Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium.
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.
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. sshete@mdanderson.org
Sanjay
S
Shete
Ching C
CC
Lau
Richard S
RS
Houlston
Elizabeth B
EB
Claus
Jill
J
Barnholtz-Sloan
Rose
R
Lai
Dora
D
Il'yasova
Joellen
J
Schildkraut
Siegal
S
Sadetzki
Christoffer
C
Johansen
Jonine L
JL
Bernstein
Sara H
SH
Olson
Robert B
RB
Jenkins
Ping
P
Yang
Nicholas A
NA
Vick
Margaret
M
Wrensch
Faith G
FG
Davis
Bridget J
BJ
McCarthy
Eastwood Hon-chiu
EH
Leung
Caleb
C
Davis
Rita
R
Cheng
Fay J
FJ
Hosking
Georgina N
GN
Armstrong
Yanhong
Y
Liu
Robert K
RK
Yu
Roger
R
Henriksson
Beatrice S
BS
Melin
Melissa L
ML
Bondy
D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002874:Chromosome Mapping; D005192:Family Health; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014481:United States; D055815:Young Adult