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 < 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.
| Original language | English |
|---|---|
| Pages (from-to) | 5234-5243 |
| Number of pages | 10 |
| Journal | Human Molecular Genetics |
| Volume | 25 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - 1 Dec 2016 |
Bibliographical note
Funding Information:'Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium' was funded by the NIH (the American Recovery and Reinvestment Act of 2009, ARRA, 5RC2HL102419). Data for 'Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium' was provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L. Adrienne Cupples, PI for the Framingham Heart Study (FHS) and Bruce Psaty, PI for the Cardiovascular Health Study (CHS). The FHS-Conducted and supported by the NHLBI in collaboration with Boston University (BU) (N01-HC-25195), and its contract with Affymetrix, Inc., for genome-wide genotyping services (N02-HL-6-4278), for quality control by FHS investigators using genotypes in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at BU School of Medicine and Boston Medical Center. The Framingham Osteoporosis Study is supported by NIAMS (R01AR 41398, R01AR 061162 and R21 AR056405). CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). David Karasik was supported by ERC FP7-PEOPLE-(CIG). A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm.
Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.