TY - JOUR
T1 - Targeted sequencing of genome wide significant loci associated with bone mineral density (BMD) reveals significant novel and rare variants
T2 - The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study
AU - Hsu, Yi Hsiang
AU - Li, Guo
AU - Liu, Ching Ti
AU - Brody, Jennifer A.
AU - Karasik, David
AU - Chou, Wen Chi
AU - Demissie, Serkalem
AU - Nandakumar, Kannabiran
AU - Zhou, Yanhua
AU - Cheng, Chia Ho
AU - Gill, Richard
AU - Gibbs, Richard A.
AU - Muzny, Donna
AU - Santibanez, Jireh
AU - Estrada, Karol
AU - Rivadeneira, Fernando
AU - Harris, Tamara
AU - Gudnason, Vilmundur
AU - Uitterlinden, Andre
AU - Psaty, Bruce M.
AU - Robbins, John A
AU - Adrienne Cupples, L.
AU - Kiel, Douglas P.
PY - 2016
Y1 - 2016
N2 - 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 < 1%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find proteincoding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS, ARHGAP1, and 5' of MEF2C (P-values < 8x10-5; false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements. 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.
AB - 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 < 1%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find proteincoding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS, ARHGAP1, and 5' of MEF2C (P-values < 8x10-5; false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements. 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.
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U2 - 10.1093/hmg/ddw289
DO - 10.1093/hmg/ddw289
M3 - Article
C2 - 27616567
AN - SCOPUS:85016082255
VL - 25
SP - 5234
EP - 5243
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 23
ER -