Genetic correlations between liver fat content, metabolic health, and adiposity distribution in the Fels Longitudinal Study

Background and aims: Hepatic steatosis is known to be heritable, but its genetic basis is mostly uncharacterized. Steatosis is associated with metabolic and adiposity features; recent studies hypothesize that shared genetic effects between these traits could account for some of the unexplained heritability. This study aimed to quantify these genetic associations in a family-based sample of non-Hispanic white adults. Methods and results: 704 participants (18-95 years, 55.8% female) from the Fels Longitudinal Study with an MRI assessment of liver fat were included. Quantitative genetic analyses estimated the age- and sex-adjusted heritability of individual traits and the genetic correlations within trait pairs. Mean liver fat was 5.95% (SE = 0.23) and steatosis (liver fat >5.56%) was present in 29.8% of participants. Heritability (h(2)+/- SE) of steatosis was 0.72 +/- 0.17 (p = 6.80e(-6)). All other traits including liver enzymes, fasting glucose, HOMA-IR, visceral and subcutaneous adipose tissue (VAT, SAT), body mass index, body fat percent, waist circumference, lipids and blood pressure were also heritable. Significant genetic correlations were found between liver fat and all traits except aspartate aminotransferase (AST), and among most trait pairs. Highest genetic correlations were between liver fat and HOMA-IR (0.85 +/- 0.08, p = 1.73e(-8)), fasting glucose and ALT (0.89 +/- 0.26, p = 6.68e(-5)), and HOMA-IR with: waist circumference (0.81 +/- 0.12, p = 3.76e(-6)), body fat percent (0.78 +/- 0.12 p = 2.42e(-5)) and VAT (0.73 +/- 0.07, p = 6.37e(-8)). Conclusions: Common genes may exist between liver fat accumulation, metabolic features and adiposity phenotypes. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).