Gene Database

I finally can get to editing and adding upon this section for the Gene Database after I found the GIANT collaborative project that was published back in one of the October editions in Nature magazine in 2010. This is the most comprehensive collection of gene that have at “significance” in height.

First, lets get through some terminology…

GIANT (Genetic Investigation of ANthropometric Traits consortium): is an international collaboration that seeks to identify genetic loci that modulate human body size and shape, including height and measures of obesity. The GIANT consortium is a collaboration between investigators from many different groups, institutions, countries, and studies, and the results represent their combined efforts. The primary approach has been meta-analysis of genome-wide association data and other large-scale genetic data sets. Anthropometric traits that have been studied by GIANT include body mass index (BMI), height, and traits related to waist circumference (such as waist-hip ratio adjusted for BMI, or WHRadjBMI). Thus far, the GIANT consortium has identified common genetic variants at hundreds of loci that are associated with anthropometric traits. (from Broad Institute website HERE)

SNP (Single Nucleotide Polymorphism): is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes in an individual. (ie, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles: C and T). Almost all common SNPs have only two alleles (from wikipedia article on SNP here)

GWAs (Genomic-Wide Association studies): In genetic epidemiology, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait. GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases. These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays. If one type of the variant (one allele) is more frequent in people with the disease, the SNP is said to be “associated” with the disease. The associated SNPs are then considered to mark a region of the human genome which influences the risk of disease. (from wikipedia article on GWAs here)

Nucleotide: molecules that, when joined, make up the individual structural units of the nucleic acids RNA and DNA.

Gene variation: variation in alleles of genes, occurs both within and among populations. Genetic variation is important because it provides the “raw material” for natural selection. Genetic variation is brought about by mutation, which is a change in the chemical structure of a gene. (from wiki)

Allele: one of two or more forms of a gene or a genetic locus (generally a group of genes). Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation. However, many variations at the genetic level result in little or no observable variation. Most multicellular organisms have two sets of chromosomes, that is, they are diploid. These chromosomes are referred to as homologous chromosomes. Diploid organisms have one copy of each gene (and therefore one allele) on each chromosome. If both alleles are the same, they are homozygotes. If the alleles are different, they are heterozygotes. A population or species of organisms typically includes multiple alleles at each locus among various individuals. Allelic variation at a locus is measurable as the number of alleles (polymorphism) present, or the proportion of heterozygotes in the population.  In many cases, genotypic interactions between the two alleles at a locus can be described as dominant or recessive, according to which of the two homozygous genotypes the phenotype of the heterozygote most resembles. Where the heterozygote is indistinguishable from one of the homozygotes, the allele involved is said to be dominant to the other, which is said to be recessive to the former. The degree and pattern of dominance varies among loci. For a further discussion see Dominance (genetics). This type of interaction was first formally described by Gregor Mendel. However, many traits defy this simple categorization and the phenotypes are modeled by polygenic inheritance. The term “wild type” allele is sometimes used to describe an allele that is thought to contribute to the typical phenotypic character as seen in “wild” populations of organisms…Such a “wild type” allele was historically regarded as dominant, common, and “normal”, in contrast to “mutant” alleles regarded as recessive, rare, and frequently deleterious. It was commonly thought that most individuals were homozygous for the “wild type” allele at most gene loci, and that any alternative ‘mutant’ allele was found in homozygous form in a small minority of “affected” individuals, often as genetic diseases, and more frequently in heterozygous form in “carriers” for the mutant allele. It is now appreciated that most or all gene loci are highly polymorphic, with multiple alleles, whose frequencies vary from population to population, and that a great deal of genetic variation is hidden in the form of alleles that do not produce obvious phenotypic differences. (from wikipedia article on allele HERE)

Loci (singular is Locus): is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map. Gene mapping is the procession of determining the locus for a particular biological trait. Diploid and polyploid cells whose chromosomes have the same allele of a given gene at some locus are called homozygous with respect to that gene, while those that have different alleles of a given gene at a locus, are called heterozygous with respect to that gene. (from wikipedia article on gene loci HERE)

Gene: is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a polypeptide or for an RNA chain that has a function in the organism. A modern working definition of a gene is “a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions, and or other functional sequence regions “. Colloquial usage of the term gene (e.g. “good genes”, “hair color gene”) may actually refer to an allele: a gene is the basic instruction—a sequence of nucleic acids (DNA or, in the case of certain viruses RNA), while anallele is one variant of that gene. Referring to having a gene for a trait is no longer the scientifically accepted usage. In most cases, all people would have a gene for the trait in question, but certain people will have a specific allele of that gene, which results in the trait variant. Further, genes code for proteins, which might result in identifiable traits, but it is the gene, not the trait, which is inherited. (from the wikipedia article on gene HERE)

Minor Allele Frequency (MAF): refers to the frequency at which the less common allele occurs in a given population. MAF is widely employed in Genome Wide Association studies for complex traits. (from wikipedia article on MAF HERE)

Now let’s get through how gene locus nomenclature is done… 


 

(the segment/pic clip posted below is taken from the wikipedia article on genetics loci above HERE)

Also Understand the Results And Measurements (specifically the P-value)…

What is P-value? – In statistical hypothesis testing, the p-value is the probability of obtaining a test statistic at least as extreme as the one that was actually observed, assuming that the null hypothesis is true. One often “rejects the null hypothesis” when the p-value is less than the significance level α (Greek alpha), which is often 0.05 or 0.01. When the null hypothesis is rejected, the result is said to be statistically significant. (from wikipedia)

Note: For a far better and more detailed explanation of what exactly is the P-value please refer to the notes from a University of Alberta Stats class located HERE.

What does it mean to be “statistically signifi cant”?

It has become scienti fic convention to say that p-values exceeding 0.05 (one in twenty) just aren’t strong enough to be the sole evidence that two treatments
being studied really di ffer in their e ffect. When the term statistically signi cant is used to describe the results from a clinical trial, it means that the p-value is less than this conventional reference point. It is possible to have very strong evidence to show that even a very small e ffect is nonetheless a real one. Consequently, it is possible to have a small p-value even though the size of the e ffect is not worth bothering with from the 5clinical standpoint. Thus, statistical signi cance and clinical importance must be completely separate assessments.

Even when one treatment is superior to another in clinically important ways, it is possible for the study not to end in statistical signi cance. The study may have been too small to detect any but the largest of di erences. And of coursechance can work against a treatment as easily as work in its favor. Consequently, not achieving statistical signi cance must not be interpreted as having shown that the treatments studied are equally e ffective. (from University of Chicago Document HERE)

List Of Genes

[Note: This list of genes that have a “significant” influence on height variation was all taken from the Supplementary Material from the GIANT project.]

Analysis 1 (from GIANT article)

 

If you can see close enough, you can see that there was 42 single nucleotide polymorphisms associated in the circular diagram above. As stated in the original article found HERE

“This analysis revealed 17 different biological pathways and 14 molecular functions nominally enriched (P<0.05) for associated genes, many of which lie within the validated height loci. These gene-sets include previously reported (e.g. Hedgehog signaling) and novel (e.g. TGF-beta signaling, histones, and growth and development-related) pathways and molecular functions (Supplementary Table 12). Several SNPs near genes in these pathways narrowly missed genome-wide significance, suggesting that these pathways likely contain additional associated variants.”

also

“Of 32 genes with highly correlated (r2>0.8) nsSNPs, several are newly identified strong candidates for playing a role in human growth. Some are in pathways enriched in our study (such as ECM2, implicated in extracellular matrix), while others have similar functions to known growth-related genes, including FGFR4 (FGFR3 underlies several classic skeletal dysplasias23) and STAT2 (STAT5B mutations cause growth defects in humans24). Interestingly, Fgfr4-/- Fgfr3-/- mice show severe growth retardation not seen in either single mutant25, suggesting that the FGFR4 variant might modify FGFR3-mediated skeletal dysplasias. Other genes at associated loci, such as NPPC and NPR3 (encoding the C-type natriuretic peptide and its receptor), influence skeletal growth in mice and will likely also influence human growth17. Many of the remaining 180 loci have no genes with obvious connections to growth biology, but at some our data provide modest supporting evidence for particular genes…”

COMPLETE LISTING – 180 gene loci at present 

[Note: All the tables, graphs, and charts are edited and taken from the Supplementary Document for the GIANT article located HERE.]

Supplementary Table 1. Association results for Stage 1 (discovery GWAS), Stage 2 (in-silico replication), Stage 1+2 combined, and Stage 1+2 sex-specific meta-analyses, for the 180 independent signals that reached genome-wide significance (P<5×10-8) in the combined Stage 1+2 analysis. I2 represents the % heterogeneity of effect size between Stage 1 studies. Phet is the heterogeneity P-value.

SNP a Chr Position (bp) Nearest/OMIM height gene b Effect / other allele c Frequency (effect allele) Beta P-value d Phet (MvsF)
rs425277 1 2059032 PRKCZ T/C 0.28 0.024 1.70E-006 0.15
rs2284746 1 17179262 MFAP2 C/G 0.48 -0.035 5.60E-015 0.76
rs1738475 1 23409478 HTR1D C/G 0.59 0.022 1.90E-006 0.25
rs4601530 1 24916698 CLIC4 T/C 0.26 -0.024 2.00E-006 0.47
rs7532866 1 26614131 LIN28 A/G 0.67 0.022 3.30E-006 0.23
rs2154319 1 41518357 SCMH1 T/C 0.75 -0.034 4.30E-010 0.13
rs17391694 1 78396214 GIPC2 T/C 0.12 0.04 5.90E-007 0.95
rs6699417 1 88896031 PKN2 T/C 0.61 0.022 1.70E-006 0.99
rs10874746 1 93096559 RPL5 T/C 0.37 -0.022 1.70E-006 0.78
rs9428104 1 118657110 SPAG17 A/G 0.24 -0.038 8.90E-013 0.55
rs11205277 1 148159496 SF3B4 A/G 0.58 -0.045 1.20E-018 0.36
rs17346452 1 170319910 DNM3 T/C 0.73 -0.038 3.30E-014 0.56
rs1325598 1 175058872 PAPPA2 A/G 0.43 -0.026 1.60E-008 0.52
rs1046934 1 182290152 TSEN15 A/C 0.64 -0.046 6.40E-022 0.94
rs10863936 1 210304421 DTL A/G 0.53 -0.022 6.20E-007 0.06
rs6684205 1 216676325 TGFB2 A/G 0.71 -0.033 2.00E-011 0.41
rs11118346 1 217810342 LYPLAL1 T/C 0.47 -0.026 2.20E-009 0.05
rs10799445 1 225978506 JMJD4 A/C 0.77 0.031 1.20E-008 0.21
rs4665736 2 25041103 DNAJC27 T/C 0.54 0.034 1.40E-013 0.08
rs6714546 2 33214929 LTBP1 A/G 0.28 -0.025 2.20E-006 0.19
rs17511102 2 37814117 CDC42EP3 A/T 0.91 -0.06 1.30E-012 0.9
rs2341459 2 44621706 C2orf34 T/C 0.27 0.028 3.60E-008 0.14
rs12474201 2 46774789 SOCS5 A/G 0.35 0.023 1.00E-006 0.78
rs3791675 2 55964813 EFEMP1 T/C 0.23 -0.05 2.40E-020 0.71
rs11684404 2 88705737 EIF2AK3 T/C 0.67 -0.027 6.40E-009 0.46
rs7567288 2 134151294 NCKAP5 T/C 0.8 -0.031 6.70E-008 0.6
rs7567851 2 178392966 PDE11A C/G 0.08 0.041 7.50E-007 0.7
rs1351164 2 217980143 TNS1 T/C 0.79 0.028 3.70E-007 0.83
rs12470505 2 219616613 CCDC108/IHH T/G 0.9 0.048 1.30E-010 0.01
rs2629046 2 224755988 SERPINE2 T/C 0.55 0.025 2.20E-008 0.2
rs2580816 2 232506210 NPPC T/C 0.19 -0.041 1.80E-012 0.23
rs12694997 2 241911659 SEPT2 A/G 0.24 -0.027 1.80E-007 0.61
rs2597513 3 13530836 HDAC11 T/C 0.9 -0.039 1.10E-007 0.83
rs13088462 3 51046753 DOCK3 T/C 0.94 -0.054 3.10E-007 0.56
rs2336725 3 53093779 RTF1 T/C 0.55 -0.026 3.50E-008 0.85
rs9835332 3 56642722 C3orf63 C/G 0.46 -0.022 8.70E-007 0.91
rs17806888 3 67499012 SUCLG2 T/C 0.88 0.04 1.10E-007 0.93
rs9863706 3 72520103 RYBP T/C 0.22 -0.03 1.50E-008 0.6
rs6439167 3 130533446 C3orf47 T/C 0.21 -0.034 7.20E-010 0.09
rs9844666 3 137456906 PCCB A/G 0.25 -0.028 3.10E-008 0.09
rs724016 3 142588260 ZBTB38 A/G 0.56 -0.067 4.50E-052 0.42
rs572169 3 173648421 GHSR T/C 0.31 0.036 9.90E-014 0.4
rs720390 3 187031377 IGF2BP2 A/G 0.39 0.031 1.60E-010 0.14
rs2247341 4 1671115 SLBP/FGFR3 A/G 0.36 0.025 6.80E-008 0.67
rs6449353 4 17642586 LCORL T/C 0.85 0.071 1.30E-027 0.88
rs17081935 4 57518233 POLR2B T/C 0.2 0.031 4.80E-008 0.09
rs7697556 4 73734177 ADAMTS3 T/C 0.47 0.022 1.30E-006 0.56
rs788867 4 82369030 PRKG2/BMP3 T/G 0.68 -0.039 1.80E-015 0.95
rs10010325 4 106325802 TET2 A/C 0.49 0.021 2.30E-006 0.64
rs7689420 4 145787802 HHIP T/C 0.16 -0.069 1.40E-029 0.61
rs955748 4 184452669 WWC2 A/G 0.24 -0.024 2.20E-006 0.29
rs1173727 5 32866278 NPR3 T/C 0.4 0.036 4.00E-015 0.27
rs11958779 5 55037656 SLC38A9 A/G 0.7 -0.028 8.00E-009 0.8
rs10037512 5 88390431 MEF2C T/C 0.56 0.027 3.80E-009 0.3
rs13177718 5 108141243 FER T/C 0.07 -0.041 4.10E-006 0.16
rs1582931 5 122685098 CEP120 A/G 0.47 -0.025 2.10E-008 0.31
rs274546 5 131727766 SLC22A5 A/G 0.4 -0.028 8.50E-010 0.13
rs526896 5 134384604 PITX1 T/G 0.73 0.032 1.90E-009 0.15
rs4282339 5 168188818 SLIT3 A/G 0.2 -0.035 3.40E-010 0.69
rs12153391 5 171136043 FBXW11 A/C 0.25 -0.033 8.70E-010 0.57
rs889014 5 172916720 BOD1 T/C 0.36 -0.029 4.50E-010 0.51
rs422421 5 176449932 FGFR4/NSD1 T/C 0.22 -0.033 1.40E-009 0.64
rs6879260 5 179663620 GFPT2 T/C 0.39 -0.028 5.60E-010 0.41
rs3812163 6 7670759 BMP6 A/T 0.54 -0.037 6.70E-016 0.36
rs1047014 6 19949472 ID4 T/C 0.75 -0.029 1.10E-007 0.9
rs806794 6 26308656 Histone cluster A/G 0.7 0.053 5.50E-026 0.12
rs3129109 6 29192211 OR2J3 T/C 0.39 -0.026 3.30E-008 0.64
rs2256183 6 31488508 MICA A/G 0.45 0.035 2.70E-014 0.43
rs6457620 6 32771977 HLA locus C/G 0.51 -0.024 3.60E-008 0.81
rs2780226 6 34307070 HMGA1 T/C 0.92 -0.079 1.00E-018 0.96
rs6457821 6 35510783 PPARD/FANCE A/C 0.02 -0.121 1.80E-011 0.29
rs9472414 6 45054484 SUPT3H/RUNX2 A/T 0.22 -0.031 2.40E-008 0.66
rs9360921 6 76322362 SENP6 T/G 0.89 -0.048 4.60E-011 0.62
rs310405 6 81857081 FAM46A A/G 0.52 0.03 3.60E-011 0.25
rs7759938 6 105485647 LIN28B T/C 0.68 -0.042 8.70E-018 0.26
rs1046943 6 109890634 ZBTB24 A/G 0.58 0.022 8.60E-007 0.46
rs961764 6 117628849 VGLL2 C/G 0.42 -0.023 2.40E-007 0.79
rs1490384 6 126892853 C6orf173 T/C 0.5 0.037 3.20E-016 0.55
rs6569648 6 130390812 L3MBTL3 T/C 0.76 -0.036 8.90E-012 0.14
rs7763064 6 142838982 GPR126 A/G 0.29 -0.045 6.40E-019 0.29
rs543650 6 152152636 ESR1 T/G 0.4 -0.032 1.40E-009 0.36
rs9456307 6 158849430 TULP4 A/T 0.06 -0.05 4.60E-007 0.38
rs798489 7 2768329 GNA12 T/C 0.3 -0.052 8.50E-025 0.53
rs4470914 7 19583047 TWISTNB T/C 0.18 0.033 3.80E-008 0.93
rs12534093 7 23469499 IGF2BP3 A/T 0.22 -0.03 5.60E-008 0.84
rs1708299 7 28156471 JAZF1 A/G 0.3 0.042 1.50E-017 0.25
rs6959212 7 38094851 STARD3NL T/C 0.32 -0.023 2.80E-006 0.66
rs42235 7 92086012 CDK6 T/C 0.31 0.055 7.30E-028 0.01
rs822552 7 148281567 PDIA4 C/G 0.74 -0.03 1.30E-007 0.24
rs2110001 7 150147955 TMEM176A C/G 0.69 -0.033 9.80E-010 0.71
rs1013209 8 24172249 ADAM28 T/C 0.25 -0.029 4.50E-008 0.95
rs7460090 8 57356717 SDR16C5 T/C 0.87 0.055 9.60E-016 0.16
rs6473015 8 78341040 PEX2 A/C 0.72 -0.032 1.70E-010 0.84
rs6470764 8 130794847 GSDMC T/C 0.2 -0.047 5.90E-017 0.95
rs12680655 8 135706519 ZFAT C/G 0.6 0.03 4.80E-011 0.45
rs7864648 9 16358732 BNC2 T/G 0.32 0.025 4.90E-007 0.23
rs11144688 9 77732106 PCSK5 A/G 0.11 -0.055 1.50E-009 0.28
rs7853377 9 85742025 C9orf64 A/G 0.77 -0.026 3.10E-006 0.26
rs8181166 9 88306448 ZCCHC6 C/G 0.53 0.025 1.10E-007 0.07
rs2778031 9 90025546 SPIN1 T/C 0.24 0.027 3.60E-007 0.78
rs9969804 9 94468941 IPPK A/C 0.44 0.028 5.60E-010 0.92
rs1257763 9 95933766 PTPDC1 A/G 0.04 0.069 2.50E-006 0.55
rs473902 9 97296056 PTCH1/FANCC T/G 0.92 0.074 1.70E-014 0.62
rs7027110 9 108638867 ZNF462 A/G 0.23 0.034 1.30E-010 0.72
rs1468758 9 112846903 LPAR1 T/C 0.25 -0.026 1.50E-006 0.24
rs751543 9 118162163 PAPPA T/C 0.72 0.029 4.50E-008 0.89
rs7466269 9 132453905 FUBP3 A/G 0.64 0.036 1.20E-014 0.92
rs7849585 9 138251691 QSOX2 T/G 0.33 0.032 3.40E-011 0.69
rs7909670 10 12958770 CCDC3 T/C 0.44 -0.022 1.30E-006 0.06
rs2145998 10 80791702 PPIF A/T 0.49 -0.025 2.70E-008 0.68
rs11599750 10 101795432 CPN1 T/C 0.38 -0.023 7.60E-007 0.32
rs2237886 11 2767307 KCNQ1 T/C 0.11 0.043 3.10E-008 0.25
rs7926971 11 12654616 TEAD1 A/G 0.55 -0.024 7.30E-008 0.4
rs1330 11 17272605 NUCB2 T/C 0.35 0.024 4.40E-007 0.56
rs10838801 11 48054856 PTPRJ/SLC39A13 A/G 0.69 -0.031 1.80E-010 0.27
rs1814175 11 49515748 FOLH1 T/C 0.34 0.023 2.60E-006 0.13
rs5017948 11 51270794 OR4A5 A/T 0.18 0.027 4.70E-006 0.02
rs3782089 11 65093395 SSSCA1 T/C 0.06 -0.058 5.90E-009 0.13
rs7112925 11 66582736 RHOD T/C 0.35 -0.023 8.50E-007 0.57
rs634552 11 74959700 SERPINH1 T/G 0.14 0.041 1.40E-009 0.69
rs494459 11 118079885 TREH T/C 0.41 0.021 4.90E-006 0.5
rs654723 11 128091365 FLI1 A/C 0.62 0.024 6.70E-007 0.82
rs2856321 12 11747040 ETV6 A/G 0.64 -0.03 1.50E-010 0.83
rs10770705 12 20748734 SLCO1C1 A/C 0.33 0.031 4.60E-011 0.77
rs2638953 12 28425682 CCDC91 C/G 0.68 0.036 8.40E-014 0.04
rs2066807 12 55026949 STAT2 C/G 0.93 -0.052 9.60E-009 0.49
rs1351394 12 64638093 HMGA2 T/C 0.49 0.054 7.80E-034 0.14
rs10748128 12 68113925 FRS2 T/G 0.35 0.035 3.80E-011 0.23
rs11107116 12 92502635 SOCS2 T/G 0.22 0.052 1.70E-023 0.1
rs7971536 12 100897919 CCDC53/GNPTAB A/T 0.46 -0.025 1.10E-007 0.75
rs11830103 12 122389499 SBNO1 A/G 0.78 -0.035 3.80E-010 0.27
rs7332115 13 32045548 PDS5B/BRCA2 T/G 0.62 -0.025 7.60E-008 0.37
rs3118905 13 50003335 DLEU7 A/G 0.29 -0.052 3.00E-025 0.15
rs7319045 13 90822575 GPC5 A/G 0.4 0.029 4.50E-010 0.6
rs1950500 14 23900690 NFATC4 T/C 0.29 0.032 3.90E-011 0.32
rs2093210 14 60027032 SIX6 T/C 0.58 -0.034 2.30E-012 0.23
rs1570106 14 67882868 RAD51L1 T/C 0.2 -0.026 4.90E-006 0.67
rs862034 14 74060499 LTBP2 A/G 0.36 -0.023 1.10E-006 0.24
rs7155279 14 91555634 TRIP11 T/G 0.36 -0.029 8.90E-010 0.38
rs16964211 15 49317787 CYP19A1 A/G 0.05 -0.051 2.50E-006 0.04
rs7178424 15 60167551 C2CD4A T/C 0.47 -0.024 2.20E-007 0.88
rs10152591 15 67835211 TLE3 A/C 0.91 0.045 3.50E-008 0.28
rs12902421 15 69948457 MYO9A T/C 0.97 -0.069 1.70E-006 0.25
rs5742915 15 72123686 PML T/C 0.54 -0.031 3.00E-010 0.08
rs11259936 15 82371586 ADAMTSL3 A/C 0.48 -0.042 2.20E-021 0.03
rs16942341 15 87189909 ACAN T/C 0.03 -0.134 1.30E-017 0.43
rs2871865 15 97012419 IGF1R C/G 0.88 0.054 1.10E-012 0.54
rs4965598 15 98577137 ADAMTS17 T/C 0.68 -0.035 1.40E-013 0.21
rs11648796 16 732191 NARFL A/G 0.74 -0.031 2.40E-007 0.71
rs26868 16 2189377 CASKIN1 A/T 0.46 0.03 3.50E-008 0.73
rs1659127 16 14295806 MKL2 A/G 0.34 0.024 2.90E-006 0.7
rs8052560 16 87304743 CTU2/GALNS A/C 0.79 0.039 1.40E-008 0.47
rs4640244 17 21224816 KCNJ12 A/G 0.61 0.028 2.00E-007 0.78
rs3110496 17 24941897 ANKRD13B A/G 0.33 -0.023 1.60E-006 0.04
rs3764419 17 26188149 ATAD5/RNF135 A/C 0.39 -0.037 8.90E-016 0.67
rs17780086 17 27367395 LRRC37B A/G 0.15 0.035 4.40E-008 0.85
rs1043515 17 34175722 PIP4K2B A/G 0.45 -0.022 1.30E-006 0.15
rs4986172 17 40571807 ACBD4 T/C 0.35 -0.028 7.10E-009 0.41
rs2072153 17 44745013 ZNF652 C/G 0.3 0.026 6.70E-008 0.03
rs4605213 17 46599746 NME2 C/G 0.34 0.023 9.30E-007 0.21
rs227724 17 52133816 NOG A/T 0.65 -0.027 1.20E-008 0.2
rs2079795 17 56851431 TBX2 T/C 0.33 0.04 1.20E-016 0.12
rs2665838 17 59320197 CSH1/GH1 C/G 0.73 -0.037 2.00E-013 0.92
rs11867479 17 65601802 KCNJ16/KCNJ2 T/C 0.34 0.024 4.90E-007 0.68
rs4800452 18 18981609 CABLES1 T/C 0.79 0.048 2.40E-017 0.8
rs9967417 18 45213498 DYM C/G 0.58 -0.038 2.60E-016 0.44
rs17782313 18 56002077 MC4R T/C 0.76 -0.025 3.50E-006 0.55
rs12982744 19 2128193 DOT1L C/G 0.6 -0.033 2.80E-012 0.6
rs7507204 19 3379834 NFIC C/G 0.24 0.028 2.30E-007 0.05
rs891088 19 7135762 INSR A/G 0.74 -0.025 1.70E-006 0.45
rs4072910 19 8550031 ADAMTS10 C/G 0.46 -0.029 2.50E-007 0.31
rs2279008 19 17144303 MYO9B T/C 0.74 0.031 2.40E-007 0.48
rs17318596 19 46628935 ATP5SL A/G 0.36 0.029 3.00E-009 0.01
rs1741344 20 4049800 SMOX T/C 0.63 -0.026 3.50E-008 0.55
rs2145272 20 6574218 BMP2 A/G 0.65 -0.039 5.90E-016 0.85
rs7274811 20 31796842 ZNF341 T/G 0.23 -0.04 6.80E-014 0.52
rs143384 20 33489170 GDF5 A/G 0.58 -0.064 4.90E-039 0.47
rs237743 20 47336426 ZNFX1 A/G 0.21 0.034 7.20E-010 0.28
rs2834442 21 34612656 KCNE2 A/T 0.65 0.027 7.30E-009 0.9
rs4821083 22 31386341 SYN3 T/C 0.84 0.033 4.80E-008 0.41
  • a SNPs most likely to be representing a previously published height locus are highlighted in green.
  • b Gene regions are named after the gene nearest to the index SNP. A near-by (within 500kb from the index SNP) OMIM height gene (defined as a gene that when mutated results in a monogenic skeletal growth defect) is also included if it is not the nearest. All OMIM height genes are highlighted in blue.
  • c Alleles are indexed to the forward strand of NCBI Build 36.
  • d All p-values are based on the inverse-variance weighted meta-analysis model (fixed effects).

Supplementary Table 10. List of 241 abnormal skeletal/growth genes identified in the OMIM database (http://www.ncbi.nlm.nih.gov/omim) using the following keywords: short stature, overgrowth, skeletal dysplasia, brachydactyly, and manually curating the list blind to GIANT height results.

ACAN COL9A3 GJA1 NEU1 SIL1
ADAMTS10 COMP GLB1 NF1 SLC26A2
ADAMTS2 CRTAP GLI3 NIPBL SLC29A3
ADAMTSL2 CTDP1 GNAS NOG SLC2A2
AGPS CTSK GNPAT NPR2 SLC34A3
ALG12 CUL4B GNPTAB NSD1 SLC35C1
ALMS1 CUL7 GPC3 OCRL SLC35D1
ALPL CYP11B1 GUSB OFD1 SLC37A4
ANKH CYP19A1 HCCS PAPSS2 SLC39A13
ARL6 CYP21A2 HESX1 PAX3 SLC4A4
ARSB CYP27B1 HMGA2 PAX8 SLC6A8
ARSE DHCR7 HOXD13 PCNT SMARCAL1
ATP6V0A2 DYM HPRT1 PEX7 SMC1A
ATP7A EBP HRAS PHEX SMC3
ATP8B1 EFNB1 HSPG2 PHF6 SMPD1
ATR EIF2AK3 HYAL1 PITX2 SMS
ATRX ERCC2 ICK POU1F1 SOS1
B3GALTL ERCC3 IDUA PQBP1 SOST
B4GALT7 ESCO2 IFT80 PROP1 SOX3
BBS1 EVC IGBP1 PTCH1 SPG20
BBS10 EVC2 IGF1 PTCH2 SRY
BBS12 EXT1 IGF1R PTEN STAT5B
BBS2 EXT2 IGF2 PTH1R TAZ
BBS4 FANCA IHH PTPN11 TBCE
BBS5 FANCB IKBKG RAB23 TBX1
BBS7 FANCC JAG1 RAB3GAP1 TBX15
BBS9 FANCD2 KCNJ2 RAB3GAP2 TCF4
BMPR1B FANCE KDM5C RAF1 TGFBR1
BRAF FANCF KIAA1279 RAI1 TGFBR2
BRCA2 FANCG KRAS RBM28 THRB
BTK FANCI LBR RECQL4 TNFRSF11B
BUB1B FANCL LEMD3 RMRP TP63
C7orf11 FANCM LEPRE1 RNF135 TRAPPC2
CA2 FBN1 LHX4 ROR2 TRIM32
CCDC28B FBN2 LIFR RPL11 TRIM37
CEP290 FGD1 LIG4 RPL35A TRPS1
CHD7 FGF23 LMNA RPL5 TRPV4
CHRNG FGFR2 LRP5 RPS17 UBR1
CHST3 FGFR3 MAP2K1 RPS19 WNT7A
CLCN5 FLNA MAP2K2 RPS24 WRN
COL10A1 FLNB MATN3 RPS6KA3 ZBTB16
COL11A1 FOXC1 MC4R RPS7
COL11A2 FUCA1 MECP2 RUNX2
COL1A1 G6PC MGP SBDS
COL1A2 GALNS MKKS SDHA
COL2A1 GDF5 MKS1 SECISBP2
COL5A1 GH1 MMP13 SEMA3E
COL5A2 GHR MRPS16 SHH
COL9A1 GHRHR MYCN SHOX
COL9A2 GHSR NBN SHROOM4
——-

Supplementary Table 11. Height SNPs found to be located near or in the abnormal skeletal/growth genes identified in the OMIM database and listed in Supplementary Table 10.

SNP

Abnormal skeletal/growth gene (OMIM)

The closest gene to the height SNP is the abnormal skeletal/growth gene

The height SNP is in the abnormal skeletal/growth gene

rs16942341

ACAN

yes

yes

rs4072910

ADAMTS10

yes

no

rs16964211

CYP19A1

yes

yes

rs9967417

DYM

yes

yes

rs11684404

EIF2AK3

yes

yes

rs6457821

FANCE

no

no

rs143384

GDF5

yes

yes

rs2665838

GH1

no

no

rs572169

GHSR

yes

yes

rs7971536

GNPTAB

no

no

rs1351394

HMGA2

yes

yes

rs2871865

IGF1R

yes

yes

rs12470505

IHH

yes

no

rs17782313

MC4R

yes

no

rs227724

NOG

yes

no

rs422421

NSD1

no

no

rs473902

PTCH1

yes

yes

rs3764419

RNF135

no

no

rs10874746

RPL5

no

no

rs9472414

RUNX2

no

no

rs10838801

SLC39A13

no

no

————-

Supplementary Table 13. Biological evidence for genes at the 180 height associated loci. The list of genes is based on genes listed in Supplementary Table 12 (i.e. within a nominally associated pathway and less than 300kb away from one of the 180 height-associated signals), genes with expression evidence where the associated signal had an r2 > 0.8 with the peak SNP in the region in any of the tissues listed in Supplementary Table 7, and genes listed in Supplementary Table 8, where the associated signal was in high LD with a nsSNP. OMIM Evidence is based on genes obtained from the OMIM database (http://www.ncbi.nlm.nih.gov/omim) and listed in Supplementary Table 11. Jackson Lab Evidence was obtained by matching Gene column entries to Jackson Lab database (http://www.informatics.jax.org/) on genes reported to have either “growth/size”, “limb/tail/digit”or “skeleton” phenotype.

Gene Expression Evidence Missense SNP in LD r2>=0.8 (amino acid change, Polyphen2 prediction) OMIM Evidence Gene nearest to height signal Jackson Lab Evidence Biological Pathways Number of lines of evidence
ACAN rs938608 (S930I, possibly damaging)rs938609 (S939T, probably damaging)

rs2882676 (E1508A, benign)

yes yes growth/sizelimbs/digit/tail

skeleton

Extracellular matrix glycoprotein 5
CDK6 Lymphocyte yes growth/size Negative regulation of epithelial cell proliferation 4
CYP19A1 yes yes growth/sizeskeleton 4
EIF2AK3 rs1805165 (A704S, benign)rs13045 (Q166R, benign)

rs867529 (S136C, benign)

yes yes growth/sizelimbs/digit/tail

skeleton

4
FGFR4 rs376618 (P136L, benign) yes growth/size MAPK signaling pathway 4
GDF5 yes yes growth/sizelimbs/digit/tail

skeleton

TGFbeta signaling pathway 4
HMGA2 yes yes growth/sizelimbs/digit/tail Chromosome 4
ID4 Omentum yes growth/size TGFbeta signaling pathway 4
IGF1R yes yes growth/sizelimbs/digit/tail

skeleton

Mammary gland development 4
NOG yes yes growth/sizelimbs/digit/tail

skeleton

TGFbeta signaling pathway 4
PML OmentumSubcutaneous fat rs5742915 (F645L, benign) yes Nuclear membrane 4
PTCH1 yes yes growth/sizelimbs/digit/tail

skeleton

Hedgehog signaling pathway 4
STAT2 LiverOmentum

Subcutaneous fat

rs2066807 (M594I, benign) yes Other transcription factor 4
ADAMTS10 yes yes Metalloprotease 3
ADAMTSL3 rs4842838 (V661L, benign) yes Extracellular matrix glycoprotein 3
BMP2 yes growth/sizelimbs/digit/tail

skeleton

Hedgehog signaling pathway 3
BMP6 yes growth/sizeskeleton Hedgehog signaling pathway 3
C3orf63 Subcutaneous fat rs9835332 (T609R, benign)rs958755 (Q38P, benign) yes 3
DYM yes yes growth/sizelimbs/digit/tail

skeleton

3
EFEMP1 yes growth/sizeskeleton Extracellular matrix glycoprotein 3
ESR1 yes growth/sizelimbs/digit/tail

skeleton

Transcription factor 3
ETV6 yes growth/size Other transcription factor 3
FANCE rs7761870 (S204L, benign) yes Role of BRCA1 in DNA damage response 3
FLI1 yes growth/size Other transcription factor 3
FRS2 yes growth/sizelimbs/digit/tail Neuroblast proliferation 3
GH1 yes growth/size JAK-STAT cascade 3
GHSR yes yes growth/sizeskeleton 3
GNA12 Lymphocyte yes MAPK signaling pathway 3
HHIP yes growth/size Hedgehog signaling pathway 3
HMGA1 yes growth/size Chromosome 3
IHH yes growth/sizelimbs/digit/tail

skeleton

Hedgehog signaling pathway 3
INSR yes growth/size Type-2 diabetes 3
LTBP1 yes skeleton TGFbeta signaling pathway 3
MC4R yes yes growth/sizeskeleton 3
MEF2C yes growth/sizelimbs/digit/tail

skeleton

MAPK signaling pathway 3
MFAP2 Omentum yes Extracellular matrix glycoprotein 3
NFATC4 yes growth/sizeskeleton MAPK signaling pathway 3
PAPPA yes growth/sizeskeleton Metalloprotease 3
PITX1 yes limbs/digit/tailskeleton Anatomical structure morphogenesis 3
PPARD yes growth/size VDR/RXR activation 3
PPARD yes growth/size VDR/RXR activation 3
PRKG2 yes growth/sizelimbs/digit/tail

skeleton

Endothelin signaling pathway 3
RUNX2 yes growth/size, limbs/digit/tail, skeleton TGFbeta signaling pathway 3
RYBP Omentum yes growth/size 3
SCMH1 yes skeleton Transcription factor 3
SLBP Lymphocyte yes Other RNA-binding protein 3
SOCS2 yes growth/sizelimbs/digit/tail

skeleton

Type-2 diabetes 3
STK36 rs1344642 (R583Q, probably damaging)rs1863704 (G1003D, benign) growth/sizeskeleton Hedgehog signaling pathway 3
TBX2 yes limbs/digit/tail Other transcription factor 3
TEAD1 yes growth/size Other transcription factor 3
TGFB2 yes growth/sizelimbs/digit/tail

skeleton

TGFbeta signaling pathway 3
TSEN15 OmentumSubcutaneous fat rs2274432 (G19D, probably damaging) yes 3
SEPT2 Lymphocyte yes 2
ADAM28 yes Metalloprotease 2
ADAMTS17 yes Metalloprotease 2
ADAMTS3 yes Metalloprotease 2
AKD1 Omentum rs2277114 (V1555I, benign) 2
ANKRD13B Subcutaneous fat yes 2
BNC2 yes growth/sizeskeleton 2
C6orf173 yes chromosome 2
CCDC108 yes 2
CCDC66 Osteoblast rs7637449 (R460Q, probably damaging) 2
CCDC91 rs11049488 (A36T, benign) yes 2
CLIC4 yes growth/size 2
CLPS rs2766597 (L8P, possibly damaging) growth/size 2
CPN1 yes Metalloprotease 2
DDX27 Subcutaneous fat rs11553387 (G206V, benign) 2
DNM3 Lymphocyte yes 2
DTL yes Nuclear membrane 2
ECM2 rs10120210 (Q56P, probably damaging) Proteinaceous extracellular matrix 2
EXOSC5 rs10853751 (T5M, benign) Exoribonuclease 2
FBLN2 Omentum Extracellular matrix glycoprotein 2
FBXW11 yes Hedgehog signaling pathway 2
FOLH1 Subcutaneous fat yes 2
FUBP3 yes Other RNA-binding protein 2
GNPTAB yes Other transcription factor 2
GPC5 yes Extracellular matrix glycoprotein 2
H1FX Lymphocyte Histone 2
HLA-B Liver Antigen processing and presentation 2
IGF2BP2 yes Other RNA-binding protein 2
IGF2BP3 yes Other RNA-binding protein 2
ITPR3 rs2229642 (L2436V, benign) growth/size 2
KCNQ1 yes growth/size 2
L3MBTL3 yes Transcription factor 2
LIN28 yes Other transcription factor 2
LIN28B yes Other transcription factor 2
LPAR1 yes growth/size 2
LRRC37B Omentum yes 2
LTBP2 yes Extracellular matrix glycoprotein 2
LUZP1 LiverSubcutaneous fat growth/size 2
MICA yes Major histocompatibility complex antigen 2
MKL2 yes Other transcription factor 2
MTMR11 rs11205303 (M159V, benign) Other phosphatase 2
MYO9B yes Nicotinic acetylcholine receptor signaling pathway 2
NFIC yes Transcription factor 2
NME2 yes growth/size 2
NPPC yes growth/sizelimbs/digit/tail

skeleton

2
NPR3 yes growth/sizelimbs/digit/tail

skeleton

2
NUCB2 yes Annexin 2
PAPPA2 yes Metalloprotease 2
PCSK5 yes growth/sizelimbs/digit/tail

skeleton

2
PDS5B yes growth/sizelimbs/digit/tail

skeleton

2
PEX2 yes growth/sizeskeleton 2
PIP4K2B yes growth/sizelimbs/digit/tail

skeleton

2
PKN2 yes Annexin 2
PPAP2A Omentum Other phosphatase 2
PPIF yes Mitochondrial inner membrane 2
PRKCZ yes Type-2 diabetes 2
PSMB3 Osteoblast Parkinson disease 2
PTPRJ yes growth/size 2
QSOX2 yes Nuclear membrane 2
REST rs3796529 (P797L, probably damaging) growth/size 2
RPL5 yes yes 2
SLC22A4 LiverSubcutaneous fat rs272893 (I306T, benign) 2
SLC22A5 yes growth/size 2
SLC39A13 yes growth/sizelimbs/digit/tail

skeleton

2
SLIT3 yes growth/size 2
SOCS5 LiverOmentum

Subcutaneous fat

yes 2
TNS1 yes Other phosphatase 2
TRIP11 yes growth/size 2
UTP6 Liver Other transcription factor 2
VGLL2 yes Transcription factor 2
ZBTB24 LymphocyteOmentum yes 2
ZNFX1 rs6512577 (M1259I, benign) yes 2
AK092571 Subcutaneous fat 1
AL117656 OmentumSubcutaneous fat 1
AL161980 OmentumSubcutaneous fat 1
ATP6V1E2 Subcutaneous fat 1
B3GNT8 rs284662 (S137G, benign) 1
BC030091 LiverOmentum

Subcutaneous fat

1
C17orf42 LiverLymphocyte

Omentum

Subcutaneous fat

1
C17orf82 Subcutaneous fat 1
C20orf199 Lymphocyte 1
C6orf1 rs1150781 (G150A, unknown) 1
CCDC100 Omentum 1
CDK2AP1 Lymphocyte 1
Contig21370_RC Omentum 1
Contig40232_RC Subcutaneous fat 1
Contig41005_RC Liver 1
Contig43791_RC Omentum 1
CWF19L1 OmentumSubcutaneous fat 1
FAM173A Lymphocyte 1
FARP2 Omentum 1
FNDC3B rs7652177 (T179S, benign) 1
HAGHL OmentumSubcutaneous fat 1
HDLBP rs7578199 (N418S, benign) 1
HSS00017874 Omentum 1
HSS00085450 Subcutaneous fat 1
HSS00174467 Omentum 1
INTS7 LymphocyteOmentum 1
JMJD4 Osteoblast 1
MSTP9 Liver 1
N4BP2L2 LiverOmentum

Subcutaneous fat

1
NSD1 yes 1
PFAAP5 LymphocyteOsteoblast 1
PIP5K2B OmentumSubcutaneous fat 1
PPA2 Omentum 1
QSCN6L1 OmentumSubcutaneous fat 1
RMI1 rs1982151 (N455S, benign) 1
RNF135 yes 1
SLC23A3 Omentum 1
SMPD2 rs1476387 (R265S, benign) 1
SNAP47 Liver 1
TCF19 rs2073721 (M211V, benign) 1
TMEM4 Lymphocyte 1
TP53I13 OmentumSubcutaneous fat 1
USP52 Osteoblast 1
VPS13C rs3784634 (R931K, benign) 1
ZNF142 rs3770213 (L956H, benign)rs3770214 (S751G, benign) 1
ZNF311 rs6456880 (K511Q, benign) 1

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