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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.

Objective: Gestational diabetes mellitus (GDM) influences fetal development and offspring's metabolic risk. We evaluated this association in 17-year-old offspring adjusting for birth weight (BW) and prepregnancy maternal BMI (mBMI)., Study Design: The JPS birth cohort contains extensive data on 92,408 births from 1964 to 1976. Offspring's BMI and blood pressure (BP) were obtained from military records. For a subcohort born between 1974 and 1976, prepregnancy mBMI was available. Offspring were classified as born to mothers with GDM (n = 293) or born to mothers without recorded GDM (n = 59,499)., Results: GDM offspring had higher mean BMI and systolic and diastolic BP compared to no-recorded-GDM offspring. After adjusting for BW, GDM remained significantly associated with offspring BMI and diastolic BP (β = 1.169 and 1.520, resp.). In the subcohort, when prepregnancy mBMI was entered to the models, it markedly attenuated the associations with GDM., Conclusions: Maternal characteristics have long-term effects on cardiometabolic outcomes of their offspring aged 17 years.

This study estimated the genetic and environmental determinants of plasma leptin and insulin levels and of obesity-related phenotypes. Included in this analysis were family members from 80 families living in kibbutz settlements, who participated in two examinations 8-10 years apart. We estimated that polygenes explained 30-50% of the adjusted leptin and insulin levels and 30-70% of the anthropometric phenotypes. This study demonstrated a significant genetic influence on longitudinal changes in leptin and BMI (h(2) = 0.45) and small-to-moderate heritability estimates for changes in insulin and other obesity-related phenotypes. In bivariate genetic analyses, we observed positive genetic correlations between leptin and anthropometric phenotypes, suggesting that shared effects of the same sets of loci account for 20-30% of the additive genetic variance in these pairs of variables. Shared genetic factors also account for 20-25% of the additive genetic variance in insulin-anthropometric pairs of variables.

Background: 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. Methods/Results: 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. Conclusions: Maternal genetic variation may account in part for associations of GWG with offspring BMI and WC in young adults. [ABSTRACT FROM AUTHOR]

Background--Accumulating evidence demonstrates that both maternal prepregnancy body mass index (mppBMI) and gestational weight gain (GWG) are associated with adult offspring adiposity. However, whether these maternal attributes are related to other cardiometabolic risk factors in adulthood has not been comprehensively studied. Methods and Results--We used a birth cohort of 1400 young adults born in Jerusalem who had extensive archival data and clinical information at 32 years of age to prospectively examine the associations of mppBMI and GWG with adiposity and related cardiometabolic outcomes. Greater mppBMI, independently of GWG and confounders, was significantly associated with higher offspring BMI, waist circumference, systolic and diastolic blood pressures, insulin, and triglycerides and with lower high-density lipoprotein cholesterol. For example, the effect sizes were translated to nearly 5 kg/m2 higher mean BMI, 8.4 cm higher waist circumference, 0.13 mmol/L (11.4 mg/dL) higher triglycerides, and 0.10 mmol/L (3.8 mg/dL) lower high-density lipoprotein cholesterol among offspring of mothers within the upper mppBMI quartile (mppBMI >26.4 kg/m2) compared with the lower quartile (mppBMI <21.0 kg/m2). GWG, independently of mppBMI, was positively associated with offspring adiposity; differences of 1.6 kg/m2 in BMI and 2.4 cm in waist were observed when offspring of mothers in the upper (GWG >14 kg) and lower (GWG <9 kg) quartiles of GWG were compared. Further adjustment for offspring adiposity attenuated the observed associations to the null. Conclusions--Maternal size both before and during pregnancy is associated with cardiometabolic risk factors in young adult offspring. The associations appear to be driven mainly by offspring adiposity. Future studies that explore mechanisms underlying the intergenerational cycle of obesity are warranted to identify potentially novel targets for cardiometabolic risk-reduction interventions. [ABSTRACT FROM AUTHOR]

Purpose: To explore the association between birth weight in offspring, a marker of the intrauterine environment, and mortality in their mothers, taking into account maternal pre-pregnancy characteristics, including maternal body mass index (BMI), smoking, and socioeconomic status. Distinguishing the effects of offspring''s birth weight and pre-pregnancy characteristics on maternal outcome may provide clues regarding mechanisms underlying the association between birth weight and maternal mortality. Methods: We studied long-term total mortality (average follow-up period, 29.1 years) in a population-based cohort of 13,185 mothers, aged 15 to 48 years at their offspring''s birth, who delivered in West Jerusalem during 1974 through 1976. Results: Univariate and multivariate Cox-proportional hazard models used to estimate the hazard of overall mortality among mothers indicated a nonlinear relationship with birth weight of offspring when introduced into the models as a continuous variable, and a linear positive association with maternal pre-pregnancy BMI. Inclusion of maternal BMI and other pre-pregnancy characteristics in the model did not alter the association between offspring''s birth weight and mothers’ all-cause mortality. When birth weight was introduced as a categorical variable, higher mortality was observed among mothers who gave birth to babies with birth weight less than 2500 g (hazard ratio [HR] = 1.90; 95% confidence interval [95%CI], 1.23–2.94) as compared to mothers whose offspring had birth weight between 3000 and 3499 g. The HR for mothers who gave birth to babies with birth weight 4000 g or more was 1.30 (95%CI, 0.88–1.91). Conclusions: Independent of pre-pregnancy maternal BMI and other characteristics, birth weight of offspring was associated with mortality in their mothers, suggesting that intrauterine metabolic events reflected by birth weight and not explained by maternal obesity, smoking, and socioeconomic status have remote consequences for maternal health. These findings underline the need to explore specific genetic and/or environmental mechanisms that account for these associations. [Copyright &y& Elsevier]