From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus

By K. Musunuru, A. Strong, M. Frank-Kamenetsky, Noemi E. Lee, Tim Ahfeldt, Katherine V Sachs, Xiaoyu Li, Hui Li, N. Kuperwasser, V. Ruda and 20 more. Nature, 2010

1,164 citations recorded by the source corpus.

Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1d5c040f478c05408ab23626c4226aa190fbda6e

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Citations in the corpus

Histone H3K27ac separates active from poised enhancers and predicts developmental state (2010, background): “Finally, genome-wide association studies have identified diseaseassociated polymorphisms that reside outside of coding regions (31).”
Beyond GWASs: illuminating the dark road from association to function. (2013, background): “For example, the likely causal variant for a GWAS association at 1p13 with low-density lipoprotein cholesterol is rs12740374, which lies in a transcriptional enhancer and alters the activity by creating a C/EBP TF-binding site.(4) On the basis of the strong correlation with expression in the liver, ”
Rare and Common Variants: Twenty arguments (2011, background): “82 ), and in some cases these have been confirmed by in vitro biochemical assays for structural and regulatory effects (for example, Ref”
Systems genetics approaches to understand complex traits (2013, background): “Although the genes at each locus can be individually tested either in cell cultures or in animal models and their mechanistic effect on the clinical trait defined using classical molecular biology approaches 1 , this strategy will clearly be challenging.”
Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics (2016, methodology): “SORT1 is a gene with strong evidence for a causal role in LDL-C levels, and as a consequence, is likely to affect risk for cardiovascular disease [33].”
Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants (2013, background): “Additionally, we demonstrate that three of three SNPs previously shown to alter long-range enhancer function [rs12740374/ SORT1 (18) and rs6983267/MYC (19, 20)] or to reside in a longrange contact point [rs7578326/IRS1 (21)] overlap a stretch enhancer specifically in the relevant cell type(s) (SI Ap”
Activity-by-Contact model of enhancer-promoter regulation from thousands of CRISPR perturbations (2019, methodology): “Observed DE-G connections (solid red arcs) are from previous experiments in which CRISPR was used to introduce indels near rs12740374 in primary hepatocytes 33 and an eQTL study in human liver 34 .”
Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data (2011, positive): “55 ), this supports the hypothesis that most weak-effect causal variants are non-coding.”