Genome-wide association study of self-reported food reactions in Japanese identifies shrimp and peach specific loci in the HLA-DR/DQ gene region
Seik‐Soon KhorRyoko MorinoKazuyuki NakazonoShigeo KamitsujiMasanori AkitaMaiko KawajiriTatsuya YamasakiAzusa KamiYuria HoshiAsami TadaKenichi L. IshikawaMaaya HineMiki KobayashiNami KurumeNaoyuki KamataniKatsushi TokunagaTodd A. Johnson
36
Citation
111
Reference
10
Related Paper
Citation Trend
Abstract:
Food allergy is an increasingly important health problem in the world. Several genome-wide association studies (GWAS) focused on European ancestry samples have identified food allergy-specific loci in the HLA class II region. We conducted GWAS of self-reported reactivity with common foods using the data from 11011 Japanese women and identified shrimp and peach allergy-specific loci in the HLA-DR/DQ gene region tagged by rs74995702 (P = 6.30 × 10-17, OR = 1.91) and rs28359884 (P = 2.3 × 10-12, OR = 1.80), respectively. After HLA imputation using a Japanese population-specific reference, the most strongly associated haplotype was HLA-DRB1*04:05-HLA-DQB1*04:01 for shrimp allergy (P = 3.92 × 10-19, OR = 1.99) and HLA-DRB1*09:01-HLA-DQB1*03:03 for peach allergy (P = 1.15 × 10-7, OR = 1.68). Additionally, both allergies' associated variants were eQTLs for several HLA genes, with HLA-DQA2 the single eQTL gene shared between the two traits. Our study suggests that allergy to certain foods may be related to genetic differences that tag both HLA alleles having particular epitope binding specificities as well as variants modulating expression of particular HLA genes. Investigating this further could increase our understanding of food allergy aetiology and potentially lead to better therapeutic strategies for allergen immunotherapies.Keywords:
Genome-wide Association Study
Genetic Association
Imputation (statistics)
Genome-wide association studies (GWAS) may be biased by population stratification (PS). We conducted empirical quantification of the magnitude of PS among human populations and its impact on GWAS. Liver tissues were collected from 979, 59 and 49 Caucasian Americans (CA), African Americans (AA) and Hispanic Americans (HA), respectively, and genotyped using Illumina650Y (Ilmn650Y) arrays. RNA was also isolated and hybridized to Agilent whole-genome gene expression arrays. We propose a new method (i.e., hgdp-eigen) for detecting PS by projecting genotype vectors for each sample to the eigenvector space defined by the Human Genetic Diversity Panel (HGDP). Further, we conducted GWAS to map expression quantitative trait loci (eQTL) for the approximately 40,000 liver gene expression traits monitored by the Agilent arrays. HGDP-eigen performed similarly to the conventional self-eigen methods in capturing PS. However, leveraging the HGDP offered a significant advantage in revealing the origins, directions and magnitude of PS. Adjusting for eigenvectors had minor impacts on eQTL detection rates in CA. In contrast, for AA and HA, adjustment dramatically reduced association findings. At an FDR = 10%, we identified 65 eQTLs in AA with the unadjusted analysis, but only 18 eQTLs after the eigenvector adjustment. Strikingly, 55 out of the 65 unadjusted AA eQTLs were validated in CA, indicating that the adjustment procedure significantly reduced GWAS power. A number of the 55 AA eQTLs validated in CA overlapped with published disease associated SNPs. For example, rs646776 and rs10903129 have previously been associated with lipid levels and coronary heart disease risk, however, the rs10903129 eQTL was missed in the eigenvector adjusted analysis.
Genome-wide Association Study
Genetic Association
Population stratification
Cite
Citations (14)
Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.
Genome-wide Association Study
Genetic Association
Cite
Citations (114)
The vast majority of genome-wide association studies (GWAS) risk loci fall
in non-coding regions of the genome. One possible hypothesis is that these
GWAS risk loci alter the disease risk through their effect on gene expression
in different tissues. In order to understand the mechanisms driving a GWAS risk
locus, it is helpful to determine which gene is affected in specific tissue types. If the same variant responsible for a GWAS locus also affects gene expression, the relevant gene and tissue may play a role in the disease mechanism. Identifying whether or not the same variant is causal in both GWAS and eQTL studies is challenging due to the uncertainty induced by linkage disequilibrium (LD) and the fact that some loci harbor multiple causal variants. However, current methods that address this problem assume that each locus contains a single causal variant. In this paper, we present a new method, eCAVIAR, that is capable of accounting for LD while computing the quantity we refer to as the colocalization posterior probability (CLPP). The CLPP is the probability that the same variant is responsible for both the GWAS and eQTL signal. eCAVIAR has several key advantages. First, our method can account for more than one causal variant in any loci. Second, it can leverage summary statistics without accessing the individual genotype data. We use both simulated and real datasets to demonstrate the utility of our method. Utilizing data from the
Genotype-Tissue Expression (GTEx) project, we demonstrate that computing CLPP can prioritize likely relevant tissues and target genes for a set of Glucose and Insulin-related traits loci. eCAVIAR is available at http://genetics.cs.ucla.edu/caviar/
Genome-wide Association Study
Linkage Disequilibrium
Genetic Association
Cite
Citations (7)
Genome-wide Association Study
Genetic Association
Cite
Citations (0)
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.
Genome-wide Association Study
Genetic Association
Linkage Disequilibrium
Cite
Citations (53)
Cite
Citations (192)
Expression quantitative trait loci (eQTL), or genetic variants associated with changes in gene expression, have the potential to assist in interpreting results of genome-wide association studies (GWAS). eQTLs also have varying degrees of tissue specificity. By correlating the statistical significance of eQTLs mapped in various tissue types to their odds ratios reported in a large GWAS by the Wellcome Trust Case Control Consortium (WTCCC), we discovered that there is a significant association between diseases studied genetically and their relevant tissues. This suggests that eQTL data sets can be used to determine tissues that play a role in the pathogenesis of a disease, thereby highlighting these tissue types for further post-GWAS functional studies.
Genome-wide Association Study
Genetic Association
Cite
Citations (10)
Summary Recent multi‐stage genome‐wide association studies ( GWAS ) have identified single nucleotide polymorphisms ( SNP s) that are robustly associated with chronic lymphocytic leukaemia ( CLL ) risk. Given that most of these SNP s map to non‐coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci ( eQTL ) data on lymphoblastoid cells lines ( LCLs ) we have globally demonstrated an association between GWAS P ‐values and eQTL s, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNP s for replication, we genotyped rs2072135 ( GWAS P ‐value = 0·0024, eQTL P ‐value = 1·510 −19 ) in five independent case‐control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P ‐value = 1 × 10 −4 ), rs2072135 defines a promising risk locus for CLL . Incorporating eQTL information offers an attractive strategy for selecting SNP s from GWAS for validation.
Genome-wide Association Study
Genetic Association
Cite
Citations (1)
Genome-wide Association Study
Genetic Association
Genetic architecture
Genetic predisposition
Cite
Citations (1)
A meta-analysis of genome-wide association studies (GWAS) with 25,580 cases and 48,466 controls was performed by the International Genomics of Alzheimer's Project (IGAP) consortium that reported over twenty susceptibility loci significantly associated with a risk for developing late-onset Alzheimer's disease (LOAD), out of which 11 were novel. Several of the GWAS identified variants are non-coding; primarily involved in transcriptional regulatory mechanisms and are enriched with expression quantitative trait loci (eQTL) in a tissue-specific manner. Here, we investigate the correlation between identified LOAD susceptibility variants with gene expression eQTLs, using publicly available datasets. We looked for overlap of our known GWAS association signals with eQTL signals. Using the IGAP GWAS data, we selected genome-wide significant variants located in ABCA7, BIN1, CD2AP, CD33, CASS4, CELF2, CLU, CR1, EPHA1, FERMT2, HLA-DRB5/DRB1, INPP5D, MEF2C, MS4A6A, NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1. The APOE locus was excluded from this analysis due to poor coverage by the GWAS platform. eQTL datasets were downloaded from Braineac (http://www.braineac.org), a database consisting of transcript-level and exon-specific expression data from 10 human brain regions from 134 neuropathologically-normal brains from individuals of European descent. We inputted our SNPs of interest into Braineac and extracted its corresponding p-values, which represent the association with gene expression levels, using the MatrixEQTL package in R. The LocusZoom tool was used to generate the LD plots for suggestive and significant eQTLs overlapped with GWAS results. Most of the GWAS identified variants were not significantly associated with gene expression except SNP rs6656401 was found to be a significant gene and exon-level cis-eQTL for CR1 (P = 6.5e-0.7 for ID t2377332 and P=3.7e-07 for ID 2377395) in the white matter (WHMT) region. Also, rs9331896 is a significant exon-level cis-eQTL for CLU (P = 6.0e-07 in average-all for expression ID 3129085). The motivation for our study was to use publically available eQTL data to further investigate the known AD risk loci. This highlights novel avenues and risk genes prioritization for follow-up functional studies to better understand the underlying mechanism associated with disease aetiology at the identified risk loci.
Genome-wide Association Study
Genetic Association
Cite
Citations (0)