Abstract 04: Using family-based genome-wide data to evaluate imprinting and maternal genetic effects: A pilot study of glioma risk.

Introduction: Glioma is the most common malignant brain tumor, however only a few established risk factors have been identified. Recent evidence from a genome-wide linkage scan using a high-density array of single-nucleotide polymorphisms (SNPs) suggests glioma susceptibility is influenced by several genetic loci. While most studies focus on the role of alleles in genes carried by affected individuals (i.e., case genetic effects), other biological mechanisms may also be involved. As some cancer phenotypes may arise in utero, one such mechanism involves maternally mediated genetic effects. Specifically, the mother not only contributes half of her genome to the offspring, she also provides the intrauterine environment of the developing fetus. Variation in the mother's genome could affect the intrauterine environment essential to the normal development. Imprinting effects, where the effect of inherited DNA depends on whether it is transmitted from the mother or the father, may be another biological mechanism important in the etiology of glioma. While these unconventional biological mechanisms may be hard to study with a case-control design, they can be tested using case-parent triads, where affected cases and their parents are genotyped. Methods: Glioma cases and families were recruited from the Gliogene Consortium through The University of Texas MD Anderson Cancer Center, Houston, Texas. DNA samples were genotyped at Baylor College of Medicine using the Human 610-Quad Bead Chip or the Hap370K Bead Chip (Illumina, San Diego, CA). Genotype data were available on a total of 57 complete and incomplete case-parent triads. For this exploratory analysis, we evaluated the 12 “top hits” from a recent assessment of glioma susceptibility among familial glioma cases: PRL rs2064193; LOC389370 rs16886628; PRMT8 rs17780102; STYK1 rs2418087; GRIN2B rs7961199; SOX5 rs7305773; LOC728762 rs9303521; WNT9B rs1530364; SPOP rs6504618; LOC729430 rs1879145; MS12 rs868728; and NFATC1 rs7236492. We applied log-linear models to investigate whether polymorphisms of maternal genes or imprinting effects influence risk of glioma in cases. Results: Three of the 12 SNPs previously identified in a larger study of familial glioma risk also had significant maternal genetic effects, even after adjusting for the case genetic effects. Specifically, maternal genotypes for GRIN2B rs7961199 A>G (OR = 2.45, p = 0.04), NFATC1 rs7236492 C>T (OR = 4.67, p = 0.01), and LOC729430 rs1879145 C>T (OR = 7.86, p = 0.002) were associated with glioma risk. Interestingly, the variant at LOC729430 is located on 17q22-23.2, which appears to be important in familial glioma. Imprinting analyses are currently underway. Conclusions: To our knowledge, this is the first assessment of maternal genetic effects in the context of glioma risk. Furthermore, we employed a family-based design, which allows the assessment of imprinting effects. As the genetic architecture of glioma susceptibility is complex, involving the co-inheritance of multiple risk variants, epistatic interactions, and gene-environment interactions, it is important to explore alternative biological mechanisms using the whole human genome. Our findings suggest that maternal genetic variation may be relevant in the etiology of glioma risk. This work was supported by the National Institutes of Health (R01CA119215). Citation Format: Philip J. Lupo, Michael E. Scheurer, Georgina N. Armstrong, Spiridon Tsavachidis, Yanhong Liu, Ching C. Lau, The Gliogene Consortium, Sanjay Shete, Melissa L. Bondy. Using family-based genome-wide data to evaluate imprinting and maternal genetic effects: A pilot study of glioma risk. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 04.