Maternal Genetic Variation Accounts in Part for the Associations of Maternal Size during Pregnancy with Offspring Cardiometabolic Risk in Adulthood

<div><p>Background</p><p>Maternal pre-pregnancy body-mass index (ppBMI) and gestational weight gain (GWG) are associated with cardiometabolic risk (CMR) traits in the offspring. The extent to which maternal genetic variation accounts for these associations is unknown.</p><p>Methods/Results</p><p>In 1249 mother-offspring pairs recruited from the Jerusalem Perinatal Study, we used archival data to characterize ppBMI and GWG and follow-up data from offspring to assess CMR, including body mass index (BMI), waist circumference, glucose, insulin, blood pressure, and lipid levels, at an average age of 32. Maternal genetic risk scores (GRS) were created using a subset of SNPs most predictive of ppBMI, GWG, and each CMR trait, selected among 1384 single-nucleotide polymorphisms (SNPs) characterizing variation in 170 candidate genes potentially related to fetal development and/or metabolic risk. We fit linear regression models to examine the associations of ppBMI and GWG with CMR traits with and without adjustment for GRS. Compared to unadjusted models, the coefficient for the association of a one-standard-deviation (SD) difference in GWG and offspring BMI decreased by 41% (95%CI −81%, −11%) from 0.847 to 0.503 and the coefficient for a 1SD difference in GWG and WC decreased by 63% (95%CI −318%, −11%) from 1.196 to 0.443. For other traits, there were no statistically significant changes in the coefficients for GWG with adjustment for GRS. None of the associations of ppBMI with CMR traits were significantly altered by adjustment for GRS.</p><p>Conclusions</p><p>Maternal genetic variation may account in part for associations of GWG with offspring BMI and WC in young adults.</p></div

Characteristics at birth and age 32, stratified by offspring sex.

<p>Values are expressed as mean (SD) or percent.</p><p>*Diabetes, hypertension, heart disease, or pre-eclampsia.</p><p>**Includes self-report of moderate or vigorous physical activity lasting at least 20 minutes, 3 or more time a week.</p

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

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

Parent-of-origin effects of <i>APOB</i> SNP rs1367117^a on adiposity and glycemic traits.

<p>JPS, Jerusalem Perinatal Study; FHS, Framingham Heart Study; FamHS, Family Heart Study; ERF, Erasmus Rucphen Family</p><p>^a Minor allele frequency (MAF) of SNP rs1367117 across studies: JPS 0.2, FHS 0.31, FamHS 0.34 (imputed data, R² = 0.925), ERF 0.31.</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>Parent-of-origin effects of <i>APOB</i> SNP rs1367117<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005573#t001fn002" target="_blank">^a</a> on adiposity and glycemic traits.</p

Genotype effect of APOB SNP rs1367117 on cardio-metabolic traits.

<p>JPS, Jerusalem Perinatal Study; FHS, Framingham Heart Study; FamHS, Family Heart Study; ERF, Erasmus Rucphen Family</p><p>^a Based on an additive genetic model.</p><p>^b Numbers of probands included in the genotype effect analysis are larger compared to the POE analysis due to exclusion of individuals who were non-informative for parental transmission.</p><p>Genotype effect of APOB SNP rs1367117 on cardio-metabolic traits.</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

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

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

Indicators of parental origin of the minor allele in JPS.

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