allele discrimination assay and polymerase chain reaction. The possible association of the alleles and genotypes of interest with pre-eclampsia was evaluated using the chi-square test and logistic regression analysis. We found no association of rs1424954 to pre-eclampsia in Finnish patients. rs1424954 was not associated to pre-eclampsia in the Finnish study population. We hypothesise that while the gene associates to pre-eclampsia worldwide, the causative polymorphism in ACVR2A may be unique in genetically differing populations. Further research is needed to characterise the haplotype structure of ACVR2A in order for the causative genetic variant to be identified.
    BMC Research Notes 12/2011; 4(1):545. DOI:10.1186/1756-0500-4-545
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    • "These assumptions hold to a large extent in many well-studied populations and sample sets, such as 120 ''Utah residents with ancestry from northern and western Europe'' [Frazer et al., 2007] or 3,000 people ''born in England, Wales or Scotland'' [The Wellcome Trust Case Control Consortium, 2007]. In contrast, these assumptions are not met when a large enough proportion of the population has been genotyped, as is increasingly the case for isolated founder populations such as Iceland [Kong et al., 2008] or Finland [Jakkula et al., 2008]. As attention shifts back from common to rare variants [Manolio et al., 2009] isolates with founder effects have revived potential for genetic research, because rare variants can more readily drift to higher frequencies hence facilitating phenotype mapping [Holm et al., 2011; Kenny et al., 2009]. "
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