Chromosome 2q32 may harbor a QTL affecting BMD variation at different skeletal sites.
BMDs at different skeletal sites share some common genetic determinants. Using PCA and bivariate linkage analysis, we identified a QTL on chromosome 2q32 with significant pleiotropic effects on BMDs at different skeletal sites.


BACKGROUND
BMDs at the hip, spine, and forearm are genetically correlated, suggesting the existence of quantitative trait loci (QTLs) with concurrent effects on BMDs at these three skeletal sites. Consequently, it is important to identify these QTLs in the human genome and, for those implicated QTLs, it is important to differentiate between pleiotropic effects, caused by a single gene that concurrently effects these traits, and co-incident linkage, caused by multiple, closely linked, genes that independently effect these traits.


METHODS
For a sample of 451 American white pedigrees made up of 4,498 individuals, we evaluated the correlations between BMDs at the three skeletal sites. We carried out principal component analysis (PCA) for the three correlated traits and obtained a major component, PC1, which accounts for >75% of the co-variation of BMDs at the three sites. We subsequently conducted a whole genome linkage scan for PC1 and performed bivariate linkage analysis for pairs of the three traits (i.e., forearm/spine BMD, hip/forearm BMD, and hip/spine BMD).


RESULTS
Chromosome region 2q32, near the marker GATA65C03M, showed strong linkage to PC1 (LOD = 3.35). Subsequent bivariate linkage analysis substantiated linkage at 2q32 for each trait pair (LOD scores were 2.65, 2.42, and 2.13 for forearm/spine BMD, hip/forearm BMD, and hip/spine BMD, respectively). Further analyses rejected the hypothesis of co-incident linkage (p(0)[forearm/spine] = 0.0005, p(0)[hip/forearm] = 0.004, p(0)(hip/spine] = 0.001) but failed to reject the hypothesis of pleiotropy (p(1)[forearm/spine] = 0.35, p(1)[hip/forearm] = 0.07, p(1)[hip/spine] = 0.15).


CONCLUSIONS
Our results strongly support the conclusion that chromosome region 2q32 may harbor a QTL with pleiotropic effects on BMDs at different skeletal sites.
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Liang
L
Wang
Yong-Jun
YJ
Liu
Peng
P
Xiao
Hui
H
Shen
Hong-Yi
HY
Deng
Christopher J
CJ
Papasian
Betty M
BM
Drees
James J
JJ
Hamilton
Robert R
RR
Recker
Hong-Wen
HW
Deng
D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000000981:diagnostic imaging*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D010375:Pedigree; D040641:Quantitative Trait Loci; D011859:Radiography
D005819:Genetic Markers