We investigated the association of common high-confidence germline copy number deletions (CNDs) with metabolic traits by analyzing UK10K consortium data, where whole genome sequencing (WGS) was performed on 3,781 participants in two UK cohorts, TwinsUK (n=1,854) and ALSPAC (n=1,927). TwinsUK enrolled adult (mean age=59) females and ALSPAC followed children from birth to adolescence. BMI, total fat mass (TFM), truncal fat mass (TrFM), HDL, LDL, VLDL, glucose and insulin were measured. After excluding rare CNDs (MAF<5%) 1,222 (TwinsUK) and 1,211 (ALSPAC) common CNDs remained for association analyses. The genome-wide significance threshold was set at 4.09×10-5(TwinsUK) and 4.13×10-5(ALSPAC) after Bonferroni correction at level α=0.05 and five CNDs achieved genome-wide significance. At ALSPAC, a common (MAF=0.11) 7kb deletion on chromosome 11 (55031591-55038554;BMI at 15yrs,β=1.49, P=2.75×10-6;TFM at 9yrs,β=0.96, P=2.63×10-6;TrFM at 9yrs,β=0.45, P=2.15×10-6) with loss of exons from 2 to 6 in TRIM48 (Tripartite Motif Containing 48), E3 ubiquitin-protein ligase, was associated with childhood obesity. Two other loci at chromosome 8 (intergenic, 24972435-24990944;BMI,β=0.93, P=1.78×10-5;TFM,β=1.39, P=3.58×10-6; TrFM,β=0.64, P=4.56×10-6) and 11 (intron 2 deletion of lincRNA, LOC44040, 49759283-49760872;BMI,β=1.03, P=1.72×10-6; TFM,β=1.29, P=1.31×10-5; TrFM,β=0.60, P=1.66×10-5) were associated with childhood obesity. At TwinsUK, a common (MAF=0.29) 823bp deletion in intron 3 of lncRNA, LINC01923, on chromosome 18 (74347187-74348010,β=-0.22, P=4.15×10-7) was associated with low HDL. The genome-wide significant association of 3kb deletion in GUSBP1 (GUSB Pseudogene 1) enhancer on chromosome 5 (21611834-21614796) with childhood obesity (TFM at 9yrs,β=1.26, P=2.52×10-5) in ALSPAC was replicated in adult females of TwinsUK (TFM, P=3.79×10-2). Studies are warranted that investigate germline CNDs associated with metabolic traits.


J.Ohn: None.


Seoul National University Bundang Hospital Research Fund (18-2018-0006)

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