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

TitleGenome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium.
Publication TypeJournal Article
Year of Publication2011
AuthorsShete, 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, EHon-chiu, Davis, C, Cheng, R, Hosking, FJ, Armstrong, GN, Liu, Y, Yu, RK, Henriksson, R, Melin, BS, Bondy, ML
Corporate AuthorsGliogene Consortium
JournalCancer Res
Volume71
Issue24
Pagination7568-75
Date Published2011 Dec 15
ISSN1538-7445
KeywordsAdolescent, Adult, Aged, Brain Neoplasms, Child, Chromosome Mapping, Family Health, Female, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Glioma, Humans, Linkage Disequilibrium, Lod Score, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, United States, Young Adult
Abstract

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.

DOI10.1158/0008-5472.CAN-11-0013
Alternate JournalCancer Res.
PubMed ID22037877
PubMed Central IDPMC3242820
Grant ListR01 CA052689-17 / CA / NCI NIH HHS / United States
R01CA126831 / CA / NCI NIH HHS / United States
5R01 CA119215 / CA / NCI NIH HHS / United States
5P30CA16672 / CA / NCI NIH HHS / United States
R01 CA126831 / CA / NCI NIH HHS / United States
R01 CA119215-05 / CA / NCI NIH HHS / United States
5R01 CA070917 / CA / NCI NIH HHS / United States
R01 CA070917 / CA / NCI NIH HHS / United States
R01 CA126831-05 / CA / NCI NIH HHS / United States
R01 CA119215 / CA / NCI NIH HHS / United States
R01CA52689 / CA / NCI NIH HHS / United States
R01 CA070917-09 / CA / NCI NIH HHS / United States
P50097257 / / PHS HHS / United States
R01 CA052689 / CA / NCI NIH HHS / United States