通过男性亲属低骨密度值确定的欧洲家系中骨密度（BMD）的全基因组连锁筛查：17q21 - 23、11q12 - 13、13q12 - 14和22q11上数量性状位点的证据

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.

作者信息

Kaufman Jean-Marc, Ostertag Agnès, Saint-Pierre Aude, Cohen-Solal Martine, Boland Anne, Van Pottelbergh Inge, Toye Kaatje, de Vernejoul Marie-Christine, Martinez Maria

机构信息

Institut National de la Santé et de la Recherche Médicale Unit 563, Hôpital Purpan, BP 31024 Toulouse, France.

出版信息

J Clin Endocrinol Metab. 2008 Oct;93(10):3755-62. doi: 10.1210/jc.2008-0678. Epub 2008 Jul 29.

DOI:10.1210/jc.2008-0678

PMID:18664539

Abstract

CONTEXT

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.

DESIGN

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

PARTICIPANTS

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.

MAIN OUTCOME MEASURES

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.

摘要

背景

骨量受强大的基因控制，遗传度估计超过50%，可能由基因和环境因素之间的复杂相互作用决定。

目的

本研究的目的是定位导致骨矿物质密度（BMD）变异的基因。

设计

采用方差成分连锁法对腰椎和股骨颈的BMD进行常染色体全基因组扫描。

参与者

通过腰椎或股骨颈BMD值较低（Z分数≤ -2）的男性亲属确定了总共103个家系（欧洲男性骨质疏松症家族研究网络）。

主要观察指标

根据年龄、性别和体重指数调整后的腰椎和股骨颈BMD值的非参数多点优势比对数分数。

结果

我们共鉴定出8个染色体区域，其优势比对数分数为1.5或更高（P≤5×10⁻³）：腰椎的1q42 - 43、11q12 - 13、12q23 - 24、17q21 - 23、21q22和22q11区域，以及股骨颈BMD的5q31 - 33和13q12 - 14区域。

结论

我们检测到的四个数量性状位点（QTL）达到了全基因组显著（17q21 - 23，P≤2×10⁻⁵）或提示性（11q12 - 13、22q11和13q12 - 14，P≤7×10⁻⁴）连锁的标准。除了新的QTL 22q11外，所有其他位点为先前报道的BMD和其他骨相关性状的QTL提供了一致的重复验证。最后，我们的几个特定连锁区域包含了重要的候选基因：17q21 - 23上的1型胶原蛋白（COL1A1）和硬骨病/范布赫姆病（SOST）基因；11q12 - 13上的低密度脂蛋白受体相关蛋白5（LRP5）基因；以及13q12 - 14上的Rank配体基因。因此，有必要通过精细连锁不平衡图谱对这些阳性区域进行进一步分析。