Variation In Adult Height Research Articles

Use of joinpoint regressions to evaluate changes over time in conscript height

AbstractObjectivesCohort variation in adult height expresses both the impact of socio‐economic change on human biology in a wide temporal perspective and social inequalities within populations. We aimed to test the use of joinpoint regressions to identify periods in which changes in height trends were statistically significant.MethodsData correspond to the height recorded in Madrid City (Spain) for 65 313 conscripts between 1936 and 1974 (cohorts from 1915 to 1953), a period of social and political turmoil. Secular trends in height were analyzed in eight districts with contrasting socio‐economic conditions, grouped in two categories, lower‐class and middle‐ and upper‐class. Trends in height were evaluated by quadratic regressions and by joinpoint regressions to identify the cut‐off years when trends changed significantly.ResultsHeight increased in both socio‐economic categories of districts, more among conscripts from the lower‐class ones. However, results clearly show differences in trends according to district of residence. Whereas the increase in height in conscripts from the middle‐ and upper‐class districts was steady, it was slower in those from the lower classes, with declines in height during the Civil War and first years of the Franco dictatorship.ConclusionsJoinpoint analysis reveals the association between urban living conditions and adult height, and that the disparities intensified during critical historical periods of Spain.

Height as an expression of life histories: A study of intergenerational variation and determinants among tribal men

Introduction: Despite the advertised impressive economic growth, stunting in children continues to be an important problem in India demanding further exploration of enigma of height. Role of socio-economic factors, environmental variables and genetic factors have been documented. Till recent past it was also argued that Indians are a different genetic pool and would need separate standards for measuring heights. It is important to understand phenomenon of height and its determinants. Objective: The aim of the study is to identify the intergenerational variation in adult height among tribal men and its determinants; to understand the structural changes in the pattern of food composition and adequacy in the neoliberal era, and illness histories along with changes in the health care service accessibility for understanding determinants of the height. Materials and Method: Two groups of villages were selected with different developmental levels as reflected in their backwardness, road connectivity, employment opportunities and poverty levels from Salumber Block in Rajasthan. The social history of these two groups of villages was collected through key person interviews and available records to understand the changes happening in living condition over a period of time. Average heights of adults and its patterns from the selected six villages were assessed through a sample of 573 adult men. The selection of 573men was done through systematic sampling process household. Adult male (20-60 years) of every 3rd household were the part of study for analysis of the intergenerational variation. Childhood history of 120 adult males (10 from each stratum of 20-40 years and 40-60 years) was collected from every 5th household for detailed analysis of determinants of height. The childhood history was corroborated with the parents/guardian/caretaker or elder person of the family member who observed the growing periods of respondents. Women respondents were excluded from the study due to the corroboration issues. Because before and after 20 years women left their parental house due to marriage. So, in that case researcher was unable to track the person who observed the growing age periods of women. The selection of generations is based on the age group division. Age group 20-40 and 40-60 represent current generation and earlier generation, respectively. Results: The average heights of tribal men from six villages are 162.19 cm (95% CI (161.74-162.64, p-0.001). The Meena community from the group two villages showed significant improvement in current height about 2.17 cm (p-0.002) while group one villages showed decline in average height of current generation about 1.05 cm. The days of food shortage and reported hunger in the growing age/years is inversely associated with average height gain (p-0.001). The frequency of pulses and dairy product consumption significantly associated with average height gain (p-0.03 and 0.001, respectively). Occurrence of disease and recurrence of disease in the growing age is significantly and inversely associated with height gain (p-0.001). The episodes of diarrhoea in the growing age were observed to be a major impediment of the height growth (95%CI, 21.48-24.40, p-0.001). The villages where the employment opportunities are frequently available round the year showed improvement in the average height of current generation. Conclusion: The average height of the current generation is marginally improved. Changes in the pattern of food consumption and adequacy affected the average height of current generation in the new globalization era. Adequate nutrition intake, lower exposure to disease environment, and better access to health care services is positively and significantly correlated with height gain of the individual. Keywords: Intergenerational, Height, Tribal, Nutrition, Hunger, Disease

Small island, big genetic discoveries.

Three new studies have identified new genes and sequence variants implicated in blood lipids, inflammatory markers, hemoglobin levels and adult height variation in Sardinia. These reports highlight the usefulness of large-scale genotype imputation based on whole-genome sequencing, particularly in isolated populations, in studying the genetics of complex human phenotypes.

Progress in genetic research of human height

It is well known that both environmental and genetic factors contribute to adult height variation in general population. However, heritability studies have shown that the variation in height is more affected by genetic factors. Height is a typical polygenic trait which has been studied by traditional linkage analysis and association analysis to identify common DNA sequence variation associated with height, but progress has been slow. More recently, with the development of genotyping and DNA sequencing technologies, tremendous achievements have been made in genetic research of human height. Hundreds of single nucleotide polymorphisms (SNPs) associated with human height have been identified and validated with the application of genome-wide association studies (GWAS) methodology, which deepens our understanding of the genetics of human growth and development and also provides theoretic basis and reference for studying other complex human traits. In this review, we summarize recent progress in genetic research of human height and discuss problems and prospects in this research area which may provide some insights into future genetic studies of human height.

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10−6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10−8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10−4) and adult height (N = 127 513; P = 1.45 × 10−5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

The Effects of Mortality, Subsistence, and Ecology on Human Adult Height and Implications forHomoEvolution

The increase in body size observed with the appearance and evolution of Homo is most often attributed to thermoregulatory and locomotor adaptations to environment; increased reliance on animal protein and fat; or increased behavioral flexibility, provisioning, and cooperation leading to decreased mortality rates and slow life histories. It is not easy to test these hypotheses in the fossil record. Therefore, understanding selective pressures shaping height variability in living humans might help to construct models for the interpretation of body size variation in the hominins. Among human populations, average male height varies extensively (145 cm–183 cm); a similar range of variation is found in Homo erectus (including African and Georgian samples). Previous research shows that height in human populations covaries with life history traits and variations in mortality rates and that different environments affect adult height through adaptations related to thermoregulation and nutrition. We investigate the interactions between life history traits, mortality rates, environmental setting, and subsistence for 89 small-scale societies. We show that mortality rates are the primary factor shaping adult height variation and that people in savanna are consistently taller than people in forests. We focus on relevant results for interpreting the evolution of Homo body size variability.

Evaluation of the genetic overlap between osteoarthritis with body mass index and height using genome-wide association scan data

ObjectivesObesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height...

Using height association studies to gain insights into human idiopathic short and syndromic stature phenotypes

Variation in adult height is not the most clinically relevant human quantitative trait, yet its study provides the foundation of many quantitative genetics theories and important statistical concepts (e.g. regression). Even today, the analysis of adult height by genome-wide association studies (GWAS) continues to significantly impact human genetics: these studies have led to the discovery of >200 loci associated with variation in adult height and have highlighted the very polygenic nature of human continuous traits. In this brief review, I discuss and provide examples on how such genetic associations, identified in individuals of normal height, could help understand the complex genetics behind such phenotypes as idiopathic short stature (ISS) or extreme/syndromic height phenotypes of unknown cause.

The Distribution of Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism in the Turkish Population

Objective: The exon 3-deleted/full-length (d3/fl) growth hormone receptor (d3/fl-GHR) polymorphism has been associated with responsiveness to GH therapy in some children and also with adult height variation in the general population. We aimed to evaluate the distribution of d3/fl-GHR polymorphism in a Turkish population. Methods: The study included 477 (54 females/423 males) healthy adults with a mean±SD age of 31.1±9.0 years (range: 18-57). Height and body mass index (BMI) were expressed as standard deviation score (SDS) according to national standards. All adults had normal height and BMI SDSs (between -2 and +2). GHR exon 3 isoforms were studied by simple multiplex polymerase chain reaction method. Insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) values were also measured and expressed as SDS. Results: The distribution of the GHR exon 3 genotypes in the Turkish healthy adults was 35% (n=167) for fl/fl, 39% (n=186) for fl/d3, and 26% (n=124) for d3/d3. There was no difference between genders in GHR exon 3 genotypes. Frequencies of fl allele and d3 allele were 54.5% and 45.5%, respectively. There were no differences in height SDS and BMI SDS among the three d3/fl-GHR genotype groups. There was a significant difference in IGFBP-3 SDS between fl/fl and fl/d3 groups (p=0.022). Conclusions: This study presents the results of GHR polymorphism in a Turkish population as a reference for further studies. The distribution was similiar to European populations. There were no correlations between GHR isoforms and height SDS or other clinical/biochemical characteristics of the individuals except for higher IGFBP-3 levels in the fl/d3 group as compared to the fl/fl group. Whether this finding implies an abnormality, needs further investigation. Conflict of interest:None declared.

Recent progress in the study of the genetics of height

Adult height is a classic polygenic trait of high narrow-sense heritability (h (2) = 0.8). In the late nineteenth to early twentieth century, variation in adult height was used as a model to set the foundation of the fields of statistics and quantitative genetics. More recently, with our increasing knowledge concerning the extent of genetic variation in the human genome, human geneticists have used genome-wide association studies to identify hundreds of loci robustly associated with adult height, providing new insights into human growth and development, and into the architecture of complex human traits. In this review, I highlight the progress made in the last 2 years in understanding how genetic variation controls height variation in humans, including non-Caucasian populations and children.

Runs of homozygosity identify a recessive locus 12q21.31 for human adult height

Background: Runs of homozygosity (ROHs) have recently been proposed to have potential recessive significance for complex traits. Human adult height is a classic complex trait with heritability estimated up to 90%, and recessive loci that contribute to adult height variation have been identified. Methods: Using the Affymetrix 500K array set, we performed a genome-wide ROHs analysis to identify genetic loci for adult height in a discovery sample including 998 unrelated Caucasian subjects from the midwest United States. For the significant ROHs identified, we replicated these findings in a family-based sample of 8385 Caucasian subjects from the Framingham Heart Study (FHS). Results: Our results revealed one ROH, located in 12q21.31, that had a strong association with adult height variation both in the discovery (P = 6.69 × 10−6) and replication samples (P = 5.40 × 10−5). We further validated the presence of this ROH using the HapMap sample. Conclusion: Our findings open a new avenue for identifying loci with...

Runs of Homozygosity Identify a Recessive Locus 12q21.31 for Human Adult Height

Runs of homozygosity (ROHs) have recently been proposed to have potential recessive significance for complex traits. Human adult height is a classic complex trait with heritability estimated up to 90%, and recessive loci that contribute to adult height variation have been identified. Using the Affymetrix 500K array set, we performed a genome-wide ROHs analysis to identify genetic loci for adult height in a discovery sample including 998 unrelated Caucasian subjects from the midwest United States. For the significant ROHs identified, we replicated these findings in a family-based sample of 8385 Caucasian subjects from the Framingham Heart Study (FHS). Our results revealed one ROH, located in 12q21.31, that had a strong association with adult height variation both in the discovery (P=6.69x10(-6)) and replication samples (P=5.40x10(-5)). We further validated the presence of this ROH using the HapMap sample. Our findings open a new avenue for identifying loci with recessive contributions to adult height variation. Further molecular and functional studies are needed to explore and clarify the potential mechanism.

Geographic altitude, surnames, and height variation of Jujuy (Argentina) conscripts

The height records of 48,589 conscripts born in Jujuy between 1870 and 1960 were examined in order to study the variation in adult male height (AMH) in terms of geographical altitude and surnames. Data were clustered by origin of surnames (divided into native and foreign names), decades, and according to the four Jujenean geographical regions distributed along an altitudinal gradient (Puna, Quebrada, Valle, and Ramal). The variation of surnames, geographical altitude, and time on human height were examined by analysis of variance. Regardless of the drafting year, individuals in the four regions bearing foreign surnames proved significantly taller (P < 0.001) than those who had a native surname. Average height, regardless of ethnic group, presented a reverse relationship to geographical altitude. A higher AMH was found in individuals bearing foreign surnames in Jujuy and lower ones in the population located in the highlands and bearing native surnames. Interregional and intergroup AMH variations would be affected by the complex interaction between geographical altitude and factors associated to it and by the ethnic characteristics of these population as well.

Comprehensive association analyses of IGF1, ESR2, and CYP17 genes with adult height in Caucasians

Human adult height is closely related to body growth that is regulated by multiple cytokines or hormones like growth hormone (GH) and estrogen. Our study focused on three potential candidate genes to human height, namely IGF1 (insulin-like growth factor 1), ESR2, and CYP17. We genotyped 43 single nucleotide polymorphisms (SNPs) and tested their associations in 1873 subjects from 405 nuclear families, using both the family-based quantitative transmission disequilibrium test (QTDT) and population-based ANOVA methods. Both analyses consistently detected that two novel SNPs of IGF1, rs5742694 and rs2033178, were significantly associated with human height, with the P-values of 0.0097 and 0.0057 in QTDT analyses, 0.0002/0.004 (sample 1/sample 2) and 8.46 x 10(-5)/1.92 x 10(-5) in ANOVA analyses. For ESR2, significant associations were only detected in women (rs1256061: QTDT P=0.002, ANOVA P=0.002/0.012; rs17766755: QTDT P=0.019, ANOVA P=0.023/0.006; rs1256044: QTDT P=0.022, ANOVA P=0.002/0.034). Haplotype analyses corroborated our single-SNP results. However, no association was detected between CYP17 and human height. In conclusion, we identified the important effects of IGF1 and ESR2 on adult height variation in Caucasians, and first suggested the potential sex-specific effect of ESR2 on height variation in Caucasian women. It will be valuable for other independent studies to replicate and confirm these findings.

Sizing up human height variation

Genome-wide association studies have identified many variants affecting susceptibility to disease. Now, three studies use this approach to study adult height variation in a combined sample size of ∼63,000 individuals and report a total of 54 validated variants influencing this trait.

Applying novel genome-wide linkage strategies to search for loci influencing type 2 diabetes and adult height in American Samoa.

Type 2 diabetes mellitus (T2DM) is a common complex phenotype that by the year 2010 is predicted to affect 221 million people globally. In the present study we performed a genome-wide linkage scan using the allele-sharing statistic Sall implemented in Allegro and a novel two-dimensional genome-wide strategy implemented in Merloc that searches for pairwise interaction between genetic markers located on different chromosomes linked to T2DM. In addition, we used a robust score statistic from the newly developed QTL-ALL software to search for linkage to variation in adult height. The strategies were applied to a study sample consisting of 238 sib-pairs affected with T2DM from American Samoa. We did not detect any genome-wide significant susceptibility loci for T2DM. However, our two-dimensional linkage investigation detected several loci pairs of interest, including 11q22 and 21q21, 9q21 and 11q22, 1p22-p21 and 4p15, and 4p15 and 15q11-q14, with a two-loci maximum LOD score (MLS) greater than 2.00. Most detected individual loci have previously been identified as susceptibility loci for diabetes-related traits. Our two-dimensional linkage results may facilitate the selection of potential candidate genes and molecular pathways for further diabetes studies because these results, besides providing candidate loci, also demonstrate that polygenic effects may play an important role in T2DM. Linkage was detected (p value of 0.005) for variation in adult height on chromosome 9q31, which was reported previously in other populations. Our finding suggests that the 9q31 region may be a strong quantitative trait locus for adult height, which is likely to be of importance across populations.

Applying Novel Genome-Wide Linkage Strategies to Search for Loci Influencing Type 2 Diabetes and Adult Height in American Samoa

Type 2 diabetes mellitus (T2DM) is a common complex phenotype that by the year 2010 is predicted to affect 221 million people globally. In the present study we performed a genome-wide linkage scan using the allele-sharing statistic Sall implemented in Allegro and a novel two-dimensional genome-wide strategy implemented in Merloc that searches for pairwise interaction between genetic markers located on different chromosomes linked to T2DM. In addition, we used a robust score statistic from the newly developed QTL-ALL software to search for linkage to variation in adult height. The strategies were applied to a study sample consisting of 238 sib-pairs affected with T2DM from American Samoa. We did not detect any genome-wide significant susceptibility loci for T2DM. However, our two-dimensional linkage investigation detected several loci pairs of interest, including 11q22 and 21q21, 9q21 and 11q22, 1p22–p21 and 4p15, and 4p15 and 15q11–q14, with a two-loci maximum LOD score (MLS) greater than 2.00. Most detected individual loci have previously been identified as susceptibility loci for diabetes-related traits. Our two-dimensional linkage results may facilitate the selection of potential candidate genes and molecular pathways for further diabetes studies because these results, besides providing candidate loci, also demonstrate that polygenic effects may play an important role in T2DM. Linkage was detected (p value of 0.005) for variation in adult height on chromosome 9q31, which was reported previously in other populations. Our finding suggests that the 9q31 region may be a strong quantitative trait locus for adult height, which is likely to be of importance across populations.

Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation

Stature (adult height) is one of the most heritable human traits, yet few genes, if any, have been convincingly associated with adult height variation in the general population. Here, we selected 150 tag SNPs from eight candidate genes in the growth hormone (GH)/insulin-like growth factor-1 (IGF1) axis (GHR, GHRH, GHRHR, IGF1, IGFALS, IGFBP3, JAK2, STAT5B), and genotyped them in approximately 2,200 individuals ascertained for short or tall stature. Nominally significant tag SNPs were then tested in three additional replication cohorts, including a family-based panel to rule out spurious associations owing to population stratification. Across the four height cohorts (N = 6,075 individuals), we did not observe any consistent associations between stature and common variants (> or =5% minor allele frequency) in these eight genes, including a common deletion of the growth hormone receptor gene exon 3. Tests of epistatic interactions between these genes did not yield any results beyond those expected by chance. Although we have not tested all genes in the GH/IGF1 axis, our results indicate that common variation in these GH/IGF1 axis genes is not a major determinant of stature, and suggest that if common variation contributes to adult height variation in the general population, the variants are in other, possibly unanticipated genes.

Variations in RANK gene are associated with adult height in Caucasians

Height is a complex trait significantly influenced by genetic factors, with heritability ranging from 48% to 98%. Previous studies have yielded a number of important genomic regions that may account for the variation of height in human populations. However, more 'height' genes still wait for identification. Recent studies have revealed that tumor necrosis factor receptor superfamily member 11a (RANK) is a vital factor for chondroclastic/osteoclastic differentiation and activity that influence the morphology of growth plates and linear bone growth. Despite its importance, little effort has been made to find out whether the RANK polymorphisms are associated with adult height variation in normal populations. Herein, we performed a family based association test (FBAT) in 1873 white subjects from 405 nuclear families. Among eighteen single nucleotide polymorphisms (SNPs) and seven blocks, SNP rs6567274 was detected to be significant even after multiple-testing correction. In corroboration with single-locus analysis, a major haplotype in block 5 bearing the variant "T" of rs6567274 was significantly associated with higher stature. Our findings firstly suggested the RANK polymorphisms might contribute to adult height variation. Further researches need to be launched to replicate the present results and further unravel the molecular mechanism underlying the significant associations discovered.

Human growth hormone (GH1) gene polymorphism map in a normal‐statured adult population

ObjectiveGH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height.Design, subjects and measurementsA systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: −2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height.ResultsTwenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5′UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6·2% of the variation in adult height (P = 0·0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (−0·063 ± 0·031, −0·693 ± 0·350 and −0·489 ± 0·265, Mean ± SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1·094 ± 0·456 and +1·184 ± 0·432).ConclusionsThis study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them.