Population-specific long-range linkage disequilibrium in the human genome and its influence on identifying common disease variants

Abstract

Despite the availability of large-scale sequencing data, long-range linkage disequilibrium (LRLD) has not been extensively studied. The theoretical aspects of LRLD estimates were studied to determine the best estimation method for the sequencing data of three different populations of African (AFR), European (EUR), and East-Asian (EAS) descent from the 1000 Genomes Project. Genome-wide LRLDs excluding centromeric regions revealed clear population specificity, presenting substantially more population-specific LRLDs than coincident LRLDs. Clear relationships between the functionalities of the regions in LRLDs denoted long-range interactions in the genome. The proportions of gene regions were increased in LRLD variants, and the coding sequence (CDS)-CDS LRLDs showed obvious functional similarities between genes in LRLDs. Application to theoretical case-control associations confirmed that the LRLDs in genome-wide association studies (GWASs) could contribute to false signals, although the impacts might not be severe in most cases. LRLDs with variants with functional similarity exist in the human genome indicating possible gene-gene interactions, and they differ depending on populations. Based on the current study, LRLDs should be examined in GWASs to identify true signals. More importantly, population specificity in LRLDs should be examined in relevant studies.

Haplotype Shuffling and Dimorphic Transposable Elements in the Human Extended Major Histocompatibility Complex Class II Region

“…After the transition into the third millennium and the publication of the analysis of the first human genomic sequence (International Human Genome Sequencing Consortium, 2001;Venter et al, 2001), haplotype studies began to spread in earnest from the continuous analysis of the MHC super locus (Jeffreys et al, 2001;Ahmad et al, 2003;Kauppi et al, 2003;Miretti et al, 2005;Blomhoff et al, 2006) to other regions of the human genome (Daly et al, 2001;Gabriel et al, 2002;Jeffreys et al, 2004;Kauppi et al, 2004;Conrad et al, 2006;The International HapMap Consortium, 2007;Baschal et al, 2012;Browning and Browning, 2020;Nait Saada et al, 2020) and across to other species (Guryev et al, 2006;Kauppi et al, 2007;Villa-Angulo et al, 2009;Ando et al, 2019;Lan et al, 2019). Genomic haplotype blocks are now more commonly described in terms of haplotype estimations using the less structurally precise population linkage disequilibrium (LD) statistics and inferred LD-allelic block analyses (Al Bkhetan et al, 2019;Park, 2019) instead of the more accurately deduced pedigree-defined segments/blocks (Alper and Larsen, 2017). The LD-phased DNA sequences are useful but can generate false information that might be misleading in disease association studies (Slatkin, 2008;Tewhey et al, 2011;Alper and Larsen, 2017;Choi et al, 2018;Al Bkhetan et al, 2019).…”

A sex-specific evolutionary interaction betweenADCY9andCETP

“…Given that the Peruvian population is admixed (26), particular enrichment of genome segments for a specific ancestry, if present, would lead to inflated LRLD between these segments (27)(28)(29)(30).…”

“…LRLD between variants can suggest the existence of gene-gene interactions, especially if they are functional variants (29). In order to be under selection, mutations typically need to modulate a phenotype or an endophenotype, such as gene expression.…”

WeightedLD: The Application of Sequence Weights to Linkage Disequilibrium

“…LD analyses are frequently applied to pairwise variable loci in a multiple sequence alignment (MSA) in order to test for the presence of recombination. Alleles presenting long-range LD can suggest functional similarities of encoding gene products 4 , the presence of population admixtures, epistatic selection, or other selection pressures 5 .…”