Amelia C. Joslin, Débora R. Sobreira, Grace T. Hansen, Noboru J. Sakabe, Ivy Aneas et al.
Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.
Amelia C. Joslin, Débora R. Sobreira, Grace T. Hansen, Noboru J. Sakabe, Ivy Aneas, Lindsey E. Montefiori, Kathryn M. Farris, Jing Gu, Donna M. Lehman, Carole Ober, Xin He, Marcelo A. Nóbrega. A functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci. 2021-09-06. https://doi.org/10.1038/s41467-021-25614-3
An episomal pMPRA1 library of 175-bp human genomic sequences centered on 2,396 high-LD BMI GWAS SNPs was tested in SGBS adipocytes at differentiation day 8, with RNA collected on day 10. The table contains the 44 study-level EMVars with at least one reported activity value across two biological libraries and the available technical replicates (two for biological replicate 1 and three for biological replicate 2).
An episomal pMPRA1 library of 175-bp human genomic sequences centered on 2,396 high-LD BMI GWAS SNPs was tested in mouse 3T3-L1 preadipocytes. The table contains the 84 study-level EMVars with at least one reported activity value across two biological libraries and four technical replicates for biological replicate 1 and three technical replicates for biological replicate 2.
An episomal pMPRA1 library of 175-bp human genomic sequences centered on 2,396 high-LD BMI GWAS SNPs was tested in the mouse HT22 hippocampal neuronal cell line. The table contains the 85 study-level EMVars with at least one reported activity value across two biological libraries and the available technical replicates (three for biological replicate 1 and two for biological replicate 2).
An episomal pMPRA1 library of 175-bp human genomic sequences centered on 2,396 high-LD BMI GWAS SNPs was tested in SGBS preadipocytes at differentiation day 0. The table contains the 44 study-level EMVars with at least one reported activity value across two biological libraries and three technical replicates per biological library.
An episomal pMPRA1 library of 175-bp human genomic sequences centered on 2,396 high-LD BMI GWAS SNPs was tested in the mouse GT1-7 hypothalamic GnRH neuronal cell line. The table contains the 68 study-level EMVars with at least one reported activity value across two biological libraries and three technical replicates per biological library.
Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.
Download all 9 files (ZIP)E-MTAB-10463.idf.txtE-MTAB-10463.sdrf.txtMPRA_Barcodes.txt.bz2supplementary_data_1-11.xlsxsupplementary_data_3_candidate_variants.tsvsupplementary_data_4_adipose_mpra_enhancers.tsvsupplementary_data_5_brain_mpra_enhancers.tsvsupplementary_data_6_emvar_activity.tsvsupplementary_information.pdf