FIRST-STAGE AUTOSOMAL GENOME SCREEN IN EXTENDED PEDIGREES SUGGESTS GENES PREDISPOSING TO LOW BONE-MINERAL DENSITY ON CHROMOSOMES 1P, 2P AND4Q

Osteoporosis is characterized by low bone density, and osteopenia is r esponsible for 1.5 million fractures in the United States annually.(1) In order to identify regions of the genome which are likely to contai n genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) wi th 330 DNA markers spread throughout the autosomal genome. Linkage ana lysis for this quantitative trait was carried out using spine and hip BMD values by the classical led-score method using a genetic model wit h parameters estimated from the seven families. In addition, non-param etric analysis was performed using the traditional Haseman-Elston appr oach in 74 independent sib pairs from the same pedigrees. The maximum lod score obtained by parametric analysis in all families combined was + 2.08 (theta = 0.05) for the marker CD3D on chromosome 11q. All othe r combined lod scores from the parametric analysis were less than +1.9 0, the threshold for suggestive linkage. Non-parametric analysis sugge sted linkage of low BMD to chromosomes 1p36 (Z(max) = + 3.51 for D1S45 0) and 2p23-24 (Z(max) = + 2.07 for D2S149). Maximum multi-point lod s cores for these regions were +2.29 and +2.25, respectively. A third re gion with associated lod scores above the threshold of suggestive link age in both single-point and multi-point non-parametric analysis was o n chromosome 4qter (Z(max) = + 2.95 for D4S1539 and Z(max) = + 2.48 fo r D4S1554). Our data suggest the existence of multiple genes involved in controlling spine and hip BMD, and indicate several candidate regio ns for further screening in this and other independent samples.