Abstract
Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.
Highlights
Genome-wide association studies (GWAS) have identified multiple loci associated with cardiometabolic risk (CMR) phenotypes and traits, such as adiposity and glycemic traits (e.g [1,2,3,4])
Genetic variants identified in large-scale genetic studies using recent technical and methodological advances explain only a small proportion of the genetic basis of obesity, diabetes and other cardiovascular risk factors
By examining 1250 young adults and their mothers from Jerusalem, we show that a specific genetic variant, rs1367117, located in the APOB gene on chromosome 2 is related to body mass index and waist circumference when inherited from mother and not from father
Summary
Genome-wide association studies (GWAS) have identified multiple loci associated with cardiometabolic risk (CMR) phenotypes and traits, such as adiposity and glycemic traits (e.g [1,2,3,4]). To explain the “missing” heritability, various research strategies for follow-up studies have been proposed, including focusing on gene-environment interactions, on rare variants with moderate effects and on parent-of-origin effects (POEs) [7, 9]. POEs are non-Mendelian transmittable genetic effects on phenotypes, where the phenotype in offspring depends on whether transmission originated from the mother or father. POEs can be caused by genomic imprinting, maternal genetic effects on the intrauterine environment, or maternally inherited mitochondrial genes [10]. The most obvious mechanism underlying POEs is genomic imprinting; imprinted genes show parental-specific monoallelic or partial expression, dictated by the parental origin of the chromosome [11, 12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
