Endophenotype-Informed Association Analyses for Liver Fat Accumulation and Metabolic Dysfunction in the Fels Longitudinal Study

The identification of causal genomic regions for liver fat accumulation in the context of metabolic dysfunction remains a challenging goal. This study aimed to identify potential endophenotypes for liver fat content and employ them in bivariate linkage searches for pleiotropic genetic regions where targeted association analysis is more likely to reveal significant variants. Multiple metabolic risk and adiposity distribution traits were assessed using the endophenotype ranking value. The top-ranked endophenotypes were then used in a bivariate linkage analysis, paired with liver fat content. Quantitative trait loci (QTLs) identified as significant or suggestive were targeted for measured genotype association analyses. The highest-ranked endophenotypes for liver fat accumulation were insulin resistance (IR), visceral adipose tissue (VAT), and high-density lipoprotein cholesterol (HDL-C). The univariate linkage analysis for liver fat content identified one significant QTL at chromosome 17p13.2 (Logarithm of odds score (LOD) = 2.90, <i>p</i> = 1.29 × 10^-4). The bivariate linkage analysis pairing liver fat with IR and VAT improved the localization of two suggestive QTLs at 13q21.31 (LOD = 2.11, <i>p</i> = 9.03 × 10^-4), and 6q21 (LOD = 2.35, <i>p</i> = 5.07 × 10^-4), respectively. Targeted association analyses within the -1-LOD score regions of these QTLs revealed 17 marginally significant single nucleotide polymorphisms (SNPs) associated with liver fat content or its combination with the selected endophenotypes. The endophenotype-informed linkage analysis successfully identified regions suitable for the targeted association analysis of liver fat content, either alone or in combination with IR or VAT, leading to the discovery of marginally significant variants with potential for future functional studies.