Personalized genealogical history inferred from biobank-scale IBD segments

Naseri, Ardalan; Tang, Kecong; Geng, Xin; Shi, Junjie; Zhang, Jing; Liu, Xiaoming; Zhang, Shaojie; Zhi, Degui

doi:10.1101/2019.12.19.883108

Cited by 3 publications

(3 citation statements)

References 17 publications

(13 reference statements)

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“…Instead of enumerating all ROH diplotypes, we focused on those that are sufficiently long and frequent. Such ROH diplotypes are of interest because they are at the extreme of distribution: the chance of ROH is determined by the chance of a pair of mates having IBD, and such chance and also the length of IBD segments will decay quickly in outbred populations, as supported by population genetics theory ( Thompson, 2013 ; Donnelly, 1983 ) and real-world data ( Ralph and Coop, 2013 ; Naseri et al, 2019b ). However, little is known about such ROH diplotypes because no existing methods can efficiently find them.…”

Section: Introductionmentioning

confidence: 99%

Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

Naseri,

Zhi,

Zhang

2024

eLife

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Runs of homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE, to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 SNPs and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended HLA region and autoimmune disorders. We found an association between a diplotype covering the HFE gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (P-value=1.82×10-11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.

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Section: Introductionmentioning

confidence: 99%

Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

Naseri,

Zhi,

Zhang

2024

eLife

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“…Ideally, IBD estimates can be obtained from phased haplotypes; this means each diploid individual in the data set is represented by two sequences each of which consists of alleles inherited from a single parent. IBD estimates that are phase aware can improve relationship and pedigree inference (Ramstetter et al 2017, 2018; Williams et al 2020), enable health and trait inheritance to be traced (Browning and Thompson 2012; Lin et al 2013; Vacic et al 2014; Henden et al 2016; Belbin et al 2017; Yang et al 2019; Henden et al 2019; Finke et al 2020), and increase the accuracy of many other inferences regarding demographic history and genetic ancestry (Palamara et al 2012; Ralph and Coop 2013; Palamara and Pe’er 2013; Martin et al 2018; Pathak et al 2018; Browning et al 2018; Naseri et al 2019c).…”

Section: Introductionmentioning

confidence: 99%

Fast and robust identity-by-descent inference with the templated positional Burrows-Wheeler transform

Freyman

McManus

Shringarpure

et al. 2020

Preprint

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Estimating the genomic location and length of identical-by-descent (IBD) segments among individuals is a crucial step in many genetic analyses. However, the exponential growth in the size of biobank and direct-to-consumer (DTC) genetic data sets makes accurate IBD inference a significant computational challenge. Here we present the templated positional Burrows-Wheeler transform (TPBWT) to make fast IBD estimates robust to haplotype and phasing errors. Using haplotype data simulated over pedigrees with realistic genotyping and phasing errors we show that the TPBWT outperforms other state-of-the-art IBD inference algorithms in terms of speed and accuracy. For each phase-aware method, we explore the false positive and false negative rates of inferring IBD by segment length and characterize the types of error commonly found. Additionally we compare the performance of the TPBWT against a widely used phase-free IBD inference approach that is robust to phasing errors. We introduce both in-sample and out-of-sample TPBWT-based IBD inference algorithms and demonstrate their computational efficiency on massive-scale datasets with millions of samples. Furthermore we describe a binary file format for TPBWT-compressed haplotypes that results in fast and efficient out-of-sample IBD computes against very large cohort panels. Finally, we demonstrate the utility of the TPBWT in a brief empirical analysis exploring geographic patterns of haplotype sharing within Mexico. Hierarchical clustering of IBD shared across regions within Mexico reveals the geographic structure of Mexico’s rich genetic diversity. Our software implementation of the TPBWT is freely available in the code repository https://github.com/23andMe/phasedibd.

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“…Instead of enumerating all ROH diplotype, we focused on those that are sufficiently long and frequent. Such ROH diplotypes are of interest because they are at the extreme of distribution: the chance of ROH is determined by the chance of a pair of mates having IBD, and such chance and also the length of IBD segments will decay quickly in outbred populations, as supported by population genetics theory 17,18 and real world data 19,20 . However, little is known about such ROH diplotypes because no existing methods can efficiently find them.…”

Section: Introductionmentioning

confidence: 99%

Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

Naseri

Zhi

Zhang

2020

Preprint

Self Cite

View full text Add to dashboard Cite

Runs of homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE, to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 SNPs and shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended HLA region and autoimmune disorders. We found an association between a diplotype covering the HFE gene and haemochromatosis, even though the well-known causal SNP was not directly genotyped nor imputed. Using genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase of mortality among COVID-19 patients. In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at population scale.

show abstract

Personalized genealogical history inferred from biobank-scale IBD segments

Cited by 3 publications

References 17 publications

Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

Fast and robust identity-by-descent inference with the templated positional Burrows-Wheeler transform

Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

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