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Study Sees Year-of-Birth Influence Over Obesity Risk Variant Association

NEW YORK (GenomeWeb) – In a study appearing online this week in the Proceedings of the National Academy of Sciences, researchers from Yale University and elsewhere describe apparent shifts in penetrance for an obesity-related variant depending on an individual's year of birth.

The researchers relied on body mass index data collected for the Framingham Heart Study between 1971 and 2008, analyzing BMI in individuals from different age groups in relation to the genotype of FTO, a gene previously implicated in obesity.

Their analyses revealed a closer association between BMI and FTO gene variant status in individuals born since 1942, suggesting year of birth and related environmental factors can impact FTO genotype-obesity phenotype interactions.

"These results — to our knowledge the first of their kind — suggest that this and perhaps other correlations between gene variants and physical traits may very significantly depending on when individuals were born, even for those born into the same families," the study's first author James Niels Rosenquist, a psychiatry researcher at Harvard Medical School, said in a statement.

"We know that environment plays a huge role in the expression of genes," Rosenquist added, "and the fact that our effect can be seen even among siblings born during different years implies that global environmental factors such as trends in food products and workplace activity, not just those found within families, may impact genetic traits."

Past research has highlighted an association between BMI and a variant in the FTO gene known as rs993609. Nevertheless, Rosenquist and his colleagues noted that there are unresolved questions about the relative influence of genetics and environment in obesity and other traits, particularly given the uptick in BMI in Western populations in the recent decades.

"Although … research studies were typically not designed to assess interactions between genetic variants and environmental factors, it is likely that environmental effects are modulated by genetic pathways," they wrote, "causing some individuals or population groups to be differentially affected by changes in the environment."

With that in mind, the researchers decided to explore genotype-phenotype effects on BMI using longitudinal data collected for more than 5,200 participants in the Framingham Heart Study and another 5,124 of their children and/or children's spouses in the "Offspring Cohort."

For the offspring study, researchers explained, individuals periodically filled out questionnaires and underwent physical exams that included BMI measurements. In addition, more than 3,700 of participants had been genotyped using Affymetrix arrays.

Based on data for these individuals, who were born over a span of some 40 years, the team used age-period-cohort regression models to assess potential relationships between BMI and rs993609 variant status in individuals who were between 27 and 63 years old during each of the time frames considered.

Somewhat unexpectedly, researchers did not see significant ties between BMI and FTO genotype in individuals born prior to 1942. On the other hand, they reported, the rs993609 variant was associated with BMI in individuals born after 1942, apparently growing stronger for those from cohorts born more recently.

"Our results suggest that the well-documented rise in BMI in the United States over the past 40 [years] may have been disproportionately driven by individuals for whom genetic factors interacted with environmental changes encountered in their development due to their era of birth — in this case, being born later," authors of the study explained.

Such apparent shifts in penetrance by the obesity-linked FTO allele hint at more widespread effects for birth year as a factor when interpreting genome-wide association studies of other traits and conditions.

"Our results underscore the importance of interpreting any genetic studies with a grain of salt and leave open the possibility that new genetic risk factors may be seen in the future due to different genetically driven responses to our ever-changing environment," Rosenquist said in a statement.