Tuesday, August 28, 2012

The genes associated with human height development

Target genes for height increase are as follows, for KO genes supplements or activities that inhibit these genes will increase height.  For OE genes supplements or activities that upregulate these genes will increase height.  For biphasic genes both overexpression and knockout decrease height.

KO(inhibit these):

OE(stimulate these):
Mef2c[chondrocyte specific]

Biphasic Genes(genes need optimal quality):

Although, the genes involved in juvenile growth are not the same as the ones involved with reinvigorating growth.  Analyzing the genes involved in juvenile growth can help illuminate the pathways involved in endochondral ossification like the HMGA2 gene which is associated with chromatin and let-7.

Identification of ten loci associated with height highlights new biological pathways in human growth.

"Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 × 10-7 to 8 × 10-22). Together, these 12 loci account for ~2% of the population variation in height. Individuals with ≤8 height-increasing alleles and ≥16 height-increasing alleles differ in height by ~3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait."<-We've looked at IHH and chromatin remodeling.  Let-7 is associated with osteoblast and type I collagen which means that Type I Collagen and osteoblasts may be more important than first thought.

The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature.

"Human height is considered highly heritable and correlated with certain disorders, such as type 2 diabetes and cancer. Despite environmental influences, genetic factors are known to play an important role in stature determination. A number of genetic determinants of adult height have already been established through genome wide association studies.
To examine 51 single nucleotide polymorphisms (SNPs) corresponding to the 46 previously reported genomic loci for height in 8,184 European American children with height measurements. We leveraged genotyping data from our ongoing GWA study of height variation in children in order to query the 51 SNPs in this pediatric cohort.
Sixteen of these SNPs yielded at least nominally significant association to height, representing fifteen different loci including EFEMP1-PNPT1, GPR126, C6orf173, SPAG17, Histone class 1, HLA class III and GDF5-UQCC. Other loci revealed no evidence for association, including HMGA1 and HMGA2. For the 16 associated variants, the genotype score explained 1.64% of the total variation for height z-score.
Among 46 loci that have been reported to associate with adult height to date, at least 15 also contribute to the determination of height in childhood."

Genome-wide association analysis identifies 20 loci that influence adult height.

"Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 × 10−7, with 10 reachingP < 1 × 10−10). Combined, the 20 SNPs explain ~3% of height variation, with a ~5 cm difference between the 6.2% of people with 17 or fewer ‘tall’ alleles compared to the 5.5% with 27 or more ‘tall’ alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait."

"Our findings clearly emphasize that Caucasians and East Asians do not share all of the genetic mechanisms for height"


-SNP in the 3′ UTR of the HMGA2 gene(Chromatin, Type I Collagen)(knockout causes growth defects)
-GDF5-UQCC(Chondrogenesis, may induce ectopic chondrogenesis thus could potentially be chondroinductive, KO reduces height, allele that increases height also reduces risk for osteoarthritis, affects peak height velocity during infancy)
-SH3GL3-ADAMTSL3( glycoprotein metalloprotease, regulates venous invasion)
-CDK6(associated with let-7, allele that associates with greater height also associates with greater risk of rheumatoid arthritis)
-ZBTB38(methyl-DNA-binding transcriptional repressor, methylation affects cellular senesence)
-GPR126(involved in myelination which is involved in nervous function thus nerves may be very important for height growth)
-HIST1H1D(compaction of chromatin into higher end structures, affects peak height velocity during infancy)
-HHIP(reduces Ihh signaling, HHIP overexpression reduces height, mouse knockout causes skeletal defects, affects peak height velocity during infancy)
-TRIP11-ATXN3(Thyroid Hormone Receptor, thyroid hormone is associated with IGF-1 receptors, mutations cause dwarfism)
-Sox5(involved in dwarfism)
-CDKAL1(affects birth length and weight)
-ADRB1(affects birth length and weight)
-LIN28B(associated with let-7)
-DOT1L(histone methyltransferase; histone modifies Sox9 transcription; associated with let-7, affects peak height velocity during puberty)
-PTCH1(SHH & IHH Receptor, knockout causes skeletal defects)
-ACAN(Aggrecan an ECM protein, KO reduces height)
-ADAMTS17(processes proteoglycans and cleaves ECM)
-ADAMTSL3(ECM-related, lacks metalloprotease and other distegrin-like domains unlike normal ADAMTS)
-SCMH1(maintains that transcriptively repressive state of some genes, modifies histone, mouse knockout causes skeletal defects)
-ANAPC13(controls progression through mitosis and G1 phase of the cell cycle)
-PRKG2(encodes the cGMP-dependent protein kinase II (cGKII); cGMP is associated with CNP and is involved in chondrocyte hypertrophy, upregulated in LSJL)
-NCAPG(required for conversion of interphase chromatin, essential for progression in mitosis)
-EFEMP1-PNPT1(EFEMP1 may play a role in cell adhesion and migration and may inhibit chondrocyte differentiationEFEMP1 is also an ECM stabilizer. overexpression stimulates proliferation and supresses chondrocyte differentiation, knockout reduces body size)
-PLAG1(upregulates IGF-II, knockout causes growth defects, has a major effect on stature according to Variants modulating the expression of a chromosome domain encompassing PLAG1 influence bovine stature.)
-SPAG17[upregulated by LSJL](maintains structural integrity of the sperm, may directly cause height or just be a correlation as it's important for parents to have SPAG17 but not yourself to maximize height)
-DLEU7(affects peak height velocity during infancy)
-Sox8(shortens rib length)
-AXIN2(Tgfb and Wnt involvement)
-CHSY1(involved in TGFBeta signaling)
-FNDC3B(some diseases with decreased bone length have this involved)
-TRIOBP(involved with Beta-Catenin binding)
-BNC2(regulates cartilage differentiation, some mutations shorten ulna)
-WWP2(cartilage and chondrocyte development, affects PDGF signaling)
-Sp3(growth plate receptor signalling pathway)
-PLAGL1(mutations reduce height)
-Cables1(affects peak height velocity in puberty, essential for progression through mitosis)
-PXMP3(knockout causes skeletal defects)
-ADYC-POMC(variant associated with increased body mass index, reduced pubertal growth and earlier puberty)
-c17orf67(affects peak height velocity in puberty)
-SOCS2(negatively regulates HGH/IGF-1 pathway, estrogen induces SOCS2 expression,KO increases height, affects peak height velocity in puberty, decreased by JAK-STAT pathway in response to GH)
-ZNF678(may be involved in transcriptional regulation)
-IHH(essential for patterning events during development, mouse knockout causes skeletal defects)
-DYM(may have a role in protein digestion or proteoglycan metabolism, KO decreases height)
-VDR(Mediates the action of Vitamin D3, knockout decreases height)
-DBP (GC)(binds to the promoters of genes like CYP2A4)
-CYP2R1(involved with Vitamin D2 and D3)
-CYP24A1(degrades the active form of Vitamin D3)
-CASR(senses changes in calcium concentration)
-ALPL(Involved with Alkaline Phosphatase)
-GCKR(gain of function causes short stature)
-LCORL(affects birth weight as well, affects peak height during infancy)
-PTHLH(encodes PTHrP, KO reduces height)
-IGF1(overexpression can cause overgrowth postnatally)
-IGF1R(KO reduces height)
-IGF2R(KO increases height by increasing circulating IGF2 levels)
-LHX3-QSOX2(LHX3 is a transcription factor involved in prolactin promotion and plays a role in the pituitary gland, QSOX2 is involved in oxidation)
-PLIN1(involved in liposis of intracellular lipid deposits)
-PLIN4(involved in liposis of intracellular lipid deposits)
-HTR1D(receptor for seratonin)
-CLIC4(enhances TGF-Beta signaling, causes cell cycle arrest, inhibits c-Myc and p21, stabilizes pSmad2/3: TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3.)
-Smad4(Smad4 is required for the normal organization of the cartilage growth plate. states that knockout reduces height)
-NOG(KO increases height, supresses BMP signaling, overexpression blocks chondrogenesis, Conditional inactivation of noggin in the postnatal skeleton causes osteopenia., where Nog is knocked out in osteoblasts reduces height)
-LATS2(Growth factor binding, TGF Beta protein complex)
-BMP6(knockout causes growth defects)
-TGFBeta1(knockout reduces height)
-TGFBeta2(Mediates the effects of Ihh on hypertrophic chondrocyte differentiation and PTHrP expression, knockout reduces height, mutations associated with tall stature)
-PTCH1(mutations increase height, 9q22.3 microdeletion causes tall stature)
-CYP19A1(codes aromatase which converts testosterone to estrogen)
-EIF2AK3(Phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis. Can cause G1 growth arrest, knockout reduces height)
-ID4(knockout reduces height)
-HMGA1(knockout causes growth defects)
-PPARD(target gene of Vitamin D, knockout causes growth defects)
-RUNX2(induces IHH expression, knockout reduces height)
-RUNX3(increases bone growth when removed except when RUNX2 is also affected, overexpression increases chondrocyte hypertrophy and induces ectopic calcification)
-STC2(involved in calcium uptake, increase bone growth when removed, overexpression reduces height)
-COL11A1(loss of function mutations cause short stature)
-GFPT2(biosynthesis of chondroitin sulfate)
-SERPINH1(matrix biosynthesis, mutations reduce height)
-GALNS(matrix degradation)
-ADAMS10(matrix degradation)
-TOP2A(DNA Synthesis)
-CENPW(mitotic spindle formation)
-CCNL1(affects birth length and birth weight)
-TACC3(mitotic spindle formation)
-E2F1(cell cycle progression, overexpression disrupts growth, if double KOed with E2F3 height growth is disturbed this is not present if only E2F1 is KOed)
-SLBP(translation of replication dependent histones)
-IGF2BP2(downregulated during growth plate senescence)
-IGF2BP3(upregulated during hypertrophic differentiation and downregulated during growth plate senescence, mutation associated with tall stature)
-IGF2BP1(removal of gene reduces bone length and drives growth plates to mineralization quicker)
-RSPO3(activates Wnt5a signaling)
-LTBP1(involved with TGFBeta and Growth factor binding)
-LTBP2(mutations associated with tall stature)
-LTBP3(KO decreases height, increases TGFBeta signaling)
-GLI2(mediates Ihh signaling in growth plate, knockout shortens long bones and delays ossification, growth factor binding, WNT protein binding)
-DCC(receptor for netrin, binding with netrin-1 activates FAK signaling, regulates venous invasion)
-CDK6(knockout causes growth defects, essential for progression through mitosis)
-Batf(controls differentiation of helper T-cells)
-BCL3(controls differentiation of helper T-cells)
-Esr1(estrogen receptor alpha, mutation resulted in increased height, knockout decreased height,disruption reduced growth hormone secretion)
-Esr2(knockout increases height in mice)
-Gas1(KO delays chondrogenesis and ossification, "Overexpression of Gas1 in limb micromass culture abolishes participation in cartilage formation"<-not sure what this means)
-Nov(regulates actin cytoskeleton organization, antagonizes BMP-2)
-Nppc(2q37 translocation induces CNP overexpression and causes overgrowth)
-Npr3(limits CNP signaling in chondrocytes, knockout increases height)
-Npr2(codes the CNP receptor, knockout decreases height)
-Pcsk5(KO reduces height, upregulated by LSJL, PCSK5 encodes the proprotein convertase subtilisin/kexin type 5, the expression of which has been linked to developmental dynamics in mice, mutations associated with tall stature)
-Pds5B(KO reduces height)
-Pitx1(KO reduces height severely)
-SHOX2(knockout results in reduced height, overexpression increases height)
-VANGL2(mutations reduce body size)
-Twist1(knockout reduces height, overexpression increases height)
-TNS3(knockout increases resting zone but decreases chondrocyte proliferation with reduced height may promote stemness but reduce differentiation)
-TRIP11(mutations decrease height)
-Tacc3(Knockout reduces height)
-RPL5(Mutations cause short stature)
-TBX15(inhibits adipocyte differentiation, Knockout results in short stature)
-PRGK2(mediates the effects of cGMP, knockout causes dwarfism)
-FGF18(interacts with FGFR3, knockout increases height)
-NSD1(mutations can cause tall stature, knockout reduces height)
-T(knockout reduces height, may induce chondrogenic differentiation)
-BNC2(knockout reduces height)
-FANCC(mutations decrease height, knockout increases height)
-ZFP36L1(KO decreases height)
-NF1(KO decreases height)
-TBX4(involved in short mandible)
-ADCY5(affects birth length and weight)
-Frs2(involved with PI3K, response to fibroblast growth factor)
-RNF135(mutations involving deletion can cause overgrowth)
-KCNJ2(KO decreases height)
-ADAMTS10(some mutations decrease height, other mutations increase height)
-Dlx5(OE reduces height)
-OASIS(Distinct mechanisms are responsible for osteopenia and growth retardation in OASIS-deficient mice., states that OASIS knockout reduces height, increases IGF-1 and GH levels, also called CREB3L1)
-WNT6(hh signaling)
-WNT9a(hh signaling)
-WNT10A(hh signaling)
-WNT3A(hh signaling)
-FBXW11(hh signaling)
-CREBBP(autosomal dominant CREBBP and EP300 genes cause short stature)
-EP300(autosomal dominant CREBBP and EP300 genes cause short stature)
-MAPK3(variant associated with additional pubertal growth and earlier monarch, aka ERK1,  adolescent height-increasing allele (G) at rs4788196 on 16p11.2 correlated with decreased expression of MAPK3, consistent with previous studies linking deactivation of the gene with increased bone growth in mice)
-DHRS1(Gamma-hexachlorocyclohexane degradation)
-ATP13A2(Folate biosynthesis)
-PCK2(Citrate Cycle)
-TAP1(antigen sensing)
-TAP2(antigen sensing)
-CS(Citrate Synthase)
-PAX3(loss of function associated with short stature)
-Il1r1(knockout increases height in mice)
-Lepr(knockin increases height in mice, Leptin receptor, mutations result in delayed puberty and reduced final height)
-Lep(Leptin, mutations result in delayed puberty and reduced final height)
-Pomc(knockout increases height in mice, gain of function causes short stature)
-SF3B4(also known as SV2A, contributes to the regognition of nRNA intron's branch points.  Binds the BMPR-IA serine/threonine kinase receptor, affects peak height velocity during infancy and puberty)
-F3B4(binds BMPR-IA and inhibits BMP-induced SMAD1/5/8 pathways)
-Kif3a(Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis, states that Kif3a knockout reduces growth plate organization and may reduce height; Mechanosensing by the primary cilium: deletion of Kif3A reduces bone formation due to loading. states Kif3a may be involved in mechanotransduction, The study identified Pkd1 as another gene involved in mechanotransduction)
-STK36(relates to Ihh signaling, Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus., upregulated in LSJL, knockout reduces height)
-H19(H19 acts as a trans regulator of the imprinted gene network controlling growth in mice., conditional knockout of H19 increases height due to effect on IGF2 although the mutation needed to cause overgrowth is fairly specific)
-GPC3(Altered hematopoiesis in glypican-3-deficient mice results in decreased osteoclast differentiation and a delay in endochondral ossification., The loss of glypican-3 induces alterations in Wnt signaling., loss of function causes overgrowth, seems to slow down terminal differentiation, Mutations cause Simson-Golabi-Behmel syndrome, an X-linked disorder with pre- and post-natal overgrowth, [with] visceral and skeletal [defects]. GPC3 is a negative regulator of Hedgehog (HH), and hyperactivation of HH signaling leads to overgrowth, non-functional GPC3 may lead to increased IGF2 signalling)
-PHLDA2(Placental growth retardation due to loss of imprinting of Phlda2., total deletion results in overgrowth, partial deletion(loss of imprinting) reduces height,  PHLDA2 overexpression can reduce height if expressed with Slc22a1l)
-KVDMR1(knockout reduces height)
-NEDD4L(partial deletion reduces height, regulator of sodium channels, could regulate TGF-Beta signaling, LSJL downregulates a few proteins in the NEDD4 family, NEDD4L binds to Smad7 which inhibits Smad's)
-FBN2(mutation can cause overgrowth)
-GNAS1(loss of function mutation reduces height, plays a role in adenylate cyclase activation, gain of function results in abnormal fibrous overgrowth in the bone)
-TRA1(knockout reduces height,
-GPR30(knockout increases height)
-GRB10(KO mice show embryo and placental overgrowth)
-FBLN5(ECM stabilizer, induces MMPs)
-MC4R(allele that is associated with greater height also associates with obesity, accelerates height during childhood)
-EGFR(KO reduces height)
-Girdin(Similar phenotypes of Girdin germ-line and conditional knockout mice indicate a crucial role for Girdin in the nestin lineage., Akt substrate, KO reduces height)
-PTEN(Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth., chondrogenic specific deletion causes overgrowth, haploinsufficiency leads to postnatal overgrowth but to reduced growth childhood leading to normal adult height)
-mitochondrian ATPase 6(Tall stature and progressive overweight in mitochondrial encephalopathy., mutation causes skeletal overgrowth)
-GHSR(GH secretagogue receptor gene polymorphisms are associated with stature throughout childhood., mutations associated with overgrowth but not necessarily adult tall stature, A genetic study of the ghrelin and growth hormone secretagogue receptor (GHSR) genes and stature., found no effect on adultheight)
-NSD1(mutations can cause tall stature, SOTOS syndrome)
-FMR1(mutations can cause tall stature, failure to express results in increased growth rate but reduced final stature)
-HDLBP(downregulated by LSJL)
-SMPD2(downregulated by LSJL)
-MAML2(transcriptional co-activator of Notch proteins)

There are several genes associated with methylation and histone related mechanisms.  cGMP and GDF5's involvement in height is as expected.  Also, of note no direct association to HGH(except for SOCS2) on height genes.

Each individual gene has only a small effect on height so maybe genes that have not been discovered yet influence proteins like BMP-2 and TGF-Beta.

Other studies used for genes:

Replication study of the association of SNPs in the LHX3-QSOX2 and IGF1 loci with adult height in the Japanese population; wide-ranging comparison of each SNP genotype distribution.

A Polymorphism in a gene encoding Perilipin 4 is associated with height but not with bone measures in individuals from the Framingham Osteoporosis Study.

<-Important study

Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size

Genome-Wide Association Study Identified CNP12587 Region Underlying Height Variation in Chinese Females.


Gene-based copy number variation study reveals a microdeletion at 12q24 that influences height in the Korean population.

Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse.

Genetic analysis of tall stature.

Genetic regulation of the growth plate.

PIK3CA, a hotspot for postzygotic mutations in nonhereditary overgrowth syndromes

Genome-Wide Association Studies of Skeletal Phenotypes: What We Have Learned and Where We Are Headed.

"finding of 12.5% of the variance in heritability of body height (by 18GWAS loci)"

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

"at the extreme tall end of the height distribution, phenotypes were consistent with the segregation of common DNA polymorphisms, each with a weak effect on height. "

Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height.

"Many of the 78 implicated genes participate in molecular pathways that are known to be important for growth plate chondrogenesis in the mouse. A large number participate in signaling pathways that regulate growth plate chondrocyte proliferation and differentiation, including Indian hedgehog, parathyroid hormone-related peptide, bone morphogenetic protein / transforming growth factor-beta superfamily, C-type natriuretic peptide, fibroblast growth factor, and insulin-like growth factor signaling"

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Finding missing heritability in less significant Loci and allelic heterogeneity: genetic variation in human height.

"including less significant loci (i.e., p-value<5×10(-4)) and accounting for effects of allelic heterogeneity substantially improved the variance explained in height."

"Height was normally distributed in both males (N = 565) and females (N = 739) with larger variability observed in males"<-Sox9 is a sex linked trait.

Reaching new heights: insights into the genetics of human stature 

Human height genes and cancer. 

"TP53, ESR1, HNF4A and MYC are main network hubs [for height increase]."

Genome-wide association study in Han Chinese identifies three novel loci for human height.

Rare copy number variants are a common cause of short stature. 

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

Genetics of obesity and overgrowth syndromes

Genetic Determinants of Height Growth Assessed Longitudinally from Infancy to Adulthood in the Northern Finland Birth Cohort 1966

Human growth is associated with distinct patterns of gene expression in evolutionarily conserved networks. 

Common DNA variants predict tall stature in Europeans. 

Defining the role of common variation in the genomic and biological architecture of adult human height.

Data from jax.org was used as well.

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