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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.

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

Data availability

The data that supports the findings of this study are available from the UK Biobank, but restrictions apply to the availability of these data, which were used under an agreement for the current study. Summary statistics from the main UK Biobank GWAS conducted in this study will be made available in the GWAS Catalog upon publication. The data from the UK Lipoedema study used here as a replication dataset are not currently publically available, but will be made publically available as part of a publication in PLoS One [25].

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Acknowledgements

This research was conducted using the UK Biobank Resource under Application Number 15678. We thank the participants and organizers of the UK Biobank. LDHUB Acknowledgements: We gratefully acknowledge all the studies and databases that made GWAS summary data available: ADIPOGen (Adiponectin genetics consortium), C4D (Coronary Artery Disease Genetics Consortium), CARDIoGRAM (Coronary ARtery DIsease Genome-wide Replication and Meta-analysis), CKDGen (Chronic Kidney Disease Genetics consortium), dbGAP (database of Genotypes and Phenotypes), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis), EAGLE (EArly Genetics & Lifecourse Epidemiology Eczema Consortium, excluding 23andMe), EGG (Early Growth Genetics Consortium), GABRIEL (A Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community), GCAN (Genetic Consortium for Anorexia Nervosa), GEFOS (GEnetic Factors for OSteoporosis Consortium), GIANT (Genetic Investigation of ANthropometric Traits), GIS (Genetics of Iron Status consortium), GLGC (Global Lipids Genetics Consortium), GPC (Genetics of Personality Consortium), GUGC (Global Urate and Gout consortium), HaemGen (haemotological and platelet traits genetics consortium), HRgene (Heart Rate consortium), IIBDGC (International Inflammatory Bowel Disease Genetics Consortium), ILCCO (International Lung Cancer Consortium), IMSGC (International Multiple Sclerosis Genetic Consortium), MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium), MESA (Multi-Ethnic Study of Atherosclerosis), PGC (Psychiatric Genomics Consortium), Project MinE consortium, ReproGen (Reproductive Genetics Consortium), SSGAC (Social Science Genetics Association Consortium) and TAG (Tobacco and Genetics Consortium), TRICL (Transdisciplinary Research in Cancer of the Lung consortium), UK Biobank. We gratefully acknowledge the contributions of Alkes Price (the systemic lupus erythematosus GWAS and primary biliary cirrhosis GWAS) and Johannes Kettunen (lipids metabolites GWAS).

Funding

YCK and PO would like to acknowledge support from a Lipedema Foundation Proof of Concept Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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YCK, PO, KLH, and ZC designed the studies. YCK and PO provided access to data. YCK, DG, MLGG, ES, and AP performed data analyses. YCK drafted paper. All authors contributed to paper revision, read and approved the submitted version.

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Correspondence to Yann C. Klimentidis.

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Klimentidis, Y.C., Chen, Z., Gonzalez-Garay, M.L. et al. Genome-wide association study of a lipedema phenotype among women in the UK Biobank identifies multiple genetic risk factors. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01231-6

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