# NAFLD and Hypothyroidism: Deciphering Pivotal Genetic Variants, Cellular Expression Landscapes, and Spatial Architectures

## TL;DR

This study explores the genetic and cellular connections between NAFLD and hypothyroidism, identifying key genes and liver-specific patterns.

## Contribution

The study introduces a spatiotemporal two-hit model and identifies novel genetic variants and cell-specific mechanisms linking NAFLD and hypothyroidism.

## Key findings

- Genetic risk for NAFLD and hypothyroidism shows spatial specificity in the liver.
- Hepatocytes are identified as the primary shared cell type affected in both conditions.
- MAGI3, RRNAD1, PRCC, and rs926103 are highlighted as key genes and loci.

## Abstract

Thyroid hormones profoundly modulate hepatic fatty acid and cholesterol synthesis and turnover. Although nonalcoholic fatty liver disease (NAFLD) shows epidemiological links to hypothyroidism, the genetic substrates of this relationship remain unresolved. Integrating large-scale genome-wide association studies with single-cell transcriptomics, spatial transcriptomics, and single-cell chromatin accessibility via state-of-the-art computational approaches, we interrogated the association between NAFLD and hypothyroidism across organ systems, cellular expression landscapes, and molecular–genetic strata. We uncovered pronounced spatial specificity in genetic risk within the liver, prioritized hepatocytes as the principal shared cell type affected, and, leveraging spatial transcriptomics, advanced a dynamic spatiotemporal two-hit model. We further nominated MAGI3, RRNAD1, and PRCC as high-confidence candidate genes and pinpointed a key risk locus, rs926103. These findings deliver a dynamic, testable framework for the full pathophysiological continuum linking NAFLD and hypothyroidism and yield new targets and leads for precision intervention.