Identification of a Linkage Disequilibrium Block in Chromosome 1q Associated With BMD in Premenopausal White Women

Ichikawa, Shoji; Koller, Daniel L.; Curry, Leah R.; Lai, Dongbing; Xuei, Xiaoling; Pugh, Elizabeth; Tsai, Ya Yu; Doheny, Kimberly F.; Edenberg, Howard J.; Hui, Siu L.; Foroud, Tatiana; Econs, Michael J.

doi:10.1359/jbmr.080509

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…We previously reported that a linkage disequilibrium block on chromosome 1q is associated with BMD (Ichikawa et al , 2008). This region was initially identified through linkage analysis using spine BMD as the phenotype of interest (Econs et al , 2004).…”

Section: Resultsmentioning

confidence: 99%

“…We applied regSNPs to prioritize regulatory SNPs within the genetic regions known to be associated with BMD from a list of candidate SNPs in the HapMap database. We previously reported that a linkage disequilibrium block on chromosome 1q is associated with BMD ( Ichikawa et al , 2008 ). This region was initially identified through linkage analysis using spine BMD as the phenotype of interest ( Econs et al , 2004 ).…”

Section: Resultsmentioning

confidence: 99%

“…The accuracy of our approach varies among diseases, with the area under the curve (AUC) of the receiver operating characteristics (ROC) curve ranging from 53.7% in schizophrenia to 77.9% in breast cancer. We applied our method to a region on chromosome 1q that had previously been found through linkage and association analysis to harbor genetic factors that contribute to the variation of femoral neck and lumbar spine bone mineral density (BMD) in premenopausal white women ( Ichikawa et al , 2008 ). Three SNPs were selected as likely to be functional, with an estimated false discovery rate (FDR) <25%.…”

Section: Introductionmentioning

confidence: 99%

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regSNPs: a strategy for prioritizing regulatory single nucleotide substitutions

et al. 2012

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Motivation: One of the fundamental questions in genetics study is to identify functional DNA variants that are responsible to a disease or phenotype of interest. Results from large-scale genetics studies, such as genome-wide association studies (GWAS), and the availability of high-throughput sequencing technologies provide opportunities in identifying causal variants. Despite the technical advances, informatics methodologies need to be developed to prioritize thousands of variants for potential causative effects.Results: We present regSNPs, an informatics strategy that integrates several established bioinformatics tools, for prioritizing regulatory SNPs, i.e. the SNPs in the promoter regions that potentially affect phenotype through changing transcription of downstream genes. Comparing to existing tools, regSNPs has two distinct features. It considers degenerative features of binding motifs by calculating the differences on the binding affinity caused by the candidate variants and integrates potential phenotypic effects of various transcription factors. When tested by using the disease-causing variants documented in the Human Gene Mutation Database, regSNPs showed mixed performance on various diseases. regSNPs predicted three SNPs that can potentially affect bone density in a region detected in an earlier linkage study. Potential effects of one of the variants were validated using luciferase reporter assay.Contact: yunliu@iupui.eduSupplementary information: Supplementary data are available at Bioinformatics online

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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regSNPs: a strategy for prioritizing regulatory single nucleotide substitutions

et al. 2012

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“…Recently, Ioannidis and colleagues have reported a meta-analysis of nine genome-wide association studies limited to women that found several chromosomal regions, including 1p13.3-1q23.3, with significant BMD association. (7) In two additional studies, Schaffer and colleagues (8) found significant association of BMD with 1q23 in young 25-to 45-year-old ORIGINAL ARTICLE J JBMR Mexican Americans, and Ichikawa and colleagues (9) reported a significant association of BMD with a haplotype block containing 11 genes on 1q in premenopausal white women, but the specific gene was not identified.…”

Section: Introductionmentioning

confidence: 99%

BMD regulation on mouse distal chromosome 1, candidate genes, and response to ovariectomy or dietary fat

Beamer

Shultz

Coombs

et al. 2010

Journal of Bone and Mineral Research

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The distal end of mouse chromosome 1 (Chr 1) harbors quantitative trait loci (QTLs) that regulate bone mineral density (BMD) and share conserved synteny with human chromosome 1q. The objective of this article was to map this mouse distal Chr 1 region and identify gene(s) responsible for BMD regulation in females. We used X-ray densitometry [ie, dual-energy X-ray Absorptiometry (DXA), micro–computed tomography (µCT), and peripheral quantitative computed tomography (pQCT)] to phenotype a set of nested congenic strains constructed from C57BL/6BmJ (B6/Bm) and C3H/HeJ (C3H) mice to map the region associated with the BMD QTL. The critical region has been reduced to an interval of 0.152 Mb that contributes to increased BMD when C3H alleles are present. Histomorphometry and osteoblast cultures indicated that increased osteoblast activity was associated with increased BMD in mouse strains with C3H alleles in this critical region. This region contains two genes, Aim2, which binds with cytoplasmic dsDNA and results in apoptosis, and AC084073.22, a predicted gene of unknown function. Ovariectomy induced bone loss in the B6/Bm progenitor and the three congenic strains regardless of the alleles present in the critical BMD region. High dietary fat treatment (thought to suppress distal Chr 1 QTL for BMD in mice) did not induce bone loss in the congenics carrying C3H alleles in the critical 0.152 Mb carrying the AIM2 and AC084073.22 genes. Gene expression studies in whole bone of key congenics showed differential expression of AC084073.22 for strains carrying B6/Bm versus C3H alleles but not for Aim2. In conclusion, our data suggest that osteoblasts are the cellular target of gene action and that AC084073.22 is the best candidate for female BMD regulation in the distal region of mouse Chr 1. © 2011 American Society for Bone and Mineral Research.

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“…Some QTLs for BMD have been replicated in large consortia (21); however, most of the variance in the heritability of the osteoporosis remains unaccounted for (71) and the identification of key candidate genes even within the replicated regions is challenging. Ongoing work continues to resolve the QTLs to a gene responsible for the signal, both in humans (20) and animal models (12). Positional candidates in the QTL may include many genes known to affect bone growth or maintenance and genes that have not yet been associated with bone mineralization, structure, or body size but potentially influence these traits.…”

Section: Discussionmentioning

confidence: 99%

Refined QTLs of osteoporosis-related traits by linkage analysis with genome-wide SNPs: Framingham SHARe

Karasik

Dupuis

Cho

et al. 2010

Bone

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Genome-wide association studies (GWAS) using high-density array of single-nucleotide polymorphisms (SNPs) offer an unbiased strategy to identify new candidate genes for osteoporosis. We used a subset of autosomal SNPs from the Affymetrix 500K+50K SNP GeneChip marker set to examine genetic linkage with multiple highly heritable osteoporosis-related traits, including BMD of the hip and spine, heel ultrasound (attenuation and speed of sound), and geometric indices of the hip, in two generations from the Framingham Osteoporosis Study. Variance component linkage analysis was performed using normalized residuals (adjusted for age, height, BMI, and estrogen status in women). Multipoint linkage analyses produced LOD scores ≥ 3.0 for BMD on chromosomes (chr.) 9 and 11, and for ultrasound speed of sound on chr. 5. Hip geometric traits were linked with higher LOD scores, such as with Shaft Width on chr. 4 (LOD = 3.9) and chr. 16 (LOD = 3.8), and with Shaft section modulus on chr. 22 (LOD = 4.0). LOD score ≥ 5.0 was obtained for femoral Neck Width on chr. 7. In conclusion, with a SNP-based linkage approach, we identified several novel potential QTLs and confirmed previously identified chromosomal regions linked to bone mass and geometry. Subsequent focus on the spectrum of genetic polymorphisms in these refined regions may contribute to finding variants predisposing to osteoporosis.

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Identification of a Linkage Disequilibrium Block in Chromosome 1q Associated With BMD in Premenopausal White Women

Cited by 9 publications

References 34 publications

regSNPs: a strategy for prioritizing regulatory single nucleotide substitutions

regSNPs: a strategy for prioritizing regulatory single nucleotide substitutions

BMD regulation on mouse distal chromosome 1, candidate genes, and response to ovariectomy or dietary fat

Refined QTLs of osteoporosis-related traits by linkage analysis with genome-wide SNPs: Framingham SHARe

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