Genome-Wide Association Study of Diabetogenic Adipose Morphology in the GENetics of Adipocyte Lipolysis (GENiAL) Cohort

• Main Authors: Veroniqa Lundbäck, Agné Kulyté, Peter Arner, Rona J. Strawbridge, Ingrid Dahlman
• Format: Article
• Language: English
• Published: MDPI AG 2020-04-01
• Series: Cells
• Subjects: adipose morphology; adipogenesis; genome-wide association study (GWAS); genetic loci; GENetics of Adipocyte Lipolysis (GENiAL) cohort
• Online Access: https://www.mdpi.com/2073-4409/9/5/1085

An increased adipocyte size relative to the size of fat depots, also denoted hypertrophic adipose morphology, is a strong risk factor for the future development of insulin resistance and type 2 diabetes. The regulation of adipose morphology is poorly understood<b>. </b>We set out to identify genetic loci associated with adipose morphology and functionally evaluate candidate genes for impact on adipocyte development. We performed a genome-wide association study (GWAS) in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort comprising 948 participants who have undergone abdominal subcutaneous adipose biopsy with a determination of average adipose volume and morphology. The GWAS identified 31 genetic loci displaying suggestive association with adipose morphology. Functional evaluation of candidate genes by small interfering RNAs (siRNA)-mediated knockdown in adipose-derived precursor cells identified six genes controlling adipocyte renewal and differentiation, and thus of potential importance for adipose hypertrophy. In conclusion<i>, </i>genetic and functional studies implicate a regulatory role for <i>ATL2</i>, ARHGEF10, <i>CYP1B1</i>, <i>TMEM200A, C17orf51,</i> and <i>L3MBTL3 </i>in adipose morphology by their impact on adipogenesis.