Identity-by-descent detection across 487,409 British samples reveals fine-scale population structure, evolutionary history, and trait associations

Abstract

1Detection of Identical-By-Descent (IBD) segments provides a fundamental measure of genetic relatedness and plays a key 2 role in a wide range of genomic analyses. We developed a new method, called FastSMC, that enables accurate biobank-3 scale detection of IBD segments transmitted by common ancestors living up to several hundreds of generations in the past. 4 FastSMC combines a fast heuristic search for IBD segments with accurate coalescent-based likelihood calculations and enables 5 estimating the age of common ancestors transmitting IBD regions. We applied FastSMC to 487,409 phased samples from the 6 UK Biobank and detected the presence of ∼214 billion IBD segments transmitted by shared ancestors within the past 1, 500 7 years. We quantified time-dependent shared ancestry within and across 120 postcodes, obtaining a fine-grained picture of 8 genetic relatedness within the past two millennia in the UK. Sharing of common ancestors strongly correlates with geographic 9 distance, enabling the localization of a sample's birth coordinates from genomic data. We sought evidence of recent positive 10 selection by identifying loci with unusually strong shared ancestry within recent millennia and we detected 12 genome-wide 11 significant signals, including 7 novel loci. We found IBD sharing to be highly predictive of the sharing of ultra-rare variants in 12 exome sequencing samples from the UK Biobank. Focusing on loss-of-function variation discovered using exome sequencing, 13 we devised an IBD-based association test and detected 29 associations with 7 blood-related traits, 20 of which were not detected 14 in the exome sequencing study. These results underscore the importance of modelling distant relatedness to reveal subtle 15 population structure, recent evolutionary history, and rare pathogenic variation. 16 Introduction 17Large-scale genomic collection, through efforts like the NIH All of Us research program (1), the UK BioBank (2), and Ge-18 nomics England (3), has yielded datasets of hundreds of thousands of individuals and is expected to grow to millions in the 19 coming years. Utilizing such datasets to understand disease and health outcomes requires understanding the fine-scale genetic 20 relationships between individuals. These relationships can be characterized using short segments (less than 10 centimorgans 21[cM] in length) that are inherited identical by descent (IBD) from a common ancestor between purportedly "unrelated" pairs of 22 individuals in a dataset (4). Accurate detection of shared IBD segments has a number of downstream applications, which include 23 reconstructing the fine-scale demographic history of a population (5-8), detecting signatures of recent adaptation (9, 10), dis-24 covering phenotypic association (11, 12), estimating haplotype phase (4, 13, 14), and imputing missing genotype data (15, 16), 25 a key step in genome-wide association studies (GWAS) (17). Detection of IBD segments in millions of individuals within 26 modern biobanks poses a number of computational challenges. A...

Demographic history mediates the effect of stratification on polygenic scores

“…In such cases, PCA based on rare variants, which are more informative about recent population history ( Gravel et al, 2011 ; Fu et al, 2013 ; O'Connor et al, 2013 ; O'Connor et al, 2015 ; Mathieson and McVean, 2015 ), would be more effective. Haplotype sharing ( Lawson et al, 2012 ) or identity-by-descent (IBD) segments are similarly informative about recent history ( Palamara et al, 2012 ; Ralph and Coop, 2013 ; Saada et al, 2020 ), and provide an alternative to rare variant PCA when sequence data are not available, or when there are relatively few rare variants to adequately capture the structure, for example in exome sequence data.…”

Patterns of genetic connectedness between modern and medieval Estonian genomes reveal the origins of a major ancestry component of the Finnish population

“…10 In parallel, fast methods for IBD estimation from tens to hundreds of thousands of individuals have been recently developed for phased [11][12][13][14] and unphased 15,16 genomic data along with scalable clustering methods for the detection of fine-scale community structure. 17,18 Late Bronze and Early Iron Age migrations have been argued to be responsible for the spread of Finnic languages together with a minor Siberian genetic component (Figure 1D) in the circum-Baltic region; 19,20,21 however, it has been less clear how much gene flow and contact over the Gulf of Finland has occurred in the last 2,000 years (Figures 1E and 1F). Linguistic studies have suggested that the differentiation of the Finnic from Finno-Volgaic languages dates back to 3,000-4,000 years ago.…”

Fine-scale population structure and demographic history of British Pakistanis

“…Larger sample sizes and data on Mendelian disease diagnoses (as opposed to proxy estimates of risk) will be needed to quantify the risk of recessive disorders for offspring of intra-versus inter-biraderi marriages accurately, noting that our results imply that this differs between biraderi, and that certain disorders may be enriched in particular biraderi as a result of founder effects. Furthermore, future studies of disease genetics in Pakistanis should consider our findings in order to best control for population stratification due to recent structure in genome-wide association studies 16 and potentially to increase power by exploiting the IBD within some groups as a proxy for rare variant sharing 84 .…”