242-OR: Single Nuclei Skeletal Muscle Chromatin and Gene Expression Profiling across 287 Individuals Reveals Cell Type-Specific Genetic Regulatory Architectures at T2D GWAS Loci

Abstract

Skeletal muscle is the largest organ, by weight (>40%), in the human body; insulin resistance in this and other peripheral tissues is a hallmark of type 2 diabetes (T2D). Recent genome wide association study (GWAS) results show enrichment for T2D and fasting insulin SNPs in skeletal muscle regulatory regions. Identifying gene regulatory mechanisms underlying these associations requires pinpointing the set of causal variants, the target genes these variants regulate, and the specific skeletal muscle cell populations in which they function. Here, we generated single nuclei chromatin (snATAC) and transcription (snRNA) profiles across 287 frozen human skeletal muscle biopsies. We integrated 414,982 nuclei across the modalities with LIGER and identified 13 cell types, ranging in abundance from 38.1% (type 1 fiber) to <1% (adipocyte) of all nuclei. We further integrated genotypes and performed expression and chromatin accessibility quantitative trait loci (e/caQTL) scans in the five most abundant cell types (type 1, type 2a, type 2x, mesenchymal stem cell, endothelial). We identified >70k associations (5% FDR) ranging from shared to cell type-specific and performed colocalization with T2D GWAS signals. Of 73 T2D GWAS signals that colocalize with caQTL, 39 (53.4%) are cell type-specific, highlighting the importance of sn-caQTL maps for GWAS functional studies. For example, in mesenchymal stem cells, we identified a cell type-specific caQTL for an ARL15 intronic peak (rs702634, p=6.6x10-10), which colocalizes with the T2D GWAS signal (coloc H4 posterior probability = 0.95). To nominate target genes for this caQTL peak, we scanned peaks in promoters of genes in the 1 Mb neighborhood and computed co-accessibility scores using Cicero in an allele-specific manner, which identified the gene FST, ~493 kb away. FST encodes for follistatin which increases muscle growth and reduces fat mass and insulin resistance. Disclosure S. Parker: None. A. Varshney: None. Fusion tissue study: n/a. Amp-t2d skeletal muscle working group: n/a. Funding American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-07 to S.P.); National Institutes of Health (R01DK117960, U01DK06237017, UM1DK126185)