A genome-wide scan for loci linked to forearm bone mineral density

Abstract

Osteoporosis is a chronic disorder characterized by low bone mass and fragility fractures. It affects more than 25 million men and women in the United States alone. Although several candidate genes, such as the vitamin-D-receptor gene or the estrogen-receptor gene, have been suggested in the pathogenesis of osteoporosis, the genetic dissection of this disorder remains a daunting task. To search systematically for chromosomal regions containing genes that regulate bone mineral density (BMD), we scanned the entire autosomal genome by using 367 polymorphic markers among 218 individuals (153 sibpairs) from 96 nuclear families collected from three townships of Anqing, China. In these 96 families, DNA samples from both parents were available for 82 (85.4%) families. By using age- and gender-adjusted forearm BMD measurements, a peak on chromosome 2 near D2S2141, D2S1400, and D2S405, a region previously linked to spinal BMD, showed evidence of linkage to both proximal and distal forearm BMD (multipoint LOD=2.15 and 2.14 for proximal and distal forearm BMD, respectively). One region on chromosome 13 (multipoint LOD=1.67) in the proximity of D13S788 and D13S800 showed evidence of linkage to distal forearm BMD only. Possible candidate genes included CALM2 (calmodulin 2) at 2p21.3-p21.1, a putative STK (serine/threonine kinase) at 2p23-24, POMC (pro-opiomelanocortin) at 2p23.3, and COL4A1 and COL4A2 (collagen IV alpha-1 and alpha-2 subunits) at 13q34. Because of the limited sample size, the suggestive evidence of linkage of this study should be considered as tentative and needs to be replicated in other larger populations.

Univariate and bivariate variance component linkage analysis of a whole-genome scan for loci contributing to bone mineral density

“…Marker D2S405 in the same region on 2p23 was reported to be linked to forearm BMD by Niu et al 23 Other regions where we observed interesting lod-scores coincide with regions reported in other studies and/or known to contain candidate genes for bone-related traits. 5,12 A formal meta-analysis will help elucidate whether these findings may in fact indicate the existence of genomic regions containing susceptibility genes for osteoporosis shared across different populations.…”

Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density

“…However, the identity of specific genes and their relative effects on BMD\BMC variation are unknown. The few studies are inconsistent in the existence and\or identification of major genes for BMD\BMC (Gueguen et al 1995 ;Livshits et al 1996Devoto et al 1998 ;Niu et al 1999 ;Duncan et al 1999 ;Koller et al 2000 ;Cardon et al 2000 ;. In 51 human pedigrees with 941 individuals (526 measured for phenotypes) identified via probands with extreme BMD values, we performed complex segregation analyses to test for the existence of a genetic locus with a major effect on BMD\BMC variation.…”

“…However, there are still very few segregation analyses in the bone genetic field, even when compared with linkage studies. The linkage studies in the bone field (Devoto et al 1998 ;Niu et al 1999 ;Koller et al 2000) have almost all been conducted without prior segregation analyses ; therefore, the likelihood of success cannot be assessed for the study designs and samples even if statistical genetic power analyses were performed. This is because the statistical power analyses require an assumed effect of a putative major gene that can only be ascertained via segregation analyses prior to linkage analyses for complex traits.…”

“…From the few linkage studies, both consistent and inconsistent findings (e.g. Devoto et al 1998 ;Niu et al 1999 ;Duncan et al 1999 ;Koller et al 2000) have been reported. In particular, results (Johnson et al 1997 ;Koller et al 1998Koller et al , 2000 concerning the marker D11S987 in chromosome 11q12-13 are under debate as to whether the genomic region contains a major gene responsible for a large proportion of BMD\BMC variation.…”

“…A few studies using alternative approaches such as QTL mapping in model organisms (e.g. Klein et al 1998) and linkage analyses in humans (Johnson et al 1997 ;Koller et al 1998Koller et al , 2000Devoto et al 1998 ;Niu et al 1999 ;Duncan et al 1999 ; have appeared to search for major genes with relatively large impacts on BMD\BMC variation. From the few linkage studies, both consistent and inconsistent findings (e.g.…”