title: Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development.
abstract: Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r(2) ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10(-8)) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10(-40)). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases.
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rigel@broadinstitute.org.
authors: Yingleong
authors: Y
authors: Chan
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Rany M
authors: RM
authors: Salem
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Yu-Han H
authors: YH
authors: Hsu
authors: School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors: George
authors: G
authors: McMahon
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Tune H
authors: TH
authors: Pers
authors: Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Sailaja
authors: S
authors: Vedantam
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
authors: Tonu
authors: T
authors: Esko
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Michael H
authors: MH
authors: Guo
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Elaine T
authors: ET
authors: Lim
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen 9700 AB, the Netherlands.
authors: Lude
authors: L
authors: Franke
authors: School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2PR, UK.
authors: George Davey
authors: GD
authors: Smith
authors: Population Health Research Institute, St George's, University of London, London SW17 0RE, UK.
authors: David P
authors: DP
authors: Strachan
authors: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: joelh@broadinstitute.org.
authors: Joel N
authors: JN
authors: Hirschhorn
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D001827:Body Height / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007867:Leg Bones / Q000254:growth & development; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics