The influence of transmitted and non-transmitted parental BMI-associated alleles on the risk of overweight in childhood

Abstract

Overweight in children is strongly associated with parental body mass index (BMI) and overweight. We assessed parental transmitted and non-transmitted genetic contributions to overweight in children from the Danish National Birth Cohort by constructing genetic risk scores (GRSs) from 941 common genetic variants associated with adult BMI and estimating associations of transmitted maternal/ paternal and non-transmitted maternal GRS with child overweight. Maternal and paternal BMI (standard deviation (SD) units) had a strong association with childhood overweight [Odds ratio (OR): 2.01 (95% confidence interval (CI) 1.74; 2.34) and 1.64 (95% CI 1.43; 1.89)]. Maternal and paternal transmitted GRSs (SD-units) increased odds for child overweight equally [OR: 1.30 (95% CI 1.16; 1.46) and 1.30 (95% CI 1.16; 1.47)]. However, both the parental phenotypic and the GRS associations may depend on maternal BMI, being weaker among mothers with overweight. Maternal non-transmitted GRS was not associated with child overweight [OR 0.98 (95% CI 0.88; 1.10)] suggesting no specific influence of maternal adiposity as such. In conclusion, parental transmitted GRSs, based on adult BMI, contribute to child overweight, but in overweight mothers other genetic and environmental factors may play a greater role. Parental overweight is a potent risk factor for childhood overweight 1 and both maternal and paternal body mass index (BMI) are associated with offspring BMI 2,3. While genetic factors in both parents, transmitted to the children, may explain a major part of these phenotypic associations, shared environmental factors may also operate, as long as they are living together 4-8. Greater maternal adiposity may enhance the risk of overweight in their children, independent of genetic transmission to the child, by altering the environment before, during or after the pregnancy (we will subsequently refer to those as specific maternal effects) 2,9. Evidence of the specific maternal effects have been reported by a number of studies, which compared the strength of the associations of maternal and paternal BMI with childhood BMI 2,10 , whereas other studies suggested little or no such effects 3,11,12. Two studies using intergenerational Mendelian randomization methods, in which maternal genetic variants associated with BMI were used as instrumental variables for greater maternal adiposity, did not find support for effects of the non-transmitted variants on child BMI 13,14. The combined effects in parents and their offspring of genetic factors, shared environmental exposures and lifestyle, in itself being determined by genetic and environmental factors, make it challenging to distinguish and quantify the impact of these factors 15 , but the rapidly expanding series of genetic variants associated with BMI

Intergenerational polygenic obesity risk throughout adolescence in a cross‐sectional study design: The HUNT study, Norway

“…This suggests the absence of dynastic effects by which the offspring phenotype is influenced indirectly by the noninherited alleles affecting parents (i.e., nurturing effects). This is in line with Scnurr et al, which showed maternal nontransmitted genetic risk score (GRS) to not be associated with offspring overweight (41). In disagreement with our results, Kong et al showed that the nontransmitted alleles from parents influence offspring by 29.9% (37), although their study design and trait (education attainment) in focus were different from ours.…”

“…As part of understanding the inheritance of obesity, the effect of nontransmitted alleles from parents that may indirectly affect the genetic variance in a family setting should be considered (37,40,41). This feature, defined as “genetic nurture,” takes into account that nontransmitted obesity‐susceptibility alleles in parents affecting parental obesogenic traits will further influence children's obesity vulnerability indirectly through their home environment (37).…”

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomization using polygenic risk scores

“…Such associations are due to indirect effects of maternal genotype on offspring adiposity, mediated via the offspring's pre or postnatal environment (67) (also known as genetic nurture (68), dynastic effects (69) and social genetic effects (70)). These observed maternal genetic effects merit further investigation in other datasets, particularly as previous studies have not found evidence for parental genetic effects on BMI in childhood (71) or adulthood (68).…”

Is the positive relationship of infant weight gain with adolescent adiposity attenuated by moderate-to-vigorous physical activity in childhood? Evidence from the Millennium Cohort Study

“…The interaction estimates in boys attenuated most upon adjustment for parental BMI values. This is unsurprising given the known strong associations between parental and offspring BMI [7,42], part of which are genetic and part of which are due to shared environmental factors [43,44]. Shared environmental factors are likely to promote rapid infant weight gain and low MVPA, perhaps in addition to genetic effects related to parental BMI [45,46].…”