Genome-wide linkage screen of bone mineral density (BMD) in European pedigrees ascertained through a male relative with low BMD values: evidence for quantitative trait loci on 17q21-23, 11q12-13, 13q12-14, and 22q11.
BACKGROUND
Bone mass is under strong genetic control, with heritability estimates greater than 50% and is likely determined by complex interactions between genetic and environmental factors.


OBJECTIVE
The objective of the study was to localize genes contributing to bone mineral density (BMD) variation.


METHODS
An autosomal genome-wide scan for BMD at the lumbar spine and femoral neck was conducted with variance components linkage methods.


METHODS
A total of 103 pedigrees (Network in Europe on Male Osteoporosis Family Study) ascertained through a male relative with low (Z-score < or = -2) BMD values at either lumbar spine or femoral neck.


METHODS
Nonparametric multipoint logarithm of the odds ratio scores for lumbar spine and femoral neck BMD values adjusted for age, gender, and body mass index.


RESULTS
We identified a total of eight chromosomal regions with logarithm of the odds ratio score of 1.5 or greater (P < or = 5 x 10(-3)): on 1q42-43, 11q12-13, 12q23-24, 17q21-23, 21q22, and 22q11 for lumbar spine and on 5q31-33 and 13q12-14 for femoral neck BMD.


CONCLUSIONS
Four of our detected quantitative trait loci (QTL) reached the genome-wide criteria for significant (17q,21-23, P < or = 2 x 10(-5)) or suggestive (11q12-13, 22q11, and 13q12-14, P < or = 7 x 10(-4)) linkage. Apart from 22q11, which is a novel QTL, all other loci provide consistent replication for previously reported QTLs for BMD and other bone-related traits. Finally, several of our specific-linkage areas encompass prominent candidate genes: type 1 collagen (COL1A1) and the sclerosteosis/van Buchem disease (SOST) genes on 17q21-23; the low-density lipoprotein receptor-related protein 5 (LRP5) gene on 11q12-13; and the rank ligand gene on 13q12-14. Further analysis of these positive regions by fine linkage disequilibrium mapping is thus warranted.
Kaufman
Jean-Marc
JM
Institut National de la Santé et de la Recherche Médicale Unit 563, Hôpital Purpan, BP 31024 Toulouse, France.
Ostertag
Agnès
A
Saint-Pierre
Aude
A
Cohen-Solal
Martine
M
Boland
Anne
A
Van Pottelbergh
Inge
I
Toye
Kaatje
K
de Vernejoul
Marie-Christine
MC
Martinez
Maria
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics*; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002882:Chromosomes, Human, Pair 13; D002886:Chromosomes, Human, Pair 17; D002892:Chromosomes, Human, Pair 22; D005190:Family; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D010375:Pedigree; D040641:Quantitative Trait Loci; D044465:White People / Q000235:genetics*