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Significance
Our finding of a significant gene-by-birth-cohort interaction adds a previously unidentified dimension to gene-by-environment interaction research, suggesting that global changes in the environment over time can modify the penetrance of genetic risk factors for diverse phenotypes. This result also suggests that presence (or absence) of...
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Context 1
... Figs. 2-4, we demonstrate that the age gradient in BMI does not significantly differ for individuals with the TT genotype across birth cohorts (Fig. 4). In contrast, we not only observe a significantly different FTO-BMI relationship across ages for those with the AT genotype, but the age gradient documented in Fig. 3 becomes steeper in the post-1942 cohort. Last, whereas the estimates in Table 2 showed that individuals with the AA polymorphism had significantly higher BMI in both the pre-and post-1942 cohorts, we did not find a significant difference in the BMI age gradient between cohorts (Fig. 2), although this may be due to low power resulting from the smaller sample size. Taken together, the set of Figs. 2-4 illustrate that there is an age gradient across all genotypes, but it does not point to an overall steepening of the age gradient. The results continue to point out differences in the estimated relationships be- tween those born before and after 1942, and, given our sample size, it would not be surprising if, with additional data, we would see the observed difference in the BMI age gradient for the AA genotype become statistically significant. Last, we note that the statistically significant differences in BMI between and within birth cohorts on the basis of genotype do not arise due to the specification of our linear model and are also observed when simply comparing the unconditional sample means of BMI across genetic variant, birth cohorts, and 5-y age intervals (as reported in Table ...
Context 2
... Figs. 2-4, we demonstrate that the age gradient in BMI does not significantly differ for individuals with the TT genotype across birth cohorts (Fig. 4). In contrast, we not only observe a significantly different FTO-BMI relationship across ages for those with the AT genotype, but the age gradient documented in Fig. 3 becomes steeper in the post-1942 cohort. Last, whereas the estimates in Table 2 showed that individuals with the AA polymorphism had significantly higher BMI in both the pre-and post-1942 cohorts, we did not find a significant difference in the BMI age gradient between cohorts (Fig. 2), although this may be due to low power resulting from the smaller sample size. Taken together, the set of Figs. 2-4 illustrate that there is an age gradient across all genotypes, but it does not point to an overall steepening of the age gradient. The results continue to point out differences in the estimated relationships be- tween those born before and after 1942, and, given our sample size, it would not be surprising if, with additional data, we would see the observed difference in the BMI age gradient for the AA genotype become statistically significant. Last, we note that the statistically significant differences in BMI between and within birth cohorts on the basis of genotype do not arise due to the specification of our linear model and are also observed when simply comparing the unconditional sample means of BMI across genetic variant, birth cohorts, and 5-y age intervals (as reported in Table ...
Context 3
... second limitation of our study is that all of the observations in our analyses were of adults; hence, we cannot examine critical periods of growth and development where many environmental factors particular to given birth cohorts may have been influential. Because most evidence suggests that the genetic influences on BMI heterogeneity are first seen in childhood and may relate to food intake levels in that developmental period (1,(38)(39)(40)(41), studies of younger subjects may elucidate which particular environmental influences might be interacting with genetic factors. Third, our observation that the 95% confidence bands for those with the AA genotype overlap between the two cohorts in Fig. 2 may reflect limited power to detect an effect and/or the stronger relative im- pact of birth-cohort-associated-factors on heterozygotes. However, in addition to sample size differences, nonlinearity in the effects of the A allele on BMI is also a possibility (42). Fourth, there re- mains the possibility of sample selection bias arising from subjects in the older cohort dying before the time when they would have been genotyped, particularly if those who died were dispropor- tionately heavier or of a certain genotype, although we saw no evidence of this in measured ...
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Citations
... However, the pattern of increasing obesogenic genes does support the microevolutionary hypothesis by itself. For example Rosenquist et al. (33) reported the gene pool frequency of the well known obesity promoting allele FTO pre and post 1942. Comparing the frequency of the obesity prone homozygote (AA) and heterozygote (AT), with the frequency of the obesity protective homozygote (TT) in the birth cohorts born before 1942 finds the pre 1942 frequency of the AA/AT was 63.1% compared with the post 1942 frequency of 66.7%. ...
The obesity epidemic represents potentially the largest phenotypic change in Homo sapiens since the origin of the species. Despite obesity’s high heritability, a change in the gene pool has not generally been presumed as a potential cause of the obesity epidemic. Here we advance the hypothesis that a rapid change in the obesogenic gene pool has occurred second to the introduction of modern obstetrics dramatically altering evolutionary pressures on obesity - the microevolutionary hypothesis of the obesity epidemic. Obesity is known to increase childbirth related mortality several fold. Prior to modern obstetrics, childbirth related mortality occurred in over 10% of women. After modern obstetrics, this mortality reduced to a fraction of a percent, thereby lifting a strong negative selection pressure. Regression analysis of data for ∼ 190 countries was carried out to examine associations between 1990 maternal death rates (MDR) and current obesity rates. Multivariate regression showed MDR correlated more strongly with national obesity rates than GDP, calorie intake and physical inactivity. Analyses controlling for confounders via partial correlation show that MDR explains approximately 11% of the variability of obesity rate between nations. For nations with MDR above the median (>0.45%), MDR explains over 20% of obesity variance, while calorie intake, and physical inactivity show no association with obesity in these nations. The microevolutionary hypothesis offers a parsimonious explanation of the global nature of the obesity epidemic.
Significance Statement
Humans underwent a rapid increase in obesity in the 20 th century, and existing explanations for this trend are unsatisfactory. Here we present evidence that increases in obesity may be in large part attributable to microevolutionary changes brought about by dramatic reduction of childbirth mortality with the introduction of modern obstetrics. Given the higher relative risk of childbirth in women with obesity, obstetrics removed a strong negative selection pressure against obesity. This alteration would result in a rapid population-wide rise in obesity-promoting alleles. A cross-country analysis of earlier maternal death rates and obesity rate today found strong evidence supporting this hypothesis. These findings suggest recent medical intervention influenced the course of human evolution more profoundly than previously realized.
... Genotype-birth cohort interactions for the debute of alcohol consumption or frequent alcohol use in early age were also found with other functional gene variants such as VMAT1 (rs1390938), NRG1 (rs6994992) and OXTR (rs53576) (see for review). Birth cohort can modify even the associations between genotype and somatic measures such as body mass index (Rosenquist et al., 2015). Given that NPY is related to anxiety regulation and social behaviour, we hypothesised that functional variants of NPY may interact with the birth cohort in shaping sociability-related traits. ...
... The fact that NPY genotypes are not directly associated with personality traits but interact with birth cohort to predict Agreeableness and its facets suggests that these genetic associations relate to the variation in environmental contexts. It is likely that the impact of environmental effects is modulated by genetic pathways, causing some individuals or population groups to be differentially affected by composite changes in the environment leading to birth cohort effects (Rosenquist et al., 2015). Possibly, the NPY gene variants might have an effect either on coping styles with stress through personality-dependent choices or through modifying the interpretation of stressful events. ...
Objective:
Neuropeptide Y (NPY) is a powerful regulator of anxious states, including social anxiety, but evidence from human genetic studies is limited. Associations of common gene variants with behaviour have been described as subject to birth cohort effects especially if the behaviour is socially motivated. This study aimed to examine the association of NPY rs16147 and rs5574 with personality traits in highly representative samples of two birth cohorts of young adults, the samples having been formed during a period of rapid societal transition.
Methods:
Both birth cohorts (original n= 1238) of the Estonian Children Personality Behaviour and Health Study (ECPBHS) self-reported personality traits of the five-factor model at 25 years of age.
Results:
A significant interaction effect of the NPY rs16147 and rs5574 and birth cohort on Agreeableness was found. The T/T genotype of NPY rs16147 resulted in low Agreeableness in the older cohort (born 1983) and in high Agreeableness in the younger cohort (born 1989). The C/C genotype of NPY rs5574 was associated with higher Agreeableness in the younger but not in the older cohort. In the NPY rs16147 T/T homozygotes, the deviations from average in Agreeableness within the birth cohort were dependent on the serotonin transporter promoter polymorphism.
Conclusions:
The association between the NPY gene variants and a personality domain reflecting social desirability is subject to change qualitatively in times of rapid societal changes, serving as an example of the relationship between the plasticity genes and environment. The underlying mechanism may involve the development of the serotonergic system.
... [6][7][8]15 Two previous studies in FHS had sought to examine geneby-birth cohort interactions on BMI. 15,16 One of the studies using the Offspring cohort (N=3720) detected an interaction between a FTO SNP (rs9939609, linkage disequilibrium: r 2 ≥0.9 with rs9922708 in our study) and birth cohort on BMI. 16 Another study on ≈5000 unrelated FHS participants described a gene by historical period interaction whereby genetic effects on BMI were larger after 1985 compared with before 1985. ...
... 15,16 One of the studies using the Offspring cohort (N=3720) detected an interaction between a FTO SNP (rs9939609, linkage disequilibrium: r 2 ≥0.9 with rs9922708 in our study) and birth cohort on BMI. 16 Another study on ≈5000 unrelated FHS participants described a gene by historical period interaction whereby genetic effects on BMI were larger after 1985 compared with before 1985. The authors further concluded that this genetic influence weakened over the life course. ...
Background
Whether genetics contribute to the rising prevalence of obesity or its cardiovascular consequences in today’s obesogenic environment remains unclear. We sought to determine whether the effects of a higher aggregate genetic burden of obesity risk on body mass index (BMI) or cardiovascular disease (CVD) differed by birth year.
Methods
We split the FHS (Framingham Heart Study) into 4 equally sized birth cohorts (birth year before 1932, 1932 to 1946, 1947 to 1959, and after 1960). We modeled a genetic predisposition to obesity using an additive genetic risk score (GRS) of 941 BMI-associated variants and tested for GRS–birth year interaction on log-BMI (outcome) when participants were around 50 years old (N=7693). We repeated the analysis using a GRS of 109 BMI-associated variants that increased CVD risk factors (type 2 diabetes, blood pressure, total cholesterol, and high-density lipoprotein) in addition to BMI. We then evaluated whether the effects of the BMI GRSs on CVD risk differed by birth cohort when participants were around 60 years old (N=5493).
Results
Compared with participants born before 1932 (mean age, 50.8 yrs [2.4]), those born after 1960 (mean age, 43.3 years [4.5]) had higher BMI (median, 25.4 [23.3–28.0] kg/m ² versus 26.9 [interquartile range, 23.7–30.6] kg/m ² ). The effect of the 941-variant BMI GRS on BMI and CVD risk was stronger in people who were born in later years (GRS–birth year interaction: P =0.0007 and P =0.04 respectively).
Conclusions
The significant GRS–birth year interactions indicate that common genetic variants have larger effects on middle-age BMI and CVD risk in people born more recently. These findings suggest that the increasingly obesogenic environment may amplify the impact of genetics on the risk of obesity and possibly its cardiovascular consequences.
... Work in this area has demonstrated how effects that appear conceptually distinct can be difficult to distinguish when specified in models . Changes in genetic effects modeled in terms of cohorts (e.g., Rosenquist et al., 2015;Sanz-de-Galdeano, Terskaya, & Upegui, 2020), for example, might equivalently be framed in terms of periods (e.g., war, socioeconomic conditions, or policy eras) which are often implicitly the focus of explanation anyway. Other research suggests that apparently simple sociological concepts might require relatively complex model features to capture when considered simultaneously against the backdrop of development . ...
We need better understanding of functional differences of behavioral phenotypes across cultures because cultural evolution (e.g., temporal changes in innovation within populations) is less important than culturally molded phenotypes (e.g., differences across populations) for understanding gene effects. Furthermore, changes in one behavioral domain likely have complex downstream effects in other domains, requiring careful parsing of phenotypic variability and functions.
... Work in this area has demonstrated how effects that appear conceptually distinct can be difficult to distinguish when specified in models . Changes in genetic effects modeled in terms of cohorts (e.g., Rosenquist et al., 2015;Sanz-de-Galdeano, Terskaya, & Upegui, 2020), for example, might equivalently be framed in terms of periods (e.g., war, socioeconomic conditions, or policy eras) which are often implicitly the focus of explanation anyway. Other research suggests that apparently simple sociological concepts might require relatively complex model features to capture when considered simultaneously against the backdrop of development . ...
Epigenetics impacts gene–culture coevolution by amplifying phenotypic variation, including clustering, and bridging the difference in timescales between genetic and cultural evolution. The dual inheritance model described by Uchiyama et al. could be modified to provide greater explanatory power by incorporating epigenetic effects.
... Work in this area has demonstrated how effects that appear conceptually distinct can be difficult to distinguish when specified in models . Changes in genetic effects modeled in terms of cohorts (e.g., Rosenquist et al., 2015;Sanz-de-Galdeano, Terskaya, & Upegui, 2020), for example, might equivalently be framed in terms of periods (e.g., war, socioeconomic conditions, or policy eras) which are often implicitly the focus of explanation anyway. Other research suggests that apparently simple sociological concepts might require relatively complex model features to capture when considered simultaneously against the backdrop of development . ...
We argue that heritability estimates cannot be used to make informed judgments about the populations from which they are drawn. Furthermore, predicting changes in heritability from population changes is likely impossible, and of limited value. We add that the attempt to separate human environments into cultural and non-cultural components does not advance our understanding of the environmental multiplier effect.
... Work in this area has demonstrated how effects that appear conceptually distinct can be difficult to distinguish when specified in models . Changes in genetic effects modeled in terms of cohorts (e.g., Rosenquist et al., 2015;Sanz-de-Galdeano, Terskaya, & Upegui, 2020), for example, might equivalently be framed in terms of periods (e.g., war, socioeconomic conditions, or policy eras) which are often implicitly the focus of explanation anyway. Other research suggests that apparently simple sociological concepts might require relatively complex model features to capture when considered simultaneously against the backdrop of development . ...
Uchiyama et al. rightly consider how cultural variation may influence estimates of heritability by contributing to environmental sources of variation. We disagree, however, with the idea that generalisable estimates of heritability are ever a plausible aim. Heritability estimates are always context-specific, and to suggest otherwise is to misunderstand what heritability can and cannot tell us.
... Obesity is a global pandemic with immense health consequences for individuals and societies. 1,2 Multiple factors, including genetic predispositions, 3,4 mode of delivery, 5,6 breastfeeding, 7 exercises, 8 and diet, 9 have been shown to affect the risk of development of obesity. In the last decade, the microbiome field has made tremendous progress in identifying a link between intestinal dysbiosis and obesity. ...
Fecal microbiota transplantation (FMT) has shown promising results in animal models of obesity, while results in human studies are inconsistent. We aimed to determine factors associated with weight loss after FMT in nine obese subjects using serial multi-omics analysis of the fecal and mucosal microbiome. The mucosal microbiome, fecal microbiome, and fecal metabolome showed individual clustering in each subject after FMT. The colonic microbiome in patients showed more marked variance after FMT compared with the duodenal microbiome, characterized by an increased relative abundance of Bacteroides. Subjects who lost weight after FMT sustained enrichment of Bifidobacterium bifidum and Alistipes onderdonkii in the duodenal, colonic mucosal, and fecal microbiome and increased levels of phosphopantothenate biosynthesis and fecal metabolite eicosapentaenoic acid (EPA), compared with those without weight loss. Fecal levels of amino acid metabolism-associated were positively correlated with the fecal abundance of Bifidobacterium bifidum, and fatty acid metabolism-associated metabolites showed positive correlations with Alistipes onderdonkii. We report for the first time the individualized response of fecal and mucosa microbiome to FMT in obese subjects and highlight that FMT is less capable of shaping the small intestine microbiota. These findings contribute to personalized microbe-based therapies for obesity.
... Birth cohort has been used as a proxy for exposure to obesogenic environments. A recent study demonstrated that birth cohort modified the association between FTO and BMI, suggesting that genotype-phenotype (outcome) correlations are likely highly dependent on the time period or birth cohort of individuals (Rosenquist et al. 2015). Using a polygenic score for BMI, another study found that the magnitude of associations of the polygenic score for BMI were larger for more recent cohorts (Walter et al. 2016). ...
... Available evidence suggests being overweight or obese at some point in early stages of life (e.g., childhood or adolescence) is significantly correlated with overweight, obesity, and related health outcomes in later life (Guo et al., 2000;Guo et al., 2002;Maner et al., 2017;Olsen et al., 2006;Simmonds et al., 2016;Singh et al., 2008;Stokes and Preston, 2016). Birth cohort effects have been found to shape body mass index (BMI) patterns at the country level; noteworthy examples include the United States (Reither et al., 2009;Rosenquist et al., 2015), Denmark (Olsen et al., 2006), and France (Diouf et al., 2010). The nexus between overweight/obesity and non-communicable diseases suggests that the observed historical growth and patterns in adult BMI represent an important 'canary in the coal mine' for developing a better understanding of the drivers shaping BMI in current cohorts as potential future trends and momentum in adult obesity and related health outcomes. ...
Current trends in adult obesity threaten global health. Although the implications of changes in diets, lifestyles, and food environments have been examined, the specific role of excess calorie availability (ECA)—understood as calorie availability in excess of human requirements for a healthy life—and the cohort mechanisms that underlie trends in adult body mass index (BMI) are poorly understood. We examine these relationships for 156 countries over the past century using an age-, sex-, and cohort-specific approach. We measure the association between increases in food energy supply and changes in BMI across countries and time. We find positive and significant associations between ECA and adult BMI for both males and females, and between ECA during early childhood and BMI at adulthood for males. We also find a strengthening of these correlations over successive generations. These cohort mechanisms are boosted by age effects, leading individuals in each successive cohort to reach unhealthy BMI levels at younger ages. Individuals in more recent cohorts are overweight or obese earlier and for larger proportions of their lifespan than those in earlier cohorts. Even after controlling for development dynamics, the pattern is consistent across countries and appears to be driven, in part, by availability of calories in excess of underlying requirements. Our findings provide novel insights into the role of ECA, and potential unintended health consequences of agricultural and trade policies directed at increasing calorie supplies.
