Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium.

Published

Journal Article

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma.

Full Text

Duke Authors

Cited Authors

  • Shete, S; Lau, CC; Houlston, RS; Claus, EB; Barnholtz-Sloan, J; Lai, R; Il'yasova, D; Schildkraut, J; Sadetzki, S; Johansen, C; Bernstein, JL; Olson, SH; Jenkins, RB; Yang, P; Vick, NA; Wrensch, M; Davis, FG; McCarthy, BJ; Leung, EH-C; Davis, C; Cheng, R; Hosking, FJ; Armstrong, GN; Liu, Y; Yu, RK; Henriksson, R; Gliogene Consortium, ; Melin, BS; Bondy, ML

Published Date

  • December 15, 2011

Published In

Volume / Issue

  • 71 / 24

Start / End Page

  • 7568 - 7575

PubMed ID

  • 22037877

Pubmed Central ID

  • 22037877

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-11-0013

Language

  • eng

Conference Location

  • United States