Abstract
BackgroundIt is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8.ResultsAlthough the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates.ConclusionThe "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology.
Highlights
It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification
The amount of Linkage disequilibrium (LD) was found to be much smaller in Sub-Saharan Africa than in any other continental region; and, in accordance with their demographic histories, Oceania and America displayed greater LD at longer distances
Under these conditions, the single nucleotide polymorphism (SNP) that would be needed to be typed are just slightly less in isolates. It is increasingly being recognized, and we provide empirical results to that effect, that the value of isolated populations in genetic epidemiology lies not in their higher LD brought about by a presumably reduced Ne, but due to other characteristics such as large and accessible families, deep genealogical records or a low environmental variance. We have explored both the levels and decay of LD with physical distance along 211 gene regions mostly related to complex disease across 39 worldwide human populations
Summary
It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, in isolated populations where it is assumed to be higher. We explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing on the populations defined as isolates. The extent of LD in non-Africans is higher than in Africans [10,11,12], reflecting the origin and spread of modern humans from Africa, the difference in LD between Africans and non-Africans varies greatly across loci, with examples in which it is similar or even more pronounced in Africans [13]
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