doi: 10.1046/j.1529-8817.2003.00117.x Genetic Dissection of Human Stature in a Large Sample of Multiplex Pedigrees Yao-Zhong Liu 1,2 , Fu-Hua Xu 1,2 , Hui Shen 1,2 , Yong-Jun Liu 1,2 , Lan-Juan Zhao 1,2 , Ji-Rong Long 1,2 , Yuan-Yuan Zhang 1,2 , Peng Xiao 1,2 , Dong-Hai Xiong 1,2 , Volodymyr Dvornyk 1,2 , Jin-Long Li 4 , Theresa Conway 1 , K. Michael Davies 1 , Robert R. Recker 1 , Hong-Wen Deng 1,2,3* 1 Osteoporosis Research Center 2 Department of Biomedical Sciences Creighton University, 601 N. 30 th St. Suite 6787, Omaha, NE 68131 3 Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, ChangSha, Hunan 410081, P. R. China 4 Center for Medical Informatics, School of Medicine, Yale University, 333 Cedar Street, P.O. Box, 208009, New Haven, Connecticut 06520-8009 Summary Recently, we reported a whole genome scan on a sample of 630 Caucasian subjects from 53 human pedigrees. Several genomic regions were suggested to be linked to height. In an attempt to confirm the identified genomic regions, as well as to identify new genomic regions linked to height, we conducted a whole genome linkage study on an extended sample of 1,816 subjects from 79 pedigrees, which includes the 53 pedigrees containing the original 630 subjects from our previous whole genome study and an additional 128 new subjects, and 26 further pedigrees containing 1,058 subjects. Several regions achieved suggestive linkage signals, such as 9q22.32 [MLS (multipoint LOD score) = 2.74], 9q34.3 [MLS = 2.66], Xq24 [two-point LOD score = 2.64 at the marker DXS8067], and 7p14.2 [MLS = 2.05]. The importance of the above regions is supported either by other whole genome studies or by candidate genes within these regions relevant to linear growth or pathogenesis of short stature. In addition, this study has tentatively confirmed the Xq24 region’s linkage to height, as this region was also detected in the previous whole genome study. To date, our study has achieved the largest sample size in the field of genetic linkage studies of human height. Together with the findings of other studies, the current study has further delineated the genetic basis of human stature. Keywords : height, stature, complex trait, linkage, whole genome Introduction Human height is the result of linear growth which oc- curs during development and childhood until epiphy- seal fusion is completed. Physiologically, linear growth is dependent on the process of endochondral ossifica- tion in the growth plates of long bones. A variety of systemic and paracrine or autocrine factors are impli- ∗ Corresponding author: Hong-Wen Deng, Ph. D., Osteoporo- sis Research Center, Tel: 402-280-5911 Creighton Univer- sity, Fax: 402-280-5034 601 N. 30 th St. Suite 6787, E-mail: deng@creighton.edu Omaha, NE 68131. Funding Sources: NIH, Health Future Foundation, US Dept. of Energy, State of Nebraska, Creighton University cated in this process, which include growth hormone (Cogan et al. 1994; Wajnrajch et al. 1996), IGF-I (Ohlsson et al. 2000), glucocorticoids (Avioli, 1993; Magiakou et al. 1994), thyroid hormone (Weiss & Refetoff, 1996), vitamin D (Boyan et al. 2002), and sex steroids (Frank, 2003). Two major signaling path- ways, the Ihh (Indian hedgehog)/PTHrP (parathyroid hormone-related peptide) pathway (Juppner 2000) and the FGF (fibroblast growth factor) pathway (Wilkie et al. 2002), are involved in proliferation and differentiation of chondrocytes, and hence represent prominent local agents involved in linear growth. Environmental factors, such as nutrition and disease, have long been recognized as important determinants 472 Annals of Human Genetics (2004) 68,472–488 C  University College London 2004