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Genome Screen for QTLs Contributing to Normal Variation in Bone Mineral Density and Osteoporosis¹

Indiana University School of Medicine (D.L.K., M.J.E., J.C.C., S.L.H., P.M.C., M.P., C.C.J., T.F.), Indianapolis, Indiana 46202; and Axys Pharmaceuticals, Inc. (P.A.M., P.P., M.E.C., L.A.R., G.J.), La Jolla, California 92037

Address all correspondence and requests for reprints to: Dr. Tatiana Foroud, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 West Walnut Street, Indianapolis, Indiana 46202.

A major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12–13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans).

The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21–23 with lumbar spine BMD. Chromosome 5q33–35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11–12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12–13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.

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