圆锥角膜同胞对家族的两阶段全基因组连锁扫描

Two-stage genome-wide linkage scan in keratoconus sib pair families.

作者信息

Li Xiaohui, Rabinowitz Yaron S, Tang Yongming G, Picornell Yoana, Taylor Kent D, Hu Mingshu, Yang Huiying

机构信息

Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

出版信息

Invest Ophthalmol Vis Sci. 2006 Sep;47(9):3791-5. doi: 10.1167/iovs.06-0214.

DOI:10.1167/iovs.06-0214

PMID:16936089

Abstract

PURPOSE

To identify susceptibility gene loci for keratoconus.

METHODS

A genome-wide linkage analysis was performed with data from 67 keratoconus sib pair families with 110 affected sib pairs of white or Hispanic origin. A total of 351 subjects were genotyped for 380 microsatellite markers along the genome at approximately 10-cM density. An additional 58 microsatellite markers at approximately 2-cM density in the identified linkage regions on chromosomes 4, 5, 9, 12, and 14 were also genotyped. Multipoint linkage analysis was performed in all pedigrees by nonparametric methods and maximum likelihood estimates of identity by descent sharing as implemented in GeneHunter (http://linkage.rockefeller.edu/soft/gh/ provided in the public domain by Rockefeller University, New York, NY).

RESULTS

The strongest evidence of linkage was observed at the telomere (159 cM) of chromosome 9 (lod = 4.5) in all pedigrees. Other regions suggestive of linkage were identified at 176 cM of chromosome 4 (lod = 2.7), 143 cM of chromosome 5 (lod = 2.0), 7 cM of chromosome 9 (lod = 2.8), 12 cM of chromosome 11 (lod = 2.3), 27 cM of chromosome 12 (lod = 2.3), and 14 cM of chromosome 14 (lod = 2.9). Two significant linkage regions were also observed on chromosomes 17 at 86 cM (lod = 3.9) and 9 at 34 cM (lod = 3.8) in the Hispanic subjects only. After fine mapping these regions (with the exception of chromosomes 11 and 17), most linkage peaks remained similar (lod = 2.2 at 176 cM on chromosome 4; lod = 1.7 at 146 cM on chromosome 5; lod = 3.5 at 160 cM on chromosome 9; lod = 2.5 at 7 cM on chromosome 12; and lod = 2.6 at 19 cM on chromosome 14).

CONCLUSIONS

These results indicate that one or more loci may contribute to keratoconus susceptibility.

摘要

目的

确定圆锥角膜的易感基因位点。

方法

对67个圆锥角膜同胞对家族的数据进行全基因组连锁分析，这些家族中有110对受影响的同胞对，其来源为白种人或西班牙裔。对总共351名受试者进行基因分型，检测沿着基因组以大约10厘摩（cM）密度分布的380个微卫星标记。另外，还对位于4号、5号、9号、12号和14号染色体上已确定的连锁区域中密度约为2厘摩的58个微卫星标记进行基因分型。通过非参数方法在所有家系中进行多点连锁分析，并使用GeneHunter（http://linkage.rockefeller.edu/soft/gh/，由纽约洛克菲勒大学在公共领域提供）中实现的基于同源等位基因共享的最大似然估计。

结果

在所有家系中，9号染色体端粒（159厘摩）处观察到最强的连锁证据（对数优势比分[lod]=4.5）。在4号染色体176厘摩处（lod=2.7）、5号染色体143厘摩处（lod=2.0）、9号染色体7厘摩处（lod=2.8）、11号染色体12厘摩处（lod=2.3）、12号染色体27厘摩处（lod=2.3）和14号染色体14厘摩处（lod=2.9）也发现了提示连锁的其他区域。仅在西班牙裔受试者中，在17号染色体86厘摩处（lod=3.9）和9号染色体34厘摩处（lod=3.8）也观察到两个显著的连锁区域。在对这些区域进行精细定位后（11号和17号染色体除外），大多数连锁峰仍然相似（4号染色体176厘摩处lod=2.2；5号染色体146厘摩处lod=1.7；9号染色体160厘摩处lod=3.5；12号染色体7厘摩处lod=2.5；14号染色体19厘摩处lod=2.6）。