First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q.
Osteoporosis is characterized by low bone density, and osteopenia is responsible for 1.5 million fractures in the United States annually. In order to identify regions of the genome which are likely to contain genes predisposing to osteopenia, we genotyped 149 members of seven large pedigrees having recurrence of low bone mineral density (BMD) with 330 DNA markers spread throughout the autosomal genome. Linkage analysis for this quantitative trait was carried out using spine and hip BMD values by the classical lod-score method using a genetic model with parameters estimated from the seven families. In addition, non-parametric analysis was performed using the traditional Haseman-Elston approach 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 other combined lod scores from the parametric analysis were less than +1.90, the threshold for suggestive linkage. Non-parametric analysis suggested linkage of low BMD to chromosomes 1p36 (Zmax = +3.51 for D1S450) and 2p23-24 (Zmax = +2.07 for D2S149). Maximum multi-point lod scores for these regions were +2.29 and +2.25, respectively. A third region with associated lod scores above the threshold of suggestive linkage in both single-point and multi-point non-parametric analysis was on chromosome 4qter (Zmax = +2.95 for D4S1539 and Zmax = +2.48 for D4S1554). Our data suggest the existence of multiple genes involved in controlling spine and hip BMD, and indicate several candidate regions for further screening in this and other independent samples.
Laboratory of Statistical Genetics, Rockefeller University, New York, USA.
M
M
Devoto
K
K
Shimoya
J
J
Caminis
J
J
Ott
A
A
Tenenhouse
M P
MP
Whyte
L
L
Sereda
S
S
Hall
E
E
Considine
C J
CJ
Williams
G
G
Tromp
H
H
Kuivaniemi
L
L
Ala-Kokko
D J
DJ
Prockop
L D
LD
Spotila
D015519:Bone Density / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1; D002889:Chromosomes, Human, Pair 2; D002894:Chromosomes, Human, Pair 4; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D018895:Microsatellite Repeats; D010375:Pedigree; D011110:Polymorphism, Genetic; D019655:Quantitative Trait, Heritable