Date Published: May 30, 2019
Publisher: Public Library of Science
Author(s): Matt J. Neville, Laura B. L. Wittemans, Katherine E. Pinnick, Marijana Todorčević, Risto Kaksonen, Kirsi H. Pietiläinen, Jian’an Luan, Robert A. Scott, Nicholas J. Wareham, Claudia Langenberg, Fredrik Karpe, Yvonne Böttcher.
Waist-to-hip ratio (WHR) is a prominent cardiometabolic risk factor that increases cardio-metabolic disease risk independently of BMI and for which multiple genetic loci have been identified. However, WHR is a relatively crude proxy for fat distribution and it does not capture all variation in fat distribution. We here present a study of the role of coding genetic variants on fat mass in 6 distinct regions of the body, based on dual-energy X-ray absorptiometry imaging on more than 17k participants. We find that the missense variant CCDC92S70C, previously associated with WHR, is associated specifically increased leg fat mass and reduced visceral but not subcutaneous central fat. The minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue samples. In addition, we identify two coding variants in SPATA20 and UQCC1 that are associated with arm fat mass. SPATA20K422R is a low-frequency variant with a large effect on arm fat only, and UQCC1R51Q is a common variant reaching significance for arm but showing similar trends in other subcutaneous fat depots. Our findings support the notion that different fat compartments are regulated by distinct genetic factors.
While generalised adiposity, as measured by body mass index (BMI), is a well-established and major risk factor for cardio-metabolic diseases, body fat distribution is increasingly being recognised as an even stronger determinant of metabolic risk[1, 2]. For example, Yusuf et al. showed that waist-to-hip ratio (WHR) is a stronger predict of myocardial infarction than BMI. To date, the overwhelming majority of genome and exome-wide association studies on fat distribution have focussed on waist and hip circumference and WHR[3, 4]. While these measures are easy and cheap to obtain on a large scale, they do not capture all variation in fat distribution. For example, WHR does not capture peripheral fat stored in the upper limbs and the distribution of overall central fat over the subcutaneous and visceral compartments, of which the latter have been suggested to have discordant effects on cardio-metabolic risk[5–8]. Furthermore, circumference-based estimates of fat accumulation do not take into account differences in lean mass and bone structure and mass. Therefore, genetic association studies based on direct measures of regional fat mass may help unpick mechanisms underlying the expansion of distinct fat depots.
We tested the associations of all non-synonymous genetic variants covered on the Illumina Human Exome Bead chip with DXA-derived fat mass in the 6 body fat regions: arm fat, leg fat, gynoid fat, total android fat, visceral abdominal fat and subcutaneous abdominal fat (S1 Table). The regional fat phenotypes were adjusted for the first 4 genetic principal components, age and % body fat and the residuals were rank-based inverse normally transformed for men and women separately. The exome chip meta-analyses included up to 17,212 participants of European ancestry from the Oxford Biobank, Fenland and EPIC-Norfolk cohorts (Table 1 and S1 Table). Three non-synonymous variants reached exome-wide significance (p<2×10−7) (Fig 1, Table 2 and S2 Table): rs11057401, a common missense variant in Coiled-Coil Domain Containing 92 (CCDC92S70C); rs62621401, a novel low-frequency missense variant in Spermatogenesis Associated 20 (SPATA20K422R) and rs4911494, a common missense variant in Ubiquinol-Cytochrome C Reductase Complex Assembly Factor 1 (UQCC1R51Q). Heterogeneity tests based on Cochran’s Q statistics indicate no significant differences among the effect estimates in the 6 contributing datasets (p for Cochran’s Q statistic for rs11057401 = 0.19, for rs4911494 = 0.61 and rs62621401 = 0.42). The three loci identified here show the same direction of effect in both men and women. However, the effect size of rs11057401(CCDC92) on visceral fat was two-fold stronger in men than in women whereas the association with lower body fat mass showed no difference between the sexes. An additional 30 non-synonymous variants reached suggestive significance across 38 tests (p<10−6, S3 Table), including a large haplotype block on chromosome 17 containing 8 missense variants across the SPPL2C, MAPT, KANSL1 genes and GDF5S276A in LD with UQCC1R51Q. Source: http://doi.org/10.1371/journal.pone.0217644