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Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.

ABSTRACT: Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1x10(-8) and rs910316 in TMED10, P-value = 1.4x10(-7)) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3x10(-7) and rs849141 in JAZF1, P-value = 3.2x10(-11)). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4x10(-5) and rs6817306 in LCORL, P-value = 4x10(-4)), hip axis length (including rs6830062 at LCORL, P-value = 4.8x10(-4) and rs4911494 at UQCC, P-value = 1.9x10(-4)), and femur length (including rs710841 at PRKG2, P-value = 2.4x10(-5) and rs10946808 at HIST1H1D, P-value = 6.4x10(-6)). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

SUBMITTER: Soranzo N

PROVIDER: S-EPMC2661236 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.

Soranzo Nicole N Rivadeneira Fernando F Chinappen-Horsley Usha U Malkina Ida I Richards J Brent JB Hammond Naomi N Stolk Lisette L Nica Alexandra A Inouye Michael M Hofman Albert A Stephens Jonathan J Wheeler Eleanor E Arp Pascal P Gwilliam Rhian R Jhamai P Mila PM Potter Simon S Chaney Amy A Ghori Mohammed J R MJ Ravindrarajah Radhi R Ermakov Sergey S Estrada Karol K Pols Huibert A P HA Williams Frances M FM McArdle Wendy L WL van Meurs Joyce B JB Loos Ruth J F RJ Dermitzakis Emmanouil T ET Ahmadi Kourosh R KR Hart Deborah J DJ Ouwehand Willem H WH Wareham Nicholas J NJ Barroso Inês I Sandhu Manjinder S MS Strachan David P DP Livshits Gregory G Spector Timothy D TD Uitterlinden André G AG Deloukas Panos P

PLoS genetics 20090403 4

Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1x10(-8) and rs910316 in ...[more]

PMID: 19343178

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Project description:Abstract Objectives Ancient DNA provides an opportunity to separate the genetic and environmental bases of complex traits by allowing direct estimation of genetic values in ancient individuals. Here, we test whether genetic scores for height in ancient individuals are predictive of their actual height, as inferred from skeletal remains. We estimate the contributions of genetic and environmental variables to observed phenotypic variation as a first step towards quantifying individual sources of morphological variation. Materials and methods We collected stature estimates and femur lengths from West Eurasian skeletal remains with published genome‐wide ancient DNA data (n = 182, dating from 33,000–850 BP). We also recorded genetic sex, genetic ancestry, date and paleoclimate data for each individual, and δ13C and δ15N stable isotope values where available (n = 69). We tested different methods of calculating polygenic scores, using summary statistics from four different genome wide association studies (GWAS) for height, and three methods for imputing missing genotypes. Results A polygenic score for height predicts 6.3% of the variance in femur length in our data (n = 132, SD = 0.0069%, p = 0.001), controlling for sex, ancestry, and date. This is consistent with the predictive power of height PRS in present‐day populations and the low coverage of ancient samples. Comparatively, sex explains about 17% of the variance in femur length in our sample. Environmental effects also likely play a role in variation, independent of genetics, though with considerable uncertainty (longitude: R2 = 0.033, SD = 0.008, p = 0.011). Genotype imputation did not improve polygenic prediction, and results varied based on the GWAS summary statistics we used. Discussion Polygenic scores explain a small but significant proportion of the variance in height in ancient individuals, though not enough to make useful predictions of individual phenotypes. However, environmental variables also contribute to phenotypic outcomes and understanding their interaction with direct genetic predictions will provide a framework with which to model how plasticity and genetic changes ultimately combine to drive adaptation and evolution.

Dataset Information

Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.

Publications

Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.

Similar Datasets

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