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Summary   Objective  A novel single‐nucleotide polymorphism (SNP) associated with morbid obesity was recently identified by exome sequencing. The purpose of this study was to follow up this low‐frequency coding SNP located within the  SYPL2  locus and associated with body mass index in order to reveal novel associations with obesity‐related traits.    Methods  The body mass index‐associated SNP (rs62623713 A>G [chr1:109476817/hg19]) and two tagging SNPs within the  SYPL2  locus, rs9661614 T>C (chr1:109479215) and rs485660 G>A (chr1:109480810), were genotyped in the obesity ( n  = 3,017) and the infogene ( n  = 676) cohorts, which were further combined, leading to a larger cohort of 3,693 individuals. Association testing was performed by general linear models in the obesity cohort and validated by joint analysis in the combined cohort.    Results  rs9661614 and rs485660 were significantly associated with hip circumference (HC) in the obesity cohort, with heterozygotes exhibiting a significantly lower HC. These results were validated by joint analysis for rs9661614 (false discovery rate [FDR]‐corrected  P  = 7.5 × 10 −4 ) and, to a lesser extent, for rs485660 (FDR corrected  P  = 3.9 × 10 −2 ). The association with HC remained significant for rs9661614 when tested independently in women (FDR‐corrected  P  = 1.7 × 10 −2 ), but not for rs485660 (FDR‐corrected  P  = 0.2). Both associations were absent in men.    Conclusions  This study reveals strong evidence for a novel association between rs9661614 (T>C) and HC in women, which likely reflects a preferential association of  SYPL2  to a gynoid profile of fat distribution. The study findings support a clinical significance of  SYPL2  worth considering when assessing risk factors associated with obesity.

A GWAS follow‐up of obesity‐related SNPs in SYPL2 reveals sex‐specific association with hip circumference