Abstract 16915: The Contactin-Associated Protein-Like 2 gene (CNTNAP2) is Associated with Parent of Origin Effects for Body Mass Index (BMI) in High Risk Families

Abstract

Background: Studies suggest that obesity may be genetically determined and transmitted maternally. Genome-wide association studies (GWAS) of BMI have been reported, but have lacked consideration of parent of origin effects (POE). Important association signals for BMI may therefore have been missed. To find novel loci with differential parental transmission of BMI, we performed a GWAS in 2 generations of healthy Caucasian family members of probands with early onset coronary disease (GeneSTAR).

Methods: All subjects were genotyped with the Illumina 1M chip. Using a two stage model, in Stage 1, we used a non-transmission based test (F-test for heteroskedasticity) to enrich the genomic database for SNPs with a high probability of allelic association with BMI variance (p<10^-6), and in Stage 2 tested only these SNPs for POE- specific associations of genotype with BMI in heterozygous offspring of nuclear families with informative parental genotypes. Stage 1 analysis included 1014 persons (age mean[SD] 46.8±12.9 years, 56% women), and second stage analysis included 211 persons (age mean[SD] 33.3±8.2 years, 51% women) who were excluded from Stage 1. Mixed model regression analyses were adjusted for age, sex, population structure principal components and familial correlation.

Results: Two single nucleotide polymorphism (SNP) signals crossed the Stage 1 threshold (rs17386448, p= 2.2×10^-7; rs12703764, p=3.0×10^-7); rs12703764 (A/C, MAF 6.7%) on chromosome 7 also crossed the Stage 2 Bonferroni-corrected significance level (the maternal vs. paternal A allele was associated with 5.3 kg/m2 higher BMI, p = 0.02). This SNP is 3’ of the CNTNAP2 gene.

Conclusions: Using a 2 stage GWAS approach, we identified a novel SNP in the CNTNAP2 locus, associated with POE-specific BMI, with higher BMI if the A allele is present and inherited from the mother, consistent with maternal transmission. CNTNAP2 is a large neurexin gene; in traditional GWAS, neurexin genes have been associated with waist circumference and BMI, via a putative neurobehavioral mechanism affecting eating behaviors. We also show that family studies and parent of origin effects may uncover biologically plausible novel genetic loci for BMI.