Linkage-Disequilibrium-Based Binning Affects the Interpretation of GWASs

Abstract

Genome-wide association studies (GWASs) are critically dependent on detailed knowledge of the pattern of linkage disequilibrium (LD) in the human genome. GWASs generate lists of variants, usually SNPs, ranked according to the significance of their association to a trait. Downstream analyses generally focus on the gene or genes that are physically closest to these SNPs and ignore their LD profile with other SNPs. We have developed a flexible R package (LDsnpR) that efficiently assigns SNPs to genes on the basis of both their physical position and their pairwise LD with other SNPs. We used the positional-binning and LD-based-binning approaches to investigate whether including these "LD-based" SNPs would affect the interpretation of three published GWASs on bipolar affective disorder (BP) and of the imputed versions of two of these GWASs. We show how including LD can be important for interpreting and comparing GWASs. In the published, unimputed GWASs, LD-based binning effectively "recovered" 6.1%-8.3% of Ensembl-defined genes. It altered the ranks of the genes and resulted in nonnegligible differences between the lists of the top 2,000 genes emerging from the two binning approaches. It also improved the overall gene-based concordance between independent BP studies. In the imputed datasets, although the increases in coverage (>0.4%) and rank changes were more modest, even greater concordance between the studies was observed, attesting to the potential of LD-based binning on imputed data as well. Thus, ignoring LD can result in the misinterpretation of the GWAS findings and have an impact on subsequent genetic and functional studies.

RETRACTED: Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…Once SNPs were mapped to gene bins the minimum SNP association P value per gene was extracted, and a gene score was produced using a modified Sidak test as implemented in LDsnpR (92). This method has been shown to successfully control any length bias that may arise from large genes that bear a considerable number of SNPs (90).…”

“…To map individual SNPs to genes and derive a genelevel summary score, we used the LDsnpR package, previously implemented by Ersland et al (26,90). The LDsnpR package was used to assign SNPs to genes using chromosomal position and linkage disequilibrium information from Human Emsembl 66 release and the CEU (Utah residents with ancestry from northern and western Europe) sample from HapMap Phase II.…”

Recently evolved human-specific methylated regions are enriched in schizophrenia signals

“…We used both methods because DMR-localized SNPs that were not genotyped in a specific GWAS would be missed if we used positional binning alone (39) (Supplemental Table S1). The LD file utilized in HDF5 format was constructed on the European reference population of 1KGP and can be publicly downloaded at:…”

“…The DMR SNPs driving the enrichment were determined from QQ plots using the method of Schork et al (29). These SNPs were then mapped to genes using LDsnpR (39 …”

Analysis of Family‐ and Population‐Based Samples Using Multiple Linkage Disequilibrium Mapping

“…It can also be applied to imputed sequence data as long as they are properly imputed (Liang et al, 2001a). Recently, it has been shown that ignoring LD in association analysis can result in the misinterpretation of GWAS findings and have an impact on subsequent genetic and function studies (Christoforou et al, 2012). This disease locus localization method based on LD patterns can ease this concern as well as the concern of multiple testing.…”