Adult Obesity Influenced by Childhood Genes at Key Development Timepoint

Body mass index (BMI) in infants, children, and adults is influenced by different genetic factors that change as we age, according to the results of a major international study headed by scientists at Imperial College London, the University of Surrey, and the University of Oulu. Their research, founded on a genome-wide association study (GWAS) encompassing data on more than 20,000 infants and children, found that BMI in babies is influenced by a distinct set of genetic variants that play little role in determining weight in later life. The results indicated that it is not until individuals reach 4–7 years of age that genetic variants associated with adult BMI start to play an influential role. This suggests that the origins of obesity in adults may lie during this key stage of childhood.

The new study, published in Science Advances, hints that identifying ways to intervene during childhood may enable the development of new strategies for preventing unhealthy weight trajectories in later life. “Our study shows that nearly 100 genetic variants which increase a person’s risk of obesity in adulthood seem to start taking effect at an important stage of childhood development, from the age of around four,” said senior author Marjo-Riitta Jarvelin, MD, PhD, professor and chair in lifecourse epidemiology at Imperial’s School of Public Health. “Environmental factors like the food we eat and our lifestyle have more and more impact on obesity development as we age. These external factors seem to unmask gradually the genetic contributors to obesity that we have from early life, programming development towards an unhealthy direction.”

The team’s findings are published in a paper titled, “GWAS on longitudinal growth traits reveals different genetic factors influence infant, child, and adult BMI.”

Childhood obesity and its association with later adult health and factors such as social inequality, and psychosocial wellbeing, remain one of the most important “unsolved health concerns of the 21st century,” the authors wrote. They point out that epidemiological studies to date have uncovered “unambiguous” links between changes to childhood BMI trajectories and the risk of adult obesity, type 2 diabetes, and other cardiometabolic disorders. It’s thus possible that genetic and environmental factors that drive child growth may also influence future adult health, and understanding these associations will be key to future clinical potential. “Within this framework, identification of the genetic determinants of the critical periods in child development is important for understanding the mechanisms underpinning adult health and preventing disease development,” the team noted.

“If we can explain what is happening in early life, then we can start to understand why some people become obese and some people don’t even though they are eating the same amount of calories,” Jarvelin commented. “This may allow us to tackle the risk factors that are leading to the obesity epidemic.”

BMI does not follow a linear path through a person’s life. Rather, there are three distinct periods of change. BMI rises rapidly from birth until the age of nine months, at which point it peaks (adiposity peak; AP), before declining again until the age of 5–6 years old. This is known as the adiposity rebound (AR) point. From here an individual’s BMI will steadily increase until early adulthood, and previous studies have suggested that AR is a key period for determining obesity in later life. However, as the authors noted, “We have yet to determine whether changes in timing, velocity, or amplitude of this trajectory, during infancy and childhood, are influenced by specific genetic factors, acting at different developmental stages.”

Their newly reported study was conducted as part of the Early Growth Genetics Consortium, which combines data from multiple GWAS, and was designed to identify genetic variants that might be implicated in human development at different developmental time points. “ … we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health,” the scientists explained.

Their analyses included measures of BMI and growth rates for more than 22,000 infants and children aged from 2 weeks to 13 years. These measures were evaluated in parallel with variations in genetic make-up, to identify common genetic variants associated with the peaks and troughs in BMI, and their timings in childhood.

Adiposity rebound has been identified as a key period for determining obesity in later life and results from the new research may help to explain those findings. The results indicated that common variants at FTP, TFAP2B, and GNPDA2, which linked with the timing of AR and/or BMI-AR, were also associated with adult BMI and other adiposity traits. The findings also highlighted a new genetic variant at the LEPR/LEPOT locus, which impacted on infant BMI. This region harbors the leptin receptor, which in adults is involved in controlling the activity of leptin, a hormone produced by fat cells that regulates appetite. Evidence also suggests that leptin may also play a role in early brain development.

Interestingly, the new gene variant didn’t appear to be associated with adult weight regulation, so its effects may be limited to infancy. “… the newly discovered variant at the LEPR/LEPROT locus associated with BMI-AP did not associate with other growth traits reported here, or in previous studies on childhood/adult BMI and obesity,” the investigators wrote. “This may indicate that genetic variants involved in adult BMI only start influencing BMI after AP and are robustly associated with child BMI by the time of AR … These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.”

Jarvelin said the results indicate that there are “distinct biological processes driving BMI in infancy compared to later in childhood and into adulthood … We have shown that the origins of adult obesity lie in early childhood, and that there are clear windows across the life course which should be better considered in obesity prevention … We would like to further explore this variation in genetic makeup in infancy to better understand its role in development.”

Sylvain Sebert, PhD, an associate professor from the University of Oulu added: “We are hopeful that the next international efforts we are running will help further tackling the early risk of obesity.”