A meta-analysis of clinically ascertained lipoedema cohorts from the UK and Spain identifies overlapping susceptibility loci with the UK Biobank

Abstract Lipoedema is a chronic adipose tissue disorder mainly affecting women with excess subcutaneous fat deposition on the lower limbs, associated with pain and tenderness. There is often a family history of lipoedema, suggesting a genetic origin, but the contribution of genetics is not well studied. We conducted a genome-wide association study (GWAS) for this disorder in a clinically ascertained cohort from Spain and performed a meta-analysis with the UK lipoedema cohort GWAS. We then used the results of this study as a replication of the inferred UK Biobank “lipoedema phenotype” study. Whilst our meta-analysis alone did not identify any genome-wide significant associations, our clinical cohorts provide support for three loci identified through the UKBB study: the chr2q24.3 GRB14-COBLL1 locus (rs6753142, P META =1.64x10 -6 ), chr6p21.1 VEGFA locus (rs4711750, P META =8.99x10 -7 ) and the chr5q11.2 ANKRD55-MAP3K1 locus (rs3936510, P META =1.67x10 -5 ). We identify numerous rare SNPs with strong association signals in our meta-analysis ( P <1x10 -6 ) with support in both UK and Spanish datasets, three of which also show nominal support in the UKBB ( P <0.05). These findings provide a starting point towards understanding the genetic basis of clinical lipoedema and demonstrate the utility of the interplay of large-scale biobanks genetic data and clinically ascertained cohorts to elucidate the genetic architecture of lipoedema.