Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.

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

Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.

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

Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults

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 p0.6). 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

Estimated dosage of maternally- and paternally-derived minor allele indicators for heterozygous (Aa) mothers-offspring pairs.

<p>Estimated dosage of maternally- and paternally-derived minor allele indicators for heterozygous (Aa) mothers-offspring pairs.</p

Indicators of parental origin of the minor allele in JPS.

<p>Indicators of parental origin of the minor allele in JPS.</p

Parent-of-origin effects of <i>APOB</i> SNP rs1367117 on adiposity traits in JPS.

<p>This figure illustrates the associations between <i>APOB</i> SNP rs1367117 and offspring BMI (top panel) and waist circumference (WC) (bottom panel). Adjusted means and standard errors (represented by error bars) for BMI and WC by genotype were determined using estimates from linear regression models adjusted for ethnicity and gender. Comparing offspring genotype effect (left panel), maternally-derived effect (middle panel) and paternally-derived effect (right panel) reveals a strengthened and more significant maternal-specific association with both traits.</p

Bioinformatic annotation for the <i>APOB</i> locus.

<p>Bioinformatic annotation was undertaken for rs1367117, located within the 4th exon of the <i>APOB</i> gene, using the Epigenome Browser (<a href="http://epigenomegateway.wustl.edu/" target="_blank">http://epigenomegateway.wustl.edu/</a>). <i>APOB</i> gene is shown in the blue track and the focal SNP with a vertical bar. Level of DNA methylation (whole genome bisulfite sequencing, or WGBS), histone marks indicative of promoters (H3K4me3) and enhancers (H3K4me1), and expression levels (RNA-seq) were plotted in three relevant tissues: liver, adipose, and small intestine.</p

Combined* maternally-derived effects of SNPs spanning the <i>APOB</i> locus on BMI.

<p>Forty two SNPs spanning the APOB genomic locus with their corresponding meta-analysis (z-based) p-values for the maternally-derived associations (as -log10 values) are plotted as a function of chromosomal position. Estimated recombination rates are plotted to reflect the local LD structure around the associated SNP (blue) and its correlated proxies (red:R²≥0.8; orange:0.5≥R²>0.8; yellow:0.2≥R²>0.5; white:R²<0.2). Combined (Z-based) p-value for <i>APOB</i> SNP rs1367117 excluding JPS is 7.4x10^-5 (presented in figure). Corresponding p-value including JPS is 7.8x10^-6 (presented in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005573#pgen.1005573.t001" target="_blank">Table 1</a>). *Results used to generate the plot are based on genome-wide data available in FHS, FamHS and ERF (and not including JPS where data are not available).</p

Maternally-derived effects of <i>APOB</i> SNP rs1367117 on cardio-metabolic traits with and without adjustment for BMI^a.

<p>JPS, Jerusalem Perinatal Study; FHS, Framingham Heart Study; FamHS, Family Heart Study; ERF, Erasmus Rucphen Family</p><p>^a Presented betas and standard errors (SEs) are based on models without adjustment for BMI. P-values are presented for models with and without further adjustment for BMI. Beta and standard errors for BMI-adjusted models as well as for paternally-derived effects are provided in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005573#pgen.1005573.s008" target="_blank">S7 Table</a>.</p><p>^b Standard errors (SEs) were calculated directly in JPS; in the other studies SEs were estimated by converting p-values into a z-statistic and setting: SE = beta/z.</p><p>Maternally-derived effects of <i>APOB</i> SNP rs1367117 on cardio-metabolic traits with and without adjustment for BMI<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005573#t002fn002" target="_blank">^a</a>.</p

Genes selected for examination of parent-of-origin effects in JPS.

<p>Genes selected for examination of parent-of-origin effects in JPS.</p