Targeted sequencing of genome wide significant loci associated with bone mineral density (BMD) reveals significant novel and rare variants: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study.
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Abstract | BACKGROUND: Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis. METHODS AND RESULTS: Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study (n = 925) and Cardiovascular Health Study (n = 366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80% were rare with MAF CONCLUSIONS: Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci. |
Year of Publication | 2016
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Journal | Hum Mol Genet
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Date Published | 2016 Sep 11
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ISSN | 1460-2083
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DOI | 10.1093/hmg/ddw289
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PubMed ID | 27616567
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Grant list | R01 AR057118 / AR / NIAMS NIH HHS / United States
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