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Human Molecular Genetics Oct 2018Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in ∼250000 European participants have led to the discovery of ∼700 and ∼100... (Meta-Analysis)
Meta-Analysis
Recent genome-wide association studies (GWAS) of height and body mass index (BMI) in ∼250000 European participants have led to the discovery of ∼700 and ∼100 nearly independent single nucleotide polymorphisms (SNPs) associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in ∼450000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N ∼700000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3290 and 941 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of P < 1 × 10-8), including 1185 height-associated SNPs and 751 BMI-associated SNPs located within loci not previously identified by these two GWAS. The near-independent genome-wide significant SNPs explain ∼24.6% of the variance of height and ∼6.0% of the variance of BMI in an independent sample from the Health and Retirement Study (HRS). Correlations between polygenic scores based upon these SNPs with actual height and BMI in HRS participants were ∼0.44 and ∼0.22, respectively. From analyses of integrating GWAS and expression quantitative trait loci (eQTL) data by summary-data-based Mendelian randomization, we identified an enrichment of eQTLs among lead height and BMI signals, prioritizing 610 and 138 genes, respectively. Our study demonstrates that, as previously predicted, increasing GWAS sample sizes continues to deliver, by the discovery of new loci, increasing prediction accuracy and providing additional data to achieve deeper insight into complex trait biology. All summary statistics are made available for follow-up studies.
Topics: Body Height; Body Mass Index; Body Weight; Female; Genome, Human; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; Quantitative Trait Loci; White People
PubMed: 30124842
DOI: 10.1093/hmg/ddy271 -
Maternal & Child Nutrition Oct 2018Child stunting reduction is the first of 6 goals in the Global Nutrition Targets for 2025 and a key indicator in the second Sustainable Development Goal of Zero Hunger....
Child stunting reduction is the first of 6 goals in the Global Nutrition Targets for 2025 and a key indicator in the second Sustainable Development Goal of Zero Hunger. The prevalence of child stunting in Indonesia has remained high over the past decade, and at the national level is approximately 37%. It is unclear whether current approaches to reduce child stunting align with the scientific evidence in Indonesia. We use the World Health Organization conceptual framework on child stunting to review the available literature and identify what has been studied and can be concluded about the determinants of child stunting in Indonesia and where data gaps remain. Consistent evidence suggests nonexclusive breastfeeding for the first 6 months, low household socio-economic status, premature birth, short birth length, and low maternal height and education are particularly important child stunting determinants in Indonesia. Children from households with both unimproved latrines and untreated drinking water are also at increased risk. Community and societal factors-particularly, poor access to health care and living in rural areas-have been repeatedly associated with child stunting. Published studies are lacking on how education; society and culture; agriculture and food systems; and water, sanitation, and the environment contribute to child stunting. This comprehensive synthesis of the available evidence on child stunting determinants in Indonesia outlines who are the most vulnerable to stunting, which interventions have been most successful, and what new research is needed to fill knowledge gaps.
Topics: Adolescent; Adult; Body Height; Child; Child, Preschool; Feeding Behavior; Growth Charts; Growth Disorders; Humans; Indonesia; Infant; Infant, Newborn; Mothers; Young Adult
PubMed: 29770565
DOI: 10.1111/mcn.12617 -
Current Opinion in Pediatrics Aug 2021Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening... (Review)
Review
PURPOSE OF REVIEW
Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening approach. The purpose of this review is to describe the optimal genetic approach for evaluating short stature, challenges of genetic testing, and recent advances in genetic testing for short stature.
RECENT FINDINGS
Genetic testing, such as karyotype, chromosomal microarray, targeted gene sequencing, or exome sequencing, has served to identify the underlying genetic causes of short stature. When determining which short stature patient would benefit from genetic evaluation, it is important to consider whether the patient would have a single identifiable genetic cause. Specific diagnoses permit clinicians to predict responses to growth hormone treatment, to understand the phenotypic spectrum, and to understand any associated co-morbidities.
SUMMARY
The continued progress in the field of genetics and enhanced capabilities provided by genetic testing methods expands the ability of physicians to evaluate children with short stature for underlying genetic defects. Continued effort is needed to elaborate new genetic causes of linear growth disorders, therefore, we expand the list of known genes for short stature, which will subsequently increase the rate of genetic diagnosis for children with short stature.
Topics: Body Height; Child; Dwarfism; Genetic Testing; Growth Disorders; Humans; Exome Sequencing
PubMed: 34101704
DOI: 10.1097/MOP.0000000000001033 -
Nature Reviews. Endocrinology Dec 2015In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore,... (Review)
Review
In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH-IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, which is the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-1 but also on multiple hormones, paracrine factors, extracellular matrix molecules and intracellular proteins that regulate the activity of growth plate chondrocytes. Mutations in the genes that encode many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height seems to be largely due to genes outside the GH-IGF-1 axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature that is centred not on two particular hormones but rather on the growth plate, which is the structure responsible for height gain.
Topics: Animals; Body Height; Gene Dosage; Growth Disorders; Growth Plate; Human Growth Hormone; Humans; Insulin-Like Growth Factor I
PubMed: 26437621
DOI: 10.1038/nrendo.2015.165 -
Frontiers in Endocrinology 2020Humans show marked variation in body size around the world, both within and among populations. At present, the tallest people in the world are from the Netherlands and... (Review)
Review
Humans show marked variation in body size around the world, both within and among populations. At present, the tallest people in the world are from the Netherlands and the Balkan countries, while the shortest populations are central African Pygmies. There are genetic, genetic plasticity, developmental, and environmental bases for size variation in from the recent past and the present. Early populations of species also have shown considerable size variation. Populations from the present and the past are also marked by sexual dimorphism, which, itself, shows group variation. There is abundant evidence for the effects of limited food and disease on human growth and resultant adult body size. This environmental influence has been reflected in "secular trends" (over a span of years) in growth and adult size from socioeconomic prosperity or poverty (availability of resources). Selective and evolutionary advantages of small or large body size also have been documented. Heritability for human height is relatively great with current genome-wide association studies (GWAS) identifying hundreds of genes leading to causes of growth and adult size variation. There are also endocrinological pathways limiting growth. An example is the reduced tissue sensitivity to human growth hormone (HGH) and insulin-like growth factor (IGF-1) in Philippine and African hunter-gatherer populations. In several short-statured hunter-gatherer populations (Asian, African, and South American), it has been hypothesized that short life expectancy has selected for early maturity and truncated growth to enhance fertility. Some island populations of humans and other mammals are thought to have been selected for small size because of limited resources, especially protein. The high-protein content of milk as a staple food may contribute to tall stature in East African pastoral peoples. These and other evolutionary questions linked to life history, male competition, reproduction, and mobility are explored in this paper.
Topics: Adult; Animals; Biological Evolution; Body Height; Body Size; Ethnicity; Genetic Variation; Genome-Wide Association Study; Growth Disorders; Growth and Development; Humans; Mammals; Phenotype
PubMed: 32210916
DOI: 10.3389/fendo.2020.00107 -
Canadian Family Physician Medecin de... Apr 2021
Topics: Body Height; Body Weight; Humans
PubMed: 33853917
DOI: 10.46747/cfp.6704279 -
Endocrinology and Metabolism Clinics of... Jun 2017Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes... (Review)
Review
Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown; but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, and individualized management, and help avoid unnecessary testing for endocrine and other disorders.
Topics: Body Height; Bone Development; Growth Disorders; Humans
PubMed: 28476223
DOI: 10.1016/j.ecl.2017.01.001 -
Indian Heart Journal 2021Atrial fibrillation (AF) is characterized by abnormal heart rhythm. Among other well-known associations, recent studies suggest an association of AF with height. Height... (Review)
Review
Atrial fibrillation (AF) is characterized by abnormal heart rhythm. Among other well-known associations, recent studies suggest an association of AF with height. Height is related to 50 diseases spanning different body systems, AF is one of them. Since AF, a heterogeneous disease process, is influenced by structural, neural, electrical, and hemodynamic factors, height alters this process through its contribution to increasing atrial and ventricular size, leading to altered conduction patterns, autonomic dysregulation, and development of AF. Multiple underlying mechanisms associate height with AF. Apart from these indirect mechanisms, genome-wide association studies suggest the involvement of the same genes in AF and growth pathways. Tall stature is independently associated with a higher risk of AF development in healthy individuals. Since adult height is achieved much earlier than the onset of AF, protective measures can be taken in individuals with increased height to monitor, manage, and prevent the progression of AF.
Topics: Atrial Fibrillation; Body Height; Heart Rate; Humans; Risk Factors
PubMed: 33714405
DOI: 10.1016/j.ihj.2020.11.008 -
The Journal of Clinical Endocrinology... Sep 2018In the last decade, genome-wide association studies (GWASs) have catalyzed our understanding of the genetics of height and have identified hundreds of regions of the... (Review)
Review
CONTEXT
In the last decade, genome-wide association studies (GWASs) have catalyzed our understanding of the genetics of height and have identified hundreds of regions of the genome associated with adult height and other height-related body measurements.
EVIDENCE ACQUISITION
GWASs related to height were identified via PubMed search and a review of the GWAS catalog.
EVIDENCE SYNTHESIS
The GWAS results demonstrate that height is highly polygenic: that is, many thousands of genetic variants distributed across the genome each contribute to an individual's height. These height-associated regions of the genome are enriched for genes in known biological pathways involved in growth, such as fibroblast growth factor signaling, as well as for genes expressed in relevant tissues, such as the growth plate. GWASs can also uncover previously unappreciated biological pathways, such as the STC2/PAPPA/IGFBP4 pathway. The genes implicated by GWASs are often the same genes that are the genetic causes of Mendelian growth disorders or skeletal dysplasias, and GWAS results can provide complementary information about these disorders.
CONCLUSIONS
Here, we review the rationale behind GWASs and what we have learned from GWASs for height, including how it has enhanced our understanding of the underlying biology of human growth. We also highlight the implications of GWASs in terms of prediction of adult height and our understanding of Mendelian growth disorders.
Topics: Body Height; Genome-Wide Association Study; Growth; Growth Disorders; Humans; Multifactorial Inheritance; Signal Transduction
PubMed: 29982553
DOI: 10.1210/jc.2018-01126 -
Current Opinion in Pediatrics Aug 2015Recent basic studies have yielded important new insights into the molecular mechanisms that regulate growth locally. Simultaneously, clinical studies have identified new... (Review)
Review
PURPOSE OF REVIEW
Recent basic studies have yielded important new insights into the molecular mechanisms that regulate growth locally. Simultaneously, clinical studies have identified new molecular defects that cause growth failure and overgrowth, and genome-wide association studies have elucidated the genetic basis for normal human height variation.
RECENT FINDINGS
The Hippo pathway has emerged as one of the major mechanisms controlling organ size. In addition, an extensive genetic program has been described that allows rapid body growth in the fetus and infant but then causes growth to slow with age in multiple tissues. In human genome-wide association studies, hundreds of loci associated with adult stature have been identified; many appear to involve genes that function locally in the growth plate. Clinical genetic studies have identified a new genetic abnormality, microduplication of Xq26.3, that is responsible for growth hormone excess, and a gene, DNMT3A, in which mutations cause an overgrowth syndrome through epigenetic mechanisms.
SUMMARY
These recent advances in our understanding of somatic growth not only provide insight into childhood growth disorders but also have broader medical applications because disruption of these regulatory systems contributes to oncogenesis.
Topics: Body Height; Child; Child Nutritional Physiological Phenomena; Child, Preschool; Gene Expression Profiling; Genome-Wide Association Study; Growth Disorders; Growth Plate; Hippocampus; Humans; Infant; Infant, Newborn; Mutation; Phenotype; Quantitative Trait Loci; Signal Transduction
PubMed: 26087427
DOI: 10.1097/MOP.0000000000000235