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Spinal muscular atrophy type 1 kills most infants by their second birthday. A new drug has shown positive results against the disease in young…. SOD1 gene mutations form protein clumps, leading to motor neuron degeneration in ALS, but researchers may have found a way to halt this process. What factors influence a person's height? Medically reviewed by Kevin Martinez, M. How to increase height during development What factors affect height? Can adults increase their height?
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Is intelligence determined by genetics? Is handedness determined by genetics? Is the probability of having twins determined by genetics? Is hair texture determined by genetics? Is hair color determined by genetics? Are moles determined by genetics? Are facial dimples determined by genetics? Is athletic performance determined by genetics? Is longevity determined by genetics? Although the heritable nature of height has been recognized for more than one hundred years, only a few studies have explored in detail the genetic variation of height during childhood and adolescence.
Twin studies have consistently estimated that the heritability of height is lowest 0. However, these studies leave unclear whether environmental factors shared by co-twins, which are generally important in infancy and childhood, persist in adolescence or after the cessation of growth 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , Somewhat different results were observed in a longitudinal study of two Finnish twin cohorts, which found that common environmental factors affected height at different ages in adolescence and early adulthood Height is also a classic example of a sexually dimorphic trait; on average, men are taller than women in all human populations However, much less is known about sex-differences in genetic and environmental contributions to height variation.
Greater heritability estimates for males than for females in childhood 15 and adulthood 21 have been reported. Also sex-specific genetic effects have been found for height, but the results are inconsistent across studies 18 , 19 , 20 , 21 , Further, a greater mean height has been consistently observed in Western populations as compared with East-Asian populations 13 , but most studies on the genetic and environmental factors influencing height variation to date are based on Western populations.
A multinational study on adolescent twins from eight countries showed that even when the total variation of height was higher in Western populations, the heritability estimates were largely similar between Western and East-Asian populations Descriptive statistics of height by age and sex for the pooled data all cohorts together and by geographic-cultural region are presented in Table 1.
When comparing geographic-cultural regions, mean height was tallest in Europe, somewhat shorter in North-America and Australia and shortest in East-Asia at all ages in boys and girls.
The variation of height showed a less clear pattern but was generally greatest in North-America and Australia and lowest in East-Asia. The proportion of environmental variation shared by co-twins was greatest at age 1 0. Accordingly, heritability was lowest at age 1 0.
The proportion of height variation explained by environmental factors unique to each twin individual, which also includes measurement error, did not show any clear age pattern and was largely similar at all ages 0. In spite of the observed sex differences in the relative variance components at most of ages See Supplementary Table S2 , the age pattern was generally similar in boys and girls; the biggest sex-differences were found in late adolescence when the heritability estimates were slightly greater in boys.
The point estimates for the genetic correlations within opposite-sex DZ pairs were generally lower than 0. Univariate models for height were then conducted separately in the three geographic-cultural regions.
Only the estimates of additive genetic factors are presented in Fig. The three geographic-cultural regions showed the general trend of increasing proportion of additive genetic factors with age during childhood.
Explained by its largest sample size, the pattern in Europe was practically the same to that observed for all cohorts together, but with slightly greater heritability estimates at most ages. In North-America and Australia and East-Asia, heritability estimates in childhood were generally somewhat lower than in Europe.
In spite of the roughly similar age patterns, the proportions of height variation explained by genetic and environmental factors were different between the geographic-cultural regions See Supplementary Table S2. The Chinese National Twin Registry was excluded from these analyses because the heritability estimates in that cohort were substantially lower than in other East-Asian cohorts.
When data from this cohort was included in the analyses for East-Asia, the proportion of genetic factors decreased and common environmental factors increased considerably; the change in heritability estimates was from 0.
Finally, we studied how age modifies the genetic and environmental variances of height by using gene-age interaction analysis, with data pooled across all age groups. When stratified by geographic-cultural region, genetic variation was largest in North-America and Australia, somewhat lower in Europe and lowest in East-Asia, particularly for boys.
The pattern of genetic variance increasing to a maximum and thereafter decreasing was consistent across the regions. Unique environmental variation showed a similar pattern and magnitude in the three geographic-cultural regions. When comparing sexes, in Europe and North-America and Australia there was a trend toward a greater genetic variation for boys than for girls, which increased with age.
Change of additive genetic dash line , common environmental solid line and unique environmental dot line variance with increasing age in quadratic gene-environment interaction model in Europe, North America and Australia and East Asia. The present study of , paired measurements from 86, complete twin pairs in 20 countries revealed that environmental factors shared by co-twins contribute to the inter-individual variation in height from infancy to early adulthood.
The relative proportion of common environmental factors was greatest during the first years of life, representing almost half of the variation at age 1 and decreased over childhood and adolescence. The interpretation of these results, however, deserves some caution. It has been questioned whether twin studies are suitable for estimating heritability of height in infancy, since early growth patterns in twins differ considerably from singleton growth patterns Prenatal environmental factors can act very differently on MZ twins leading to differences in body size within pairs the most extreme case is the twin-to-twin transfusion syndrome.
This is an important issue because in the classical twin design heritability is estimated by comparing the resemblance of MZ and DZ twin pairs and thus body size differences in MZ pairs will result in lower heritability estimates.
Since children may take several years to fully catch-up after birth, the high proportion of height variation explained by the shared environment in infancy may still reflect these prenatal environmental factors.
Among other possible explanations, it might be that the shared environment represents the effects of gestational age or the effects of the higher measurement error correlated in twins at earlier ages. Studies have shown that the secular trend in adult height occurs during the first two years of life mainly due to increases in leg length A plausible explanation is that the period of most rapid growth, when the effect of an adverse environment is strongest, coincides with the period when most growth takes place in the long bones of the legs Multinational studies analyzing the genetic and environmental influences on body length segments, particularly leg length, are thus needed to disentangle the aetiology of total height variation.
The small but considerable effect of unique environment on height variation, very similar across ages, may partly be due to measurement error, which is modelled as part of unique environmental factors. However, it is likely that it also reflects real environmental factors, for example, different exposure to childhood diseases. Given the rapid growth that occurs in infancy, childhood and adolescence, in this individual-based pooled analysis we analyzed the heritability of height in one year age groups.
We found that genetic contributions increase over childhood with heritability estimates in the range of previous studies in children and adults 15 , 16 , 18 , 20 , GWA studies have identified many common genetic variants for adult height.
The most recent GWA meta-analysis in , individuals of European ancestry identified genome-wide significant SNPs in loci that together explained one-fifth of the heritability for adult height However, much less is known on the genetics of height in children.
Van der Valk et al. The pattern of total height variation across ages was largely driven by genetic variance. After that point, even if mean height continued to increase, genetic variance started to decrease in such a way that in late adolescence the magnitude was similar to that before pubertal events start.
Adolescence is characterized by the onset of puberty and the occurrence of growth spurts. In this study, twins within age groups are at various stages of puberty. In addition to the substantial heritability reported for pubertal timing 32 , a genome-wide genetic correlation 0. In fact, a genome-wide association meta-analysis showed that five loci associated with pubertal timing impacted multiple aspects of growth, both before and during puberty Therefore, it is possible that some of the genetic variance in height at these ages is confounded with genetic variance in pubertal events.
In spite of the largely similar age patterns observed in boys and girls, boys showed somewhat greater heritability estimates and genetic variation, especially in late adolescence.
Moreover, some studies have shown a sex-specific genetic effect on height variation in adolescents 19 and adults It is clear that both of the sex chromosomes are implicated in determining mean height. Short stature has been demonstrated in females with Turner syndrome who have only one X chromosome 35 and taller stature seen in XYY men compared with XY men However, sex chromosomes have also been associated with height variation; for example, Gudbjartsson et al. Comparison between geographic-cultural regions showed that mean height was greatest in Europe, somewhat shorter in North-America and Australia and shortest in East-Asia, but total variance was largest in North-America and Australia.
Accordingly, genetic variation was also greatest in North-America and Australia and lowest in East-Asia. However, the relative proportions of additive and environmental variations were more similar in the different geographic-cultural regions. These results are consistent with a previous comparative twin study which found that the mean and variance of height were larger in Caucasian than in East-Asian populations in adolescence, but the heritability estimates were still at the same level An important proportion of the differences in total variances between geographic-cultural regions were attributable to genetic differences.
It may be that allelic frequencies and effects of the genes involved in height vary between Europeans, North-Americans and Australians and East-Asians, leading to differences in genetic variation between the three population groups. However, a major part of the differences in genetic variation may also be because of gene-environment interactions modelled as part of the additive genetic component in our model.
That is, the higher genetic variation observed in Caucasians could arise because there is a set of genes expressed more strongly in Western environments. For example, a study of adults of Japanese descent living in the United States and native Japanese found that Japanese men and women were shorter than Japanese-Americans, suggesting that environmental factors play a role in physical growth Analyzing this question in detail would require collection of twins or GWA studies in unrelated individuals with East-Asian origin living in a Western environment.
However, our study found that shared environmental variance also differed between geographic-cultural regions. The lower shared environmental variance observed in East Asian girls and greater in North-America and Australia during childhood may reflect cultural differences in terms of nutrition and other environmental resources.
It is also important to note that we limited our East-Asian cohorts to affluent East-Asian populations including the Shandong and Guangdong provinces but excluding poorer areas of China. As reported previously, the heritability estimates of height were considerably lower and common environmental estimates higher in the poorer areas 40 , which may indicate larger differences between families in nutrition and infection history in these areas of China.
This emphasizes the need to collect data on twins living under different environmental exposures. Twin participants are from 20 different countries, thereby making it possible to stratify the analyses by regions representing different ethnicities and environments. Important advantages of individual-based data are better opportunities for statistical modelling and lack of publication bias. However, our study also has limitations. The authors speculate that there may have been stronger survival effects in men, but this will be unnecessary speculation if there is no evidence of a difference between sexes.
Instead can the authors place some bounds on their conclusions? On a related note, there are no p values or effect sizes anywhere in the main text. This makes the reader take the results on faith e. It is not clear whether "trend" means a statistically robust trend or just a hint. It is worth noting that the genetic variance appears to go up in line with the overall variance.
The reasons for this are not testable I imagine, but presumably could be due to increased ethnic diversity, and greater variation in living standards, as the average increases. It is clear in Figure 1 but not in the text. It would help the reader to see some stats in the main section of the paper. As mentioned by the reviewer, changes in twinning rates are largely attributable to dizygotic DZ twinning.
Monozygotic MZ twinning is considered an essentially random event with fairly constant rates worldwide, but a significant increase from has been reported for some countries Imaizumi et al.
This increasing MZ twinning rate could be explained by the improvements in obstetric care over time increasing the survivability of MZ twins but it has also been associated with increasing use of oral contraceptives Imaizumi et al. Changes in DZ twinning rates are influenced by maternal age, ethnicity, family history, and height and weight. The higher DZ twinning rate since the s have been attributed to the widespread use of IVF and other fertility treatments in most industrialized countries Imaizumi et al.
Therefore, after the introduction of fertility drugs and IVF, variations in the DZ twinning were not only due to biological factors, but also depended on the popularity of fertility drugs and IVF in each country. In a previous study on this database, we showed that there was no zygosity difference in height variance, neither in childhood nor in adulthood Jelenkovic et al.
Therefore, there is no reason to think that changes in the proportion of MZ to DZ twins would affect variance components estimates. This has now been discussed in limitations. This has now been mentioned in the manuscript. A decreasing trend in the proportion of variation due to unique environmental factors E across birth-year cohorts was observed only for the four earliest birth cohorts, and was more noticeable in Europe and in women.
That is, this trend was not observed in East Asia or North America and Australia except for the slightly greater relative E variance in for women in North America and Australia , nor in Europe from onwards. Moreover, in men, the decrease in relative E variance was not associated with a parallel increase in relative A variance because relative C variance increased , which does not support the declining-deprivation hypothesis. That is, since height is influenced by environmental factors during the whole growth period particularly in infancy and puberty , we expect that some of these environmental factors are shared by co-twins; therefore, and according to the hypothesis, this should have been seen as a decrease in C variance, which was not observed.
In fact, in several cases a decrease in relative E variance was associated with an increase in relative C variance. If we look at the raw variances, the decreasing trend in E variance in the earliest birth cohorts is noticeable for women but not clear for men. In summary, the parallel decrease in relative E variance and increase in relative A variance was observed only in European women for the four earliest birth-year cohorts; in fact, the heritability estimate decreased again in the two latest birth cohorts.
Therefore, we alternatively speculated that the greater influence of unique environmental factors in the earliest birth cohorts in women might be explained by shrinkage in old age. Finally, since shared environmental factors did not show any pattern across birth-years cohorts, we described the results but not discussed them in the Discussion.
We presented the results separately in men and women because the model fit statistics showed that the variance components differed between sexes in all birth-year cohorts, and the relative contribution of the genetic and environmental variance components differ in the three earliest and two latest birth-year cohorts Table 2 in Supplementary file 1. As suggested by the reviewer, we have now estimated both raw and relative genetic and environmental variances for men and women together.
However, we decided to present these combined results as a supplementary table Table 3 in Supplementary file 1 because 1 they did not provide any additional information on the trend across birth-year cohorts compared to the results for men and women separately and 2 since variance components differed between sexes, we think it is more appropriate to estimate them separately in men and women.
This has now been mentioned in the text. The variance components differed between sexes in all birth-year cohorts, and the relative contribution of the genetic and environmental variance components differed in the three earliest and two latest birth-year cohorts Table 2 in Supplementary file 1.
Based on these results, we think that it is worth to speculate that there may have been stronger survival effects in men. As suggested by the reviewer, we have quantified the increase in genetic variance per generation by using G-E interaction analyses. The results showed that genetic variance increased 1. As suggested by the reviewer, we have now also included in the main text the table showing the proportion of height variance explained by A, C and E factors.
As previously explained in comment 4, we finally decided to present in the main text the results separately in men and women and combined results in supplementary table because variance components differed between sexes and thus we think that, even if less powerful, results are more correct. Although there is a general trend to increasing total and genetic variance across birth cohorts, genetic variance does not always go up with total variance.
For example, in men, the greatest increase in total variance was observed from birth cohort to and although genetic variance also increased during this period it increased especially in the two latest birth-year cohorts and In women, although total variance also started to increase from birth cohort , genetic variance showed the greatest increase from to As can be seen in Figure 1 , part of the increase in total variance is due to the increase in shared environmental variance.
Therefore, and as suggested by the reviewer, the increase in total height variation could be due to both increased ethnic diversity and greater variation in living standards.
This has now been discussed in the text. Supplementary Table 2 is now part the main text as Table 2 : however, we have not included Supplementary Table 1 because the results are already provided in Figure 1 without CIs and we think it would provide repeated information. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Wave five was supported by funding to Alice M. Gregory from Goldsmiths, University of London.
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