Cell-Type Composition Affects Adipose Gene Expression Associations With Cardiometabolic Traits.

Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples with bulk RNA sequencing (RNA-seq) using a reference single-nuclear RNA-seq data set. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower BMI, respectively. We evaluated cell-type proportions and BMI as covariates in tests of association between >25,000 gene expression levels and 22 cardiometabolic traits. For >95% of genes, the optimal, or best-fit, models included BMI as a covariate, and for 79% of associations, the optimal models also included cell type. After adjusting for the optimal covariates, we identified 2,664 significant associations (P ≤ 2e-6) for 1,252 genes and 14 traits. Among genes proposed to affect cardiometabolic traits based on colocalized genome-wide association study and adipose expression quantitative trait locus signals, 25 showed a corresponding association between trait and gene expression levels. Overall, these results suggest the importance of modeling cell-type proportion when identifying gene expression associations with cardiometabolic traits.

Wnt activity reveals context-specific genetic effects on gene regulation in neural progenitors.

Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. TCF/LEF motifs, brain structure-, and neuropsychiatric disorder-associated variants were enriched within Wnt-responsive regulatory elements (REs). Genetically influenced REs were enriched in genomic regions under positive selection along the human lineage. Stimulation of the Wnt pathway increased the detection of genetically influenced REs/genes by 66.2%/52.7%, and led to the identification of 397 REs primed for effects on gene expression. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits.