High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density.
A quantitative trait locus (QTL) for BMD maps to chromosome 1p36. We have analyzed a high density SNP panel from this region for linkage and association to BMD in 39 osteoporosis pedigrees. Our results support the presence of genes controlling BMD on 1p36 and indicate new candidates for further analyses.


BACKGROUND
Low BMD is one of the major risk factors for osteoporosis. Following a genome scan in a sample of Caucasian families recruited through probands with low BMD, a region on 1p36 near marker D1S214 received support as a QTL for BMD from linkage (maximum lod-score = 2.87) and linkage disequilibrium (LD) analysis (p < 0.01).


METHODS
To better characterize the genetic risk factors for low BMD located in this genomic region, we have genotyped the same group of families for 1095 SNPs located across 11 Mb on 1p36. Linkage and LD analyses have been performed using the variance component approach.


RESULTS
Multivariate linkage analysis indicated two QTLs for femoral neck BMD, lumbar spine BMD and trochanter BMD simultaneously on 1p36, with maximum lod-scores of 4.37 at 12 cM and 3.59 at 22 cM. LD analysis identified several SNPs potentially associated with BMD, including the RERE gene SNP rs11121179 (p = 0.000005 for lumbar spine BMD). Other candidate genes include G1P2, SSU72 and CCDC27 (each containing 1 SNP with p < 0.001 for at least one BMD trait).


CONCLUSIONS
This study supports the presence in 1p36 of QTLs affecting BMD at multiple skeletal sites. Replication of our results in other independent cohorts is warranted.
Zhang
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Division of Human Genetics, The Children's Hospital of Philadelphia, PA 19104-4399, USA.
Sol-Church
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Rydbeck
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Stabley
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Spotila
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LD
Devoto
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D015519:Bone Density / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D005269:Femur / Q000503:physiopathology; D005272:Femur Neck / Q000503:physiopathology; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008159:Lumbar Vertebrae / Q000503:physiopathology; D010024:Osteoporosis / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D044465:White People
D002352:Carrier Proteins; D005819:Genetic Markers; C412477:RERE protein, human