Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland

Abstract

Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.

Towards a fine-scale population health monitoring system

“…This finding is supported by previous work from our group and others demonstrating evidence of founder effects in populations from the Caribbean and Americas 24,37,30 , and reviewed here 38 Overall approximately one quarter of BioMe participants harbor genetic signatures of founder effects, and extrapolating this observation to NYC, we estimate that approximately 15% of New Yorkers can be genetically linked to one or more founder populations. This finding mirrors simi-lar observations of founder effects in large, predominantly European ancestry biobanks in Finland 33 and rural Pennsylvania 40 , where founder effects we found to be ubiquitous in the former and in 22% of the latter cohort. A recent study of a direct-to-consumer genetic database of approximately 770,000 customers across the US also revealed myriad signatures of founder effects which could be attributed to both pre-diaspora population structure and/or post-diaspora isolation, i.e.…”

“…We apply a framework to detect fine-scale population structure by characterizing a network of distant relatedness within patients in the BioMe biobank, and detect 17 distinct communities that are highly correlated with culturally endogamous groups and recent diaspora to New York City from countries around the world. We demonstrate that IBD community detection robustly and stably recapitulates recent patterns of demography in NYC, and similar ideas have been explored in previous work [32][33][34] . By linking to Electronic Health Records and testing for enrichment of health outcomes within uncovered communities, using phenotypes derived from ICD-9 and ICD-10 billing codes, we demonstrate a significant community-specific enrichment of both anticipated and novel health related traits.…”

“…We show that many of the community's exhibit evidence of founder effects, as demonstrated by elevated levels of autozygosity, median within-community IBD sharing, and by applying methods that measure the degree of distance between communities in network topology. This includes canonical founder populations with known historical evidence of founder events, including Ashkenazi Jewish 35 , Finnish 33 and Garifuna populations 35,36 . We also show evidence for the timing and magnitude of founder effects in less characterized H/L founder populations in NYC, namely populations of Puerto Rican, Colombian, Ecuadorian, and Dominican descent.…”

Geographic variation and bias in polygenic scores of complex diseases and traits in Finland

“…It is noteworthy that all phenotypes with Finnish samples included in the GWAS also showed some bias accumulation in our analyses ( Figure 5). Because Finns are considered a genetic isolate (Lappalainen et al 2006;Jakkula et al 2008;Kerminen et al 2017;Martin et al 2018b), we tested whether including a small number of Finnish samples (but not our target individuals) had an effect on geographic distribution of PS. SCZ was the only phenotype in Table 3 where we had access to the original GWAS data.…”

“…Third, the genetic structure in Finland is well-characterized (Lappalainen et al 2006;Jakkula et al 2008;Salmela et al 2008;Neuvonen et al 2015;Kerminen et al 2017;Martin et al 2018b) ( Figure 1), which enables a detailed comparison between the geographic distribution of PS and the overall genetic population structure within the country.…”