Dataset Information

Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus.

ABSTRACT: Recent genome-wide association studies (GWAS) have identified variants associated with high-density lipoprotein cholesterol (HDL-C) located in or near the ANGPTL8 gene. Given the extensive sharing of GWAS loci across populations, we hypothesized that at least one shared variant at this locus affects HDL-C. The HDL-C-associated variants are coincident with expression quantitative trait loci for ANGPTL8 and DOCK6 in subcutaneous adipose tissue; however, only ANGPTL8 expression levels are associated with HDL-C levels. We identified a 400-bp promoter region of ANGPTL8 and enhancer regions within 5 kb that contribute to regulating expression in liver and adipose. To identify variants functionally responsible for the HDL-C association, we performed fine-mapping analyses and selected 13 candidate variants that overlap putative regulatory regions to test for allelic differences in regulatory function. Of these variants, rs12463177-G increased transcriptional activity (1.5-fold, P = 0.004) and showed differential protein binding. Six additional variants (rs17699089, rs200788077, rs56322906, rs3760782, rs737337, and rs3745683) showed evidence of allelic differences in transcriptional activity and/or protein binding. Taken together, these data suggest a regulatory mechanism at the ANGPTL8 HDL-C GWAS locus involving tissue-selective expression and at least one functional variant.

SUBMITTER: Cannon ME

PROVIDER: S-EPMC5592946 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus.

Cannon Maren E ME Duan Qing Q Wu Ying Y Zeynalzadeh Monica M Xu Zheng Z Kangas Antti J AJ Soininen Pasi P Ala-Korpela Mika M Civelek Mete M Lusis Aldons J AJ Kuusisto Johanna J Collins Francis S FS Boehnke Michael M Tang Hua H Laakso Markku M Li Yun Y Mohlke Karen L KL

G3 (Bethesda, Md.) 20170907 9

Recent genome-wide association studies (GWAS) have identified variants associated with high-density lipoprotein cholesterol (HDL-C) located in or near the ANGPTL8 gene. Given the extensive sharing of GWAS loci across populations, we hypothesized that at least one shared variant at this locus affects HDL-C. The HDL-C-associated variants are coincident with expression quantitative trait loci for ANGPTL8 and DOCK6 in subcutaneous adipose tissue; however, only ANGPTL8 exp ...[more]

PMID: 28754724

Similar Datasets

Project description:Background: The identification of causal variants responsible for disease associations from genome-wide association studies (GWAS) facilitates functional understanding of the disease mechanisms implicated by GWAS. One of the earliest GWAS associations to COPD spans an intragenic region within FAM13A, but the causal variants at this loci have not yet been identified. Massively parallel reporter assays (MPRA) can be used to prioritize functional regulatory variants in a high-throughput manner. Methods: We used an integrated approach using fine-mapping in over 10,000 subjects from COPD GWAS studies, two MPRA experiments, traditional reporter assays, chromatin conformation capture, and CRISPR-based gene editing to characterize COPD-associated regulatory variants in FAM13A in human bronchial epithelial cell lines. Results: Conditional genetic association and fine mapping analyses identified two independent COPD association signals in FAM13A. MPRA identified 45 common functional regulatory variants, and six COPD-associated putative functional variants were prioritized for further functional investigation. Three variants demonstrated significant activity in traditional reporter assays, and one variant, rs2013701, was selected for further testing in the endogenous genomic context based on a direction of effect consistent with postulated mechanisms of FAM13A-mediated COPD susceptibility. CRISPR-based genome editing for this variant confirmed allele-specific effects on FAM13A expression and altered rates of cellular proliferation, providing multiple levels of functional characterization for this COPD-associated variant. Conclusions: Comprehensive screening for regulatory variants near FAM13A identified the presence of extensive functional regulatory variation within a 250kb window of FAM13A in HBECs. Focused functional evaluation of the COPD-associated functional variants in LD with the two independent association signals in this region prioritized the common variant rs2013701, for which multiple parallel lines of functional evidence confirm allelic effects on FAM13A regulation.

Project description:Aims/hypothesisType 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study.MethodsWe conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci.ResultsFour novel associations were identified (p < 5 × 10-9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis.Conclusions/interpretationOur findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations.Data availabilityFull summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics ).

Project description:We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P=1.71 × 10(-34) , OR=1.43[1.26-1.60]) and rs1234317-T (P=1.16 × 10(-28) , OR=1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-?Bp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-?B interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.

Dataset Information

Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus.

Publications

<i>Trans</i>-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the <i>ANGPTL8</i> HDL-C GWAS Locus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets