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Birth Weight Influenced by Environmental, Genetic, Epigenetic Factors

NEW YORK (GenomeWeb) – Environmental, genetic, and epigenetic factors all influence birth weight and early childhood adiposity, according to a new study.

Researchers from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study, a prospective study of the developmental origins of disease, examined the links between those factors and obesity in a cohort of 987 mothers and children. As the A*Star-led researchers reported in BMC Medicine yesterday, they found that maternal lifestyle, as well as fetal genetic and epigenetic factors, affect birth weight and early childhood adiposity both separately and in combination.

"Developmental pathways to adiposity begin before birth," A*Star's Neerja Karnani and her colleagues wrote in their paper. "These pathways may have lasting effects on offspring size, adiposity, and metabolic trajectory, and have utility in identifying individuals who are susceptible to obesity and metabolic disease later in life."

For this study, the researchers drew upon 987 singleton infants born to women enrolled in the GUSTO study. The women and infants were of Chinese, Indian, and Malay ethnicity.

The researchers collected infant weight, length or height, body-mass index, and other measurements for each mother-child pair until the children reached four years of age. They also analyzed 30 prenatal environmental variables, such as maternal pre-pregnancy BMI, gestational weight gain, and fasting glucose, among other factors.

Some 11 of these 30 prenatal environmental variables appeared to influence infant birth weight. For instance, higher infant birth weights were associated with higher maternal pre-pregnancy BMI, gestational weight gain, and height as well as with higher glucose and n-6 polyunsaturated fatty acid levels. Lower infant birth weights, however, were associated with higher maternal monounsaturated fatty acid levels and maternal smoking, both before and during pregnancy.

The researchers developed a polygenic risk score based on genetic variants linked to adult BMI by the GIANT consortium that they applied to their cohort. They found that birth weight increased by 1.6 percent for every two standard deviation increases in risk score. They noted that this effect held even after controlling for the 11 prenatal environmental variables, suggesting that the environment and genetics have independent effects on birth weight.

Karnani and her colleagues also examined the newborns' methylation profiles at more than 174,200 CpG sites. Their epigenome-wide association study homed in on eight CpGs associated with birth weight, six of which were located within protein-coding genes.

The genes harboring these CpGs include ANK3, CACNA1G, CDKN2B, IGDCC4, P4HA3, and ZNF423. Two CpGs mapped to the non-coding MIRLET7BHG.

Methylation levels at three of these eight CpGs were also significantly associated with the prenatal environment, the researchers found. For instance, methylation at IGDCC4 and at CACNA1G was associated with maternal fasting glucose levels and pre-pregnancy BMI

Methylation at all eight CpGs was linked with weight at least one early childhood time point measured, the researchers said, noting that some had effects that were stronger at birth and decreased, while others were strong the decreased and increased again or were strong and then remained the same.

Together, this suggested to the researchers that birth weight is influenced by a combination of genetic and prenatal environmental factors that act both through and independently of the epigenome. This fits with the notion that predisposition to adult diseases like obesity is primed during development by environmental factors through as well as separately from the epigenome, they added. However, they also noted that as the epigenome is malleable, epigenetic variants present at birth have the potential to either become benign or remain detrimental.