Genome-wide association study of a lipedema phenotype among women in the UK Biobank identifies multiple genetic risk factors

Abstract

Lipedema is a common disorder characterized by excessive deposition of subcutaneous adipose tissue (SAT) in the legs, hips, and buttocks, mainly occurring in adult women. Although it appears to be heritable, no specific genes have yet been identified. To identify potential genetic risk factors for lipedema, we used bioelectrical impedance analysis and anthropometric data from the UK Biobank to identify women with and without a lipedema phenotype. Specifically, we identified women with both a high percentage of fat in the lower limbs and a relatively small waist, adjusting for hip circumference. We performed a genome-wide association study (GWAS) for this phenotype, and performed multiple sensitivity GWAS. In an independent case/control study of lipedema based on strict clinical criteria, we attempted to replicate our top hits. We identified 18 significant loci (p < 5 × 10^-9), several of which have previously been identified in GWAS of waist-to-hip ratio with larger effects in women. Two loci (VEGFA and GRB14-COBLL1) were significantly associated with lipedema in the independent replication study. Follow-up analyses suggest an enrichment of genes expressed in blood vessels and adipose tissue, among other tissues. Our findings provide a starting point towards better understanding the genetic and physiological basis of lipedema.

Fig. 1. Scatter plot of raw, unadjusted waist circumference and leg fat% measurements of females in the UK Biobank, indicating in green the lipedema phenotype cases.

The horizontal and vertical lines indicate the mean of leg fat% and waist circumference of entire female sample, respectively.

Fig. 2. Manhattan plot of GWAS of the inferred lipedema phenotype from the UK Biobank, at an assumed 10% prevalence.

Loci that were successfully replicated in the ‘UK Lipoedema’ cohort are shown in red. The red horizontal line represents the genome-wide significance p value threshold of 5 × 10⁻⁹.