Transmission Disequilibrium Test for Hand Bone Mineral Density and 11q12-13 Chromosomal Segment

Abstract

The main aim of the present study was to test the hypothesis that the bone mineral density (BMD) assessed from radiographs of the hand phalanges in a random sample of ethnically homogeneous pedigrees is linked to the 11q12-13 chromosomal segment. The data for the study were gathered from 574 Chuvasha individuals belonging to two- and three-generation pedigrees who live in small villages in the Bashkortostan autonomy, Russia. Preliminary statistical-genetic analysis of the BMD in the pedigrees studied showed that potential genetic effects were highly significant ( p<0.001, in comparison with the model assuming no genetic effect), and explained at least 36% of the BMD variation adjusted for sex and age differences. For the transmission/disequilibrium test (TDT) used in our study, a total of 163 nuclear families with two sibs on average were available. Seven DNA microsatellite markers ( D11S1313, D11S1765, D11S987, D11S913, D11S983, D11S1314, D11S916) with average spacing of 2 cM on the chromosomal area 11q12-13 were selected for the TDT. The nominal p values ( p<0.05-0.0015) obtained from three TDT-type tests used for random and extreme-threshold sampling designs pointed consistently to possible linkage disequilibrium between BMD and some of the DNA markers. There was evidence for possible linkage disequilibrium in the upper part of the chromosomal segment studied (markers D11S1313 and D11S1765), and also in the lower part (markers D11S1983 and D11S1314). The lowest nominal p values (0.0015-0.0067) were obtained from three TDT-type tests for marker D11S1313. However, our findings must still be treated with great caution.

Identification of Two Sex-Specific Quantitative Trait Loci in Chromosome 11q for Hip Bone Mineral Density in Chinese

“…Previous studies have provided substantial evidence in support of linkage to chromosome 11q12-23 [15][16][17][18][20][21][22] . The multiple linkages within this broad region could suggest that more than one osteoporosis susceptibility gene resides in this region.…”

“…One is located on chromosome 11q13-21 between D11S4162 and D11S4175, which affect BMD variation at FN, trochanter, and total hip in women, suggesting pleiotropic effects of this gene on hip BMD. Livshits et al [22] suggested the possible existence of two genetic sources in the chromosome 11q. One is located between the markers D11S1313 and DD11S1765, the other between D11S1983 and D11S1314.…”

“…Suggestive evidence with lumbar spine BMD was also observed at 11q12-13 in an Irish sample [21] . Evidence for association between 11q12-13 chromosomal segment and radiographically assessed BMD of hand phalanges was obtained in a Chuvasha population [22] . Third, QTLs affecting BMD in inbred mice and baboons also map to a region syntenic to human chromosome 11q [23][24] .…”

Gene variants for osteoporosis and their pleiotropic effects in aging

“…Moreover, mice with targeted disruption of LRP5 have a deficit in bone formation and sustain fractures (Kato et al, 2002), whereas transgenic mice carrying the LRP5 gain-offunction mutation (G171V) develop increased bone mass and strength (Babij et al, 2003). Most importantly, a QTL for bone mineral density in the general population was mapped at 11q12-13, the LRP5 locus (Carn et al, 2002;Koller et al, 1998;Livshits et al, 2002).…”

Genes and osteoporosis

“…In the general population a QTL for BMD [59][60][61] and stature [62,63] has been mapped to chromosome 11q12-13, where LRP5 is also located. Mice with targeted disruption of LRP5 have a deficit in bone formation and sustain spontaneous fractures [64]; and LRP5 has been shown to encode a transmembrane protein that mediates the Wnt/beta-catenin signaling pathway, that controls osteoblastic activity and bone formation [65,66].…”