Dataset Information

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.

ABSTRACT: Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.

SUBMITTER: Sinnott-Armstrong N

PROVIDER: S-EPMC7928941 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.

Sinnott-Armstrong Nasa N Sousa Isabel S IS Laber Samantha S Rendina-Ruedy Elizabeth E Nitter Dankel Simon E SE Ferreira Teresa T Mellgren Gunnar G Karasik David D Rivas Manuel M Pritchard Jonathan J Guntur Anyonya R AR Cox Roger D RD Lindgren Cecilia M CM Hauner Hans H Sallari Richard R Rosen Clifford J CJ Hsu Yi-Hsiang YH Lander Eric S ES Kiel Douglas P DP Claussnitzer Melina M

Cell metabolism 20210128 3

Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to dif ...[more]

PMID: 33513366

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Project description:BackgroundGenome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.MethodsNovel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.ResultsWe identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.ConclusionMost of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Project description:Leg weakness is a prevalent health condition in pig farms. The augmentation of cannon bone circumference and bone mineral density can effectively improve limb strength in pigs and alleviate leg weakness. This study measured forelimb cannon bone circumference (fCBC) and rear limb cannon bone circumference (rCBC) using an inelastic tapeline and rear limb metatarsal area bone mineral density (raBMD) using a dual-energy X-ray absorptiometry bone density scanner. The samples of Yorkshire castrated boars were genotyped using a 50K single-nucleotide polymorphism (SNP) array. The SNP-chip data were imputed to the level of whole-genome sequencing data (iWGS). This study used iWGS data to perform genome-wide association studies and identified novel significant SNPs associated with fCBC on SSC6, SSC12, and SSC13, rCBC on SSC12 and SSC14, and raBMD on SSC7. Based on the high phenotypic and genetic correlations between CBC and raBMD, multi-trait meta-analysis was performed to identify pleiotropic SNPs. A significant potential pleiotropic quantitative trait locus (QTL) regulating both CBC and raBMD was identified on SSC15. Bayes fine mapping was used to establish the confidence intervals for these novel QTLs with the most refined confidence interval narrowed down to 56 kb (15.11 to 15.17 Mb on SSC12 for fCBC). Furthermore, the confidence interval for the potential pleiotropic QTL on SSC15 in the meta-analysis was narrowed down to 7.45 kb (137.55 to137.56 Mb on SSC15). Based on the biological functions of genes, the following genes were identified as novel regulatory candidates for different phenotypes: DDX42, MYSM1, FTSJ3, and MECOM for fCBC; SMURF2, and STC1 for rCBC; RGMA for raBMD. Additionally, RAMP1, which was determined to be located 23.68 kb upstream of the confidence interval of the QTL on SSC15 in the meta-analysis, was identified as a potential pleiotropic candidate gene regulating both CBC and raBMD. These findings offered valuable insights for identifying pathogenic genes and elucidating the genetic mechanisms underlying CBC and BMD.

Dataset Information

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.

Publications

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.

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