Genome screen for a combined bone phenotype using principal component analysis: The Framingham study

D. Karasik, L. A. Cupples, M. T. Hannan, D. P. Kiel

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Genetic factors substantially contribute to variation in bone mass. There is a controversy as to whether shared genetic factors exist for bone mass at different sites. We hypothesize that using a composite phenotypic score of several correlated bone mass measures may provide complementary results for linkage studies. In the members of 323 pedigrees from the Framingham Osteoporosis Study, bone mineral density (BMD) was measured at the lumbar spine and three femoral sites (Lunar DPX-L), and quantitative ultrasound (QUS) measured at the calcaneus (Hologic Sahara). Data on age, sex, anthropometry, alcohol and caffeine intake, smoking status, physical activity, menopause, and estrogen use (in females) were also obtained. Principal component analyses of BMD and QUS phenotypes were performed in each sex and generation (parents and offspring). The principal component analyses yielded two components, whose loadings were extracted as principal component scores (PC1 and PC2) for each individual, with PC1 explaining up to 66% of the total variation of all bone mass measurements, and PC2 an additional 24%. Principal component analysis of the three femoral BMD measures resulted in one component (PC_hip) that explained 89-91% of the common variation of hip BMD measures. Quantitative genetic analysis (using the variance components method) revealed that both principal component scores were under significant genetic influences (covariate-adjusted heritabilities of PC1, PC2, and PC_hip were 0.66 ± 0.07, 0.44 ± 0.07, and 0.61 ± 0.06, respectively). For PC1, loci of suggestive linkage were identified on chromosomes 1q21.3 and 8q24.3 with the maximum multipoint LOD scores 2.5 and 2.4, respectively. For PC2, multipoint LOD score was 2.1 on 1p36. Suggestive linkage of PC_hip was found on 8q24.3 and 16p13.2 (LODs > 1.9). In conclusion, an approach to linkage analysis using the linear combination of several correlated bone phenotypes suggests that there are chromosomal loci regulating bone mass, with seemingly pleiotropic effects at different skeletal sites.

Original languageEnglish
Pages (from-to)547-556
Number of pages10
Issue number3
StatePublished - Mar 2004
Externally publishedYes

Bibliographical note

Funding Information:
From the Framingham Heart Study (supported by NIH/NHLBI Contract N01-HC-25195). We gratefully acknowledge the Framingham Study members who participated in this study, as well as the study coordinators who contributed to the success of this work. We would also like to express our thanks to Dr. S. Demissie for her useful suggestions in preparing the manuscript and Dr. M.C. Mahaney for his help with power calculations in our sample. This work was supported by a grant RO1 AR/AG 41398 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases and the National Institute on Aging. Presented in part as an abstract at the 24th Annual Meeting of the American Society for Bone and Mineral Research, San Antonio, TX.


  • Framingham
  • Genome
  • Phenotype


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